Immunodeficiency 98 With Autoinflammation

Mendelian MONDO:0024777 Pathograph 14 Show in embeddings browser inborn error of immunity bone marrow failure syndrome autoinflammatory syndrome

Immunodeficiency 98 with autoinflammation is caused by gain-of-function variants in TLR8, the X-linked endosomal sensor of single-stranded RNA degradation products. TLR8 is expressed mainly by myeloid cells and signals through NF-kB to produce proinflammatory cytokines. The disease-causing variants make the receptor hypersensitive to ligand rather than constitutively active, so patient cells over-respond to stimulation. The clinical picture pairs two things that usually pull in opposite directions: immunodeficiency - severe refractory neutropenia, recurrent infection, impaired B-cell maturation - and autoinflammation, with activated T cells, raised serum cytokines and lymphoproliferation. Bone marrow characteristically shows severe myeloid hypoplasia with activated T-cell infiltrates. Disease is refractory to granulocyte colony-stimulating factor and corticosteroids, and allogeneic haematopoietic cell transplantation is the only intervention shown to resolve the phenotype. Two features of this disease are unusual enough to be the reason it is worth a separate entry rather than a line in a TLR-signalling review. First, most patients are somatic mosaics with variant allele fractions between 7 and 26 per cent, and the phenotype is full-blown anyway - so a minority clone of hypersensitive cells is sufficient, and the disease would be missed by any workflow assuming germline heterozygosity. Second, TLR8 turns out to act inside the erythroid lineage as well, blocking EPO signalling by a mechanism that has been worked out in detail, which makes the anaemia a second molecular arm rather than a consequence of the marrow inflammation.

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1
Inheritance
8
Pathophys.
13
Phenotypes
2
Hypotheses
14
Pathograph
1
Genes
5
Medical Actions
1
Trials
1
Models
3
References
1
Deep Research
👪

Inheritance

1
X-linked dominant, frequently somatic mosaic HP:0001423
TLR8 is at Xp22.2. The disease was first described in males, but a female patient with a germline variant has since been reported, which establishes the mode as X-linked dominant rather than X-linked recessive. Most patients carry the variant as a post-zygotic somatic mosaic rather than in the germline, and mosaicism has been demonstrated outside the haematopoietic compartment in skin fibroblasts - so the mutational event is early and not confined to blood.
X-linked dominant inheritance
Show evidence (2 references)
PMID:41370196 SUPPORT Human Clinical
"TLR8 GOF is an X-linked dominant disorder that should be considered in male and female patients with cytopenia, particularly severe neutropenia, lymphoproliferation with immune dysregulation, increased LGLs, and new to this cohort, red cell aplasia."
States the inheritance mode explicitly, and the female patient is what changed it from the X-linked recessive assumption of the original male-only cohort.
PMID:33512449 SUPPORT Human Clinical
"Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment."
Establishes that the mosaicism is developmental rather than a clonal haematopoietic event, which matters for how and where to test for it.
◈

Mechanistic Hypotheses

2
How a somatic clone at 7-26 per cent variant allele fraction produces the full phenotype
low_vaf_mosaic_sufficiency EMERGING
Evidence balance 8 support
Eight of the ten reported patients are somatic mosaics with peripheral blood variant allele fractions between 7 and 26 per cent. A minority of hypersensitive cells is therefore sufficient to produce severe, refractory, transplant-requiring disease. The original authors read this as evidence of a dominant mechanism. What "dominant" means here is the open part, but the authors are not neutral between the two readings and this entry should not present them as though they were. They call the neutropenia likely cell-extrinsic, on the grounds that patients with the variant in a small fraction of cells carry a large burden of disease, and they make a sharper version of the same argument for the lymphoid arm: T and B cells do not express TLR8 at all, so whatever is dysregulating them cannot be acting inside them. They also name candidates for the intermediate, which is the step the pathograph leaves as INDIRECT_UNKNOWN_INTERMEDIATES. By analogy with the neutropenia of large granular lymphocyte leukaemia, the proposals are high soluble Fas ligand triggering apoptosis of neutrophil and myeloid progenitors, and direct destruction by infiltrating T cells. Soluble Fas ligand has been measured as elevated in these patients, so the first is a candidate with a measurement behind it rather than a guess. What remains genuinely open is whether either candidate is doing the work. A cell-autonomous account would require the mutant clone to have a competitive advantage that the data do not establish; the cell-extrinsic account fits the observed picture and explains why transplantation with full donor chimerism resolves the phenotype, but neither candidate intermediate has been tested in these patients. Two practical consequences follow regardless of which is right. A germline-only variant calling pipeline at standard heterozygous thresholds will miss most of these patients, and a negative blood test does not exclude the disease, since mosaicism has been found in fibroblasts.
Show evidence (8 references)
PMID:41370196 SUPPORT Human Clinical
"Eight patients had somatic mosaicism with peripheral blood variant allele fractions of 7% to 26%, and age of disease onset of 9 months to 28 years."
The observation the hypothesis is about - low variant allele fractions with full disease.
PMID:33512449 SUPPORT Human Clinical
"Somatic mosaicism is a prominent molecular mechanism of this new disease."
The authors' framing of mosaicism as a defining feature rather than an incidental one.
PMID:41370196 SUPPORT Human Clinical
"Five patients are surviving at 1 to 3 years after HCT with full donor myeloid and T-cell chimerism, and resolution of disease phenotype."
Replacing the haematopoietic compartment resolves the disease, which is consistent with the non-cell-autonomous reading but does not by itself distinguish the two.
+ 5 more references
Whether gain of function here is conformational stabilisation rather than more receptor
conformational_gain_not_receptor_gain EMERGING
Evidence balance 4 support
The A518T allele produces more NF-kB activation and more cytokine from *less* protein: turnover assays show reduced abundance of the mutant, through faster proteasomal degradation. So whatever "gain of function" means in this disease, it is not gain of receptor. The proposal is that the substitution stabilises the *active* TLR8 homodimer interface - computational modelling predicts additional water-mediated hydrogen bonds there - so each remaining receptor spends more of its time in the signalling conformation. That is consistent with the ligand-hypersensitivity phenotype the founding cohort reported, and it would explain why a somatic clone at low variant allele fraction suffices, since the effect is per-receptor rather than per-cell. It is one allele, and the structural claim is a prediction rather than a solved structure. Whether the other reported variants share the mechanism has not been tested; they were characterised as gain of function by reporter activity, which does not distinguish more receptor from better receptor.
Show evidence (4 references)
PMID:41729082 SUPPORT In Vitro
"Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation."
The observation the hypothesis exists to explain - less protein with more signal.
PMID:41729082 SUPPORT Computational
"Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in"
The authors' summary, calling the mutation ligand-specific - which is the conformational reading rather than an abundance one. Truncated at a line boundary in the cached record.
PMID:41370196 SUPPORT INDIRECT In Vitro
"The results demonstrate that CU-CPT9a inhibited WT TLR8 activity, but cells with the p.P432L variant were resistant to CU-CPT9a treatment (Figure 2G)."
Independent support for the conformational reading, from a drug experiment rather than from structure. CU-CPT9a binds TLR8 in its inactive conformation, so an inhibitor that works on wild-type and fails on the variant implies the variant is not occupying that conformation. Marked INDIRECT because the inference runs through the inhibitor's stated binding mode rather than being measured directly, and because the variant tested is p.P432L while the hypothesis was framed around A518T.
+ 1 more reference
⚙

Pathophysiology

8
TLR8 Gain-of-Function Variant
The initiating lesion. Missense variants in TLR8 confer gain of function on the encoded receptor. In most patients the variant is present as a somatic mosaic at a low variant allele fraction rather than in every cell, which is recorded here in genetic_context because it is the defining molecular feature of the disease rather than an incidental finding in a few cases.
Genetic context variant_origin: SOMATIC functional_impact_category: GAIN_OF_FUNCTION
Downstream
Hypersensitivity of the Endosomal ssRNA Sensor The variants do not make the receptor constitutively active; they lower its threshold, so patient cells over-respond when ligand is present.
Show evidence (5 references)
PMID:33512449 SUPPORT Human Clinical
"Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype."
Records both the mosaicism and the inference the authors draw from it - that a minority clone suffices, which is what makes the mechanism dominant.
PMID:33512449 SUPPORT In Vitro
"All variants conferred gain of function to TLR8 protein"
Establishes the direction of the functional effect for every variant described.
PMID:41729082 SUPPORT In Vitro
"Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect."
A further gain-of-function allele, characterised in two male siblings with recurrent infection and systemic inflammation.
+ 2 more references
Hypersensitivity of the Endosomal ssRNA Sensor
TLR8 sits in the endosome and recognises single-stranded RNA degradation products, signalling through NF-kB. A hypersensitive receptor converts ordinary ligand exposure - which for an endosomal RNA sensor is routine - into a disproportionate signal. Myeloid cells differentiated from patient-derived induced pluripotent stem cells show the increased responsiveness directly, which matters because it locates the defect in the cell rather than in the patient's inflammatory milieu.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
toll-like receptor signaling pathway GO:0002224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves toll-like receptor signaling pathway (GO:0002224), qualified as gain of function. GO:0002224 is a biological process from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
TIRAP-MyD88 Adaptor Assembly and IRAK Activation An activated TLR8 dimer recruits its adaptors. This is the step the receptor's signal actually passes through, and it is separated out because it is where the human and mouse pathways diverge.
Show evidence (5 references)
PMID:33512449 SUPPORT In Vitro
"Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8."
Demonstrates the cellular phenotype in a patient-derived system independent of the patient's circulating inflammatory environment.
PMID:21949866 SUPPORT INDIRECT Computational
"The primary sequences of rodent and non-rodent TLR8s are similar, but the antiviral compound (R848) that activates the TLR8 pathway is species-specific."
Why a human patient-derived system is the right model and a rodent one would not be: the receptor does not respond to the same ligands across species. Graded COMPUTATIONAL because the mechanistic account is homology modelling and docking; the species difference in R848 response it starts from is an established experimental fact.
PMID:41370196 SUPPORT BACKGROUND Other
"Toll-like receptor 8 (TLR8) is an endosomal pattern recognition receptor primarily expressed by myeloid cells that recognizes microbial single-stranded RNA degradation products, with activation ultimately resulting in the production of NF-κB–dependent cytokines and proinflammatory signature."
Describes the normal function the variants exaggerate. BACKGROUND: introduction physiology in a human clinical cohort study, not a result of it. OTHER is kept rather than raised to a study type, because the sentence is textbook receptor biology that describes no single study - which is a different reason for OTHER than the review item below, and the pair is only distinguishable now that `quote_role` says which is which.
+ 2 more references
TIRAP-MyD88 Adaptor Assembly and IRAK Activation
The step between the receptor and its transcriptional output, and the reason to curate it separately is that it is where this disease's species problem lives. TLR8 signals through MyD88, and recent work shows TIRAP - long thought to serve only plasma-membrane TLRs - is also recruited to the endosomal TLR8-MyD88 complex, where it is required for late IRAK1 activation, IKK phosphorylation and IRF5 nuclear translocation. A peptide that disrupts the TIRAP-MyD88 interaction blocks TLR8-induced IFN-beta and IL-12 in human monocytes and whole blood, and fails entirely against murine TLR7, because TIRAP is not recruited to MyD88 in mouse macrophages after ligand stimulation. That last observation matters for this entry specifically. The entry's argument against a mouse model rests on species-specific ligand recognition at the receptor; this adds a second, independent divergence one step downstream, in the adaptor complex itself. IRAK-2 shows the same pattern from the other direction: human IRAK-2 is required for TLR8-mediated NF-kB and p38 activation in primary human cells, where the inbred mouse knockout said it was not needed. Note the gain-of-function claim here is inferred, not measured. No study has shown the adaptor complex assembling excessively in TLR8-GOF patient cells; what is established is that the step is required, and that the receptor above it is hypersensitive.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
MyD88-dependent toll-like receptor signaling pathway GO:0002755 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased MyD88-dependent toll-like receptor signaling pathway (GO:0002755). GO:0002755 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Excess NF-kB-Dependent Cytokine Production Adaptor assembly and IRAK activation are what convert receptor engagement into IKK phosphorylation and NF-kB-dependent transcription.
Show evidence (3 references)
PMID:41159953 SUPPORT In Vitro
"In primary human monocytes and a whole blood model, P7-Pen inhibited TLR7- and TLR8-induced expression and secretion of IRF5-regulated cytokines IFNβ, IL-12p40, and IL-12p70, without effect on TNF or IL-6."
That the adaptor step is required for part of the TLR8 cytokine output, and which part: the IRF5-regulated arm rather than TNF or IL-6. Worth noting because the patient cell readout used elsewhere in this entry is IL-6.
PMID:41159953 SUPPORT INDIRECT In Vitro
"Notably, P7-Pen failed to inhibit murine TLR7 responses, which correlated with a lack of TIRAP recruitment to MyD88 in mouse macrophages following TLR7 ligand stimulation, highlighting species-specific differences in TLR signaling mechanisms."
A second species divergence, one step below the ligand-recognition difference this entry already records. It strengthens the argument against a knock-in mouse model rather than restating it.
PMID:21606490 SUPPORT INDIRECT In Vitro
"These data conflict with findings from the in-bred Irak2(-/-) mice but concur with what has been seen in wild-derived mice for TLR2."
The same divergence from the kinase side: what the mouse knockout said about IRAK-2 does not hold in human cells. Recorded because this entry's no-mouse argument is a substantive claim and deserves more than one line of support.
Excess NF-kB-Dependent Cytokine Production
The proinflammatory state. Patients show activated T cells and elevated serum cytokines. This node is the shared upstream of the marrow, lymphoid and humoral consequences below, which is why they branch from it rather than from each other.
positive regulation of canonical NF-kappaB signal transduction GO:0043123 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of canonical NF-kappaB signal transduction (GO:0043123). GO:0043123 is a biological process from the Gene Ontology. ↑ INCREASED cytokine production GO:0001816 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cytokine production (GO:0001816). GO:0001816 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Myeloid Hypoplasia and Bone Marrow Failure The marrow shows myeloid hypoplasia alongside activated T-cell infiltrates. How the inflammatory state suppresses granulopoiesis - whether through the T-cell infiltrate, a cytokine effect on progenitors, or both - is not established in these patients.
Lymphoproliferation with Immune Dysregulation Activated T cells and raised cytokines are the proximate description of the lymphoproliferative phenotype.
Impaired B-Cell Maturation Humoral defects accompany the inflammatory phenotype. The paper reports the association rather than a mechanism connecting the two.
Show evidence (1 reference)
PMID:33512449 SUPPORT Human Clinical
"immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines"
The immunophenotype that defines this node in patients.
Myeloid Hypoplasia and Bone Marrow Failure
The dominant clinical problem. Neutropenia is universal and usually severe, and is refractory to the treatments that work in other neutropenias. Anaemia and thrombocytopenia are common, so the failure is not confined to the granulocytic line. An increased number of large granular lymphocytes was found in half the expanded cohort.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"All patients had neutropenia, most with severe neutropenia refractory to medical therapy. Anemia and thrombocytopenia were common."
The cytopenia profile across the full reported cohort, and its refractoriness.
Lymphoproliferation with Immune Dysregulation
The autoinflammatory arm. Lymphoproliferation was among the founding cohort's defining features and remains in the diagnostic description of the expanded one. Coexisting with the immunodeficiency, it is what makes the disease a combined picture rather than a simple bone marrow failure syndrome.
Show evidence (1 reference)
PMID:33512449 SUPPORT Human Clinical
"We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8)."
The founding clinical description, listing lymphoproliferation alongside the immunodeficiency features.
Impaired B-Cell Maturation
The humoral arm. B-cell maturation is impaired and humoral immune defects are part of the founding phenotype, contributing to the infectious susceptibility alongside the neutropenia.
Show evidence (1 reference)
PMID:33512449 SUPPORT Human Clinical
"these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure"
The authors' summary of the disease, naming the B- and T-cell defects as components.
TLR8-Driven Blockade of EPO Signaling in Erythroid Progenitors
A second, mechanistically separate arm, and the one that is worked out in most molecular detail. TLR8 is expressed in the erythroid lineage, and activating it impairs erythropoiesis from the progenitor stage onward while inhibiting it enhances erythropoiesis. The mechanism is specific: TLR8 activation blocks annexin A2-mediated plasma membrane localisation of STAT5, which disrupts erythropoietin signalling. This is an erythroid-intrinsic effect rather than a consequence of the marrow inflammation, which is why it is modelled as its own branch from the receptor node rather than downstream of the cytokine node.
erythroid progenitor cell CL:0000038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroid progenitor cell (CL:0000038). CL:0000038 is a cell type from the Cell Ontology.
erythropoietin-mediated signaling pathway GO:0038162 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased erythropoietin-mediated signaling pathway (GO:0038162). GO:0038162 is a biological process from the Gene Ontology. ↓ DECREASED erythrocyte differentiation GO:0030218 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased erythrocyte differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Human TLR8 transgenic mouse crossed onto a lupus background Mouse partially recapitulates Produces the organism-level outcome this arm ends in - fatal anaemia - and attributes it to myeloid dysregulation. It does not reproduce the node itself, which is a molecular claim about EPO receptor signalling in erythroid progenitors.
Show evidence (2 references)
PMID:38971858 SUPPORT In Vitro
"Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells."
The specific molecular mechanism by which TLR8 activation impairs erythropoiesis.
PMID:38971858 SUPPORT In Vitro
"TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage."
Establishes both the expression and the bidirectional dependence - inhibition improves erythropoiesis, which is what makes the effect causal rather than correlative.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 98 With Autoinflammation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

13
Blood 9
Severe refractory neutropenia Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total neutrophil count (HP:0001875), qualified as temporality chronic. HP:0001875 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (2 references)
PMID:41370196 SUPPORT Human Clinical
"All patients had neutropenia, most with severe neutropenia refractory to medical therapy."
Universal presence and refractoriness in the full cohort.
PMID:33512449 SUPPORT Human Clinical
"All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation."
The same finding in the original cohort, alongside the transplant decision it drove.
Bone marrow myeloid hypoplasia Bone marrow hypocellularity HP:0005528 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone marrow hypocellularity (HP:0005528). HP:0005528 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"Bone marrow characteristically demonstrated severe myeloid hypoplasia and activated T-cell infiltrates and/or aggregates."
The characteristic marrow histology.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873), qualified as severity moderate. HP:0001873 is a phenotype from the Human Phenotype Ontology.
Severity: MODERATE
Show evidence (2 references)
PMID:41370196 SUPPORT Human Clinical
"All 10 patients had mild to moderate thrombocytopenia; 5 patients had mild to moderate anemia; and 3 patients had severe anemia, including patient 10, who presented at age 2 weeks with pure red cell aplasia."
The full-text frequency statement, which gives 10 of 10 for thrombocytopenia and the severity split for the anaemia curated below.
PMID:41370196 SUPPORT Human Clinical
"Mild, moderate, and severe thrombocytopenia were defined as platelet counts 100 × 109/L to 150 × 109/L, 50 × 109/L to 100 × 109/L, and <50 × 109/L, respectively."
The definitions behind the severity qualifier, so "mild to moderate" is a platelet range rather than a clinical impression.
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"5 patients had mild to moderate anemia; and 3 patients had severe anemia"
The severity split, which the abstract's "common" does not carry.
Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"Six patients had hypogammaglobulinemia requiring immunoglobulin replacement."
The frequency and, in the same sentence, the treatment it drove.
CD8-positive CD57-positive large granular lymphocytes in marrow Abnormal lymphocyte morphology HP:0004332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is CD8+/CD57+ large granular lymphocytes, annotated with Abnormal lymphocyte morphology (HP:0004332). HP:0004332 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:41370196 SUPPORT Human Clinical
"several (n = 5) patients had CD8+/CD57+ large granular lymphocytes (LGLs)"
The frequency, from the bone marrow findings section.
PMID:41370196 SUPPORT Human Clinical
"Two patients received treatment for LGL leukemia (1 with oligoclonal LGLs and 1 with polyclonal LGLs) before discovery of TLR8 GOF."
The misdiagnosis this finding caused in the cohort itself, which is why the authors raise it as a sequencing trigger.
PMID:41370196 SUPPORT Human Clinical
"many patients had CD8+/CD57+ LGLs present, which may be an additional clinical phenotype to consider for TLR8 sequencing, especially in pediatric or young adult patients"
The authors' recommendation, which is the practical use of this phenotype.
Pure red cell aplasia HP:0012410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pure red cell aplasia (HP:0012410). HP:0012410 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"We identify the first female patient with TLR8 GOF who presented during infancy with pure red cell aplasia due to a germ line TLR8 variant"
The single case establishing this presentation, and the one that established female involvement.
Lymphoproliferation Lymphoproliferative disorder HP:0005523 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphoproliferative disorder (HP:0005523). HP:0005523 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"Toll-like receptor 8 (TLR8) gain-of-function (GOF) somatic variants were recently identified as causing severe neutropenia, lymphoproliferation, and immune dysregulation."
Names lymphoproliferation among the disease's defining features.
Autoimmune myelofibrosis HP:0011974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myelofibrosis (HP:0011974). HP:0011974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42023410 SUPPORT Human Clinical
"To our knowledge, this is the first reported association between TLR8-GOF mutation and AIMF, expanding the phenotypic spectrum of TLR8-related disorders."
The authors' own characterisation of the finding as a first report, which is why this phenotype is curated with that qualification rather than as established.
Cardiovascular 2
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"In addition, all patients had evidence of lymphoproliferation with lymphadenopathy and/or splenomegaly."
Universal in the cohort. The "and/or" is why lymphadenopathy and splenomegaly are curated as two entries rather than one combined finding.
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"all patients had evidence of lymphoproliferation with lymphadenopathy and/or splenomegaly"
The same universal statement, cited here for the splenic half.
Head and Neck 1
Oral ulcers HP:0000155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral ulcer (HP:0000155), qualified as temporality recurrent. HP:0000155 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"Most (n = 7) patients had a history of oral ulcers, and all patients had a history of bacterial and/or fungal infection, which were often severe."
The frequency, alongside the universal infection history already curated separately.
Immune 1
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33512449 SUPPORT Human Clinical
"We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects"
Records infection among the presenting features of the original cohort.
🧬

Genetic Associations

1
TLR8 (Causal)
Gene: TLR8 hgnc:15632 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TLR8 (hgnc:15632). hgnc:15632 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (6 references)
PMID:33512449 SUPPORT Human Clinical
"associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8)"
Establishes TLR8 as the causal gene and names its product.
PMID:41370196 SUPPORT Human Clinical
"Novel missense variants in the TLR8 gene, located on the short arm of chromosome X (Xp22.2), were recently identified in 6 unrelated male patients with severe neutropenia, lymphoproliferation, and immune dysregulation, known as INFLTR8 (inflammation, neutropenia, bone marrow failure, and..."
Gives the cytogenetic location and the acronym the disease is also known by.
PMID:42023410 SUPPORT Human Clinical
"Whole-exome sequencing revealed a TLR8-G572D mutation, leading to a diagnosis of autoimmune myelofibrosis (AIMF) secondary to TLR8 gain of function (GOF)."
A further variant and the presentation it was found in.
+ 3 more references
💊

Medical Actions

5
Allogeneic Hematopoietic Cell Transplantation
Action: allogeneic hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
The only intervention shown to resolve the disease. Seven of ten reported patients were transplanted; five are surviving at one to three years with full donor myeloid and T-cell chimerism and resolution of the phenotype. The counterfactual is stark - both patients who presented in childhood and were not transplanted died of the disease. It is not a benign option: post-transplant cytopenia of unclear aetiology and graft-versus-host disease were both common.
Mechanism Target:
TLR8 Gain-of-Function Variant — Replacing the haematopoietic compartment removes the mutant clone from blood and marrow. Note that it does not remove it from other tissues, since the mosaicism extends to fibroblasts - so this addresses the compartment that produces the disease rather than the variant itself.
Show evidence (5 references)
PMID:41370196 SUPPORT Human Clinical
"Five patients are surviving at 1 to 3 years after HCT with full donor myeloid and T-cell chimerism, and resolution of disease phenotype."
The efficacy result, with chimerism as the mechanistic correlate of the clinical resolution.
PMID:41370196 SUPPORT Human Clinical
"High rates of post-HCT cytopenia of unclear etiology and graft-versus-host disease were observed."
The toxicity side of the same cohort, recorded so the treatment is not read as straightforwardly successful.
PMID:41370196 SUPPORT Human Clinical
"The 2 patients who presented during childhood and did not undergo HCT ultimately died from disease."
The untransplanted outcome, which is what makes the case for transplantation despite its toxicity.
+ 2 more references
Granulocyte Colony-Stimulating Factor and Corticosteroids
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: filgrastim NCIT:C1474 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses filgrastim (NCIT:C1474). NCIT:C1474 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Recorded because they do not work. Both are standard for the presentations this disease mimics - chronic neutropenia and immune-mediated cytopenia - and the neutropenia is refractory to both. That refractoriness is a diagnostic signal as much as a therapeutic failure.
Mechanism Target:
Myeloid Hypoplasia and Bone Marrow Failure — Both agents act on the marrow failure node, and both fail there - which locates the problem upstream of anything a growth factor or a broad immunosuppressant can reach.
Show evidence (1 reference)
PMID:41370196 REFUTE Human Clinical
"The neutropenia was refractory to granulocyte-colony stimulating factor (G-CSF) and corticosteroids, and 3 patients underwent allogeneic hematopoietic cell transplant (HCT)."
Direct evidence against these agents as treatments for this disease. Recorded as REFUTE rather than omitted because "tried and failed" is a finding a curator or a clinician needs, and because the refractoriness is itself diagnostically useful.
TLR8 Inhibition
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
Preclinical, and the evidence now comes from two directions that need separating. In patient cells. Three inhibitors were tested in iPSC-derived macrophages carrying the p.P432L variant, the commonest one in this disease. Chloroquine, which raises endosomal pH, and CPG-52364, a small-molecule TLR7/8 inhibitor, both suppressed IL-6 production from the gain-of-function receptor. CU-CPT9a did not: it inhibited wild-type TLR8 and the p.P432L cells were resistant to it. That split is informative beyond the drug screen, because CU-CPT9a works by binding TLR8 in its inactive conformation - so a variant that resists it is a variant that is not spending its time in that conformation, which is what the conformational-gain hypothesis in this entry predicts. In other erythroid systems. TLR8 inhibition also improves erythropoiesis in RPS19-haploinsufficient cells and in CD34-positive cells from healthy donors and from patients with inherited non-haemolytic anaemia. That work was done in the context of inherited anaemia rather than in TLR8 gain-of-function patients, so it supports the erythroid arm by analogy rather than directly. Neither line has reached a patient. There are no clinical data for any TLR8 inhibitor in this disease, and the one endosomal-signalling inhibitor that was given to a patient - hydroxychloroquine, in one case - had no effect on the neutrophil count.
Mechanism Target:
TLR8-Driven Blockade of EPO Signaling in Erythroid Progenitors — Inhibition acts on the receptor node directly, which is the one point in the erythroid arm upstream of the STAT5 mislocalisation.
Show evidence (5 references)
PMID:38971858 SUPPORT In Vitro
"TLR8 inhibition improves erythropoiesis in RPS19+/- HuDEP2 cells and CD34+ cells from healthy donors and inherited non-hemolytic anemic patients."
The rescue result. Note the cell systems named are not from TLR8 gain-of-function patients, which is the limitation recorded in the description.
PMID:38971858 SUPPORT In Vitro
"we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia."
The authors' own framing of the therapeutic implication as something to explore rather than established.
PMID:41370196 SUPPORT In Vitro
"CHQ and CPG-52364 both inhibited IL-6 production by macrophages expressing WT and GOF TLR8 (Figure 2H-I)."
The positive result, and the only inhibitor data generated in cells carrying a disease-causing TLR8 variant rather than in a surrogate system.
+ 2 more references
Immunoglobulin Replacement
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Protein replacement
Given to the six of ten patients with hypogammaglobulinemia. Unlike the other medical therapies in this entry it is not being tried against the neutropenia; it replaces a deficiency the disease produces, and the cohort report records it as administered rather than as trialled. It does nothing for the marrow failure.
Mechanism Target:
Impaired B-Cell Maturation — Substitutes exogenous antibody for the antibody the impaired B-cell compartment cannot produce. It is pure replacement: the maturation defect is untouched.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"Six patients had hypogammaglobulinemia requiring immunoglobulin replacement."
The therapy and its indication in one sentence, in six of ten patients.
Sirolimus, Mycophenolate Mofetil and JAK Inhibitors
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sirolimus CHEBI:9168 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sirolimus (CHEBI:9168). CHEBI:9168 is a therapeutic agent from Chemical Entities of Biological Interest. mycophenolate mofetil CHEBI:8764 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses mycophenolate mofetil (CHEBI:8764). CHEBI:8764 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Recorded for the same reason G-CSF and corticosteroids are: they were tried and none of them worked. Sirolimus in four patients, mycophenolate mofetil in two, JAK inhibitors in two, all without response, and a further patient received azathioprine, methotrexate, cyclophosphamide and rituximab over three to four months with no improvement in neutrophil count. The pattern is the finding. These agents span mTOR, purine synthesis, JAK-STAT and B-cell depletion, and the neutropenia is indifferent to all of them. That is what makes transplantation the only intervention in this entry with a positive result, and it is a substantive claim about where the lesion sits rather than a list of disappointments.
Mechanism Target:
Excess NF-kB-Dependent Cytokine Production — All of these are aimed, directly or indirectly, at the inflammatory output of this node. Their uniform failure is evidence that suppressing the output downstream does not reach the receptor-level lesion that generates it.
Show evidence (2 references)
PMID:41370196 REFUTE Human Clinical
"Other therapies that were trialed in >1 patient included sirolimus (n = 4), mycophenolate mofetil (n = 2), and JAK inhibitors (n = 2), all without response."
Direct evidence against three drug classes in this disease, with the numbers treated. Recorded as REFUTE for the same reason the G-CSF entry is.
PMID:41370196 REFUTE Human Clinical
"One patient received alemtuzumab for suspected evolving T-cell LGL leukemia, and 1 patient received azathioprine, methotrexate, cyclophosphamide, and rituximab therapy for 3 to 4 months with no improvement in neutrophil count."
The single-patient failures, including the one given four agents in sequence. Kept with the multi-patient failures above because the claim is about the class of approach rather than about any one drug.
🔬

Diagnosis

2
Targeted deep sequencing for low-variant-allele-fraction somatic TLR8 variants
The diagnostic problem in this disease is not recognising the phenotype, it is detecting the variant. Eight of ten patients are somatic mosaics with peripheral blood variant allele fractions between 7 and 26 per cent, and a germline exome or genome pipeline calling at standard heterozygous thresholds will filter those out. The authors state the remedy directly: a high index of suspicion, and targeted deep sequencing when standard analysis is negative. Two details change the threshold for reaching for it. In female patients the fraction is expected to be lower still, because there are two X chromosomes to dilute it - which is precisely the group least likely to be suspected in what was described as a male disease. And a negative blood test does not exclude the diagnosis, since the mosaicism has been found in skin fibroblasts as well.
targeted deep sequencing NCIT:C101293 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:41370196 SUPPORT Human Clinical
"A high index of suspicion is necessary, as somatic mutations may be missed on standard exome and genome analysis, especially in female patients where VAFs may be lower due to the presence of 2 X chromosomes."
The reason standard sequencing fails here, and the group it fails hardest in.
PMID:41370196 SUPPORT Human Clinical
"Alternative methodologies to identify variants, such as targeted deep sequencing, may be required."
The recommended alternative, stated by the authors as a methodology rather than a suggestion.
PMID:36119097 SUPPORT REVIEW SYNTHESIS Other
"This not only has repercussions for the diagnostic workup of these disorders, inasmuch that routine genetic testing may miss somatic variants, but has therapeutic implications as well, for example, with the approach to curative treatment, such as hematopoietic stem cell transplantation."
The same problem stated from the review literature, and generalized: TLR8 gain of function is one of a growing set of disorders caused by both germline and somatic variants, for which routine testing is systematically blind.
Bone marrow biopsy with immunophenotyping
The marrow is where this disease looks like itself: myeloid hypoplasia to agranulocytosis with predominantly CD8-positive T-cell infiltrates or aggregates, and in half the cohort CD8-positive CD57-positive large granular lymphocytes. No patient showed dysplasia, which matters because the differential includes marrow failure syndromes that do. The finding to be careful with is the negative one. The first reported female patient had myeloid predominance with erythroid hypoplasia and lacked the inverted CD4:CD8 ratio and memory skewing seen in the others, and the authors say plainly that absent characteristic findings do not exclude the diagnosis. So the biopsy supports the diagnosis and cannot rule it out.
bone marrow biopsy NCIT:C15193 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:41370196 SUPPORT Human Clinical
"Most patients had marked myeloid hypoplasia to agranulocytosis, and the presence of predominantly CD8+ T-cell lymphoid infiltrates or aggregates."
The characteristic marrow picture.
PMID:41370196 SUPPORT Human Clinical
"There was no evidence of dysplasia on any of the bone marrow biopsies."
A negative that does diagnostic work: it separates this from the myelodysplastic end of the marrow-failure differential.
PMID:41370196 REFUTE Human Clinical
"Nevertheless, the absence of characteristic findings on bone marrow biopsy and immune phenotyping does not preclude a diagnosis of TLR8 GOF."
Evidence against treating the biopsy as a rule-out test. Recorded as REFUTE against that use of it, not against its value when positive.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Ten patients in the expanded cohort, which incorporates the original six. Further single cases have been reported since. The disease was first described in 2021, so the reported count reflects how recently it was recognised at least as much as how rare it is - a point the mosaic molecular mechanism sharpens, since routine germline pipelines would not have found these patients.
Show evidence (1 reference)
PMID:41370196 SUPPORT Human Clinical
"We report the expanded clinical and laboratory phenotype and management of 10 patients, including the original cohort of 6 male patients."
The cohort size and its relationship to the founding series.
🔬

Clinical Trials

1
NCT04339777 PHASE_II RECRUITING
A phase II allogeneic haematopoietic stem cell transplant protocol for inborn errors of immunity, on which one patient in the reported cohort (patient 8) was transplanted. It is not a TLR8-specific trial - the eligible population is primary immunodeficiency or primary immune regulatory disorder where standard management has failed or does not exist - which is the usual route to transplant for a disease with ten reported patients.
Target Phenotypes: Severe refractory neutropenia HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Severe refractory neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
clinicaltrials:NCT04339777 SUPPORT Other
"To see if stem cell transplant can be successfully performed in people with primary immunodeficiency disease and cure them."
The trial's stated objective, which is the intervention this entry curates as the only effective one.
PMID:41370196 SUPPORT Human Clinical
"Patient 8 underwent HCT on a clinical trial (ClinicalTrials.gov identifier: NCT04339777)."
The link between this trial and the cohort, naming the patient transplanted on it.
🐁

Animal Models

1
Human TLR8 transgenic mouse crossed onto a lupus background
The humanised route around this disease's species problem. A knock-in mouse carrying the homologous substitution would not help, because murine TLR8 does not recognise the same ligands - that objection stands. Putting the human receptor into a mouse sidesteps it, and that experiment has been done: mice transgenic for human TLR8, crossed onto a lupus background, develop fatal anaemia driven by myeloid cell dysregulation. The authors of the patient cohort cite it as indicating a potential mechanism for the pure red cell aplasia in their own patients, which is why it is curated here rather than treated as unrelated lupus work. It converges on the erythroid arm this entry models, and by a myeloid route rather than an erythroid-intrinsic one, which is a different account from the erythroid-intrinsic TLR8 signalling reported in inherited anaemia. Two things it is not. It is not a model of TLR8 gain of function - the transgene is wild-type human TLR8, and what is varied is dose and background, not receptor activity. And the anaemia arises on a lupus-prone background that contributes its own autoimmunity, so the phenotype cannot be attributed to TLR8 alone.
Species
Mouse
Genotype
Transgenic expression of human TLR8, crossed with a lupus-prone strain
Publication
PMID:41370196
Pathograph links
TLR8-Driven Blockade of EPO Signaling in Erythroid Progenitors partially recapitulates fidelity: low observes: organism Produces the organism-level outcome this arm ends in - fatal anaemia - and attributes it to myeloid dysregulation. It does not reproduce the node itself, which is a molecular claim about EPO receptor signalling in erythroid progenitors.
Limitations: The transgene is wild-type human TLR8, not a gain-of-function variant, so the model tests the consequence of human TLR8 activity in a mouse rather than the consequence of this disease's variants. The lupus-prone background contributes autoimmunity of its own and is required for the phenotype. Transgenic expression is not the mosaic, low-variant-allele-fraction state patients are in. And the mechanism reported is myeloid dysregulation, whereas the node it is linked to is erythroid-intrinsic.
Divergences from the human mechanism
contested assumption qualifying
The model assumes that expressing human TLR8 at transgenic levels in a mouse is equivalent to a hypersensitive human TLR8 in a subset of human myeloid cells. The equivalence is between quantity of normal receptor and quality of abnormal receptor, and this entry's own conformational-gain hypothesis argues those are different lesions.
proxy quantity qualifying
The model's quantity is fatal anaemia in a whole animal. The node's quantity is blocked EPO receptor signalling in erythroid progenitors. The model reports the outcome and not the mechanism, and reaches it by a myeloid route rather than the erythroid-intrinsic one the node describes.
population mismatch qualifying
A lupus-prone inbred background is not the genetic context of these patients, and the phenotype requires it. No anaemia is reported from the human TLR8 transgene alone.
Show evidence (1 reference)
PMID:41370196 SUPPORT INDIRECT Model Organism
"a recent study that crossed transgenic mice expressing human TLR8 with lupus mice demonstrated that expression of human TLR8 in lupus mice induces fatal anemia via myeloid cell dysregulation,16 indicating a potential mechanism in our patients."
The model and the authors' own reason for raising it, in one sentence. INDIRECT because the inference to the patients is theirs and is offered as potential.
{ }

Source YAML

click to show 
name: Immunodeficiency 98 With Autoinflammation
creation_date: "2026-09-13T00:00:00Z"
category: Mendelian
synonyms:
- IMD98
- immunodeficiency 98 with autoinflammation, X-linked
- TLR8 gain-of-function disorder
- TLR8 GOF
- INFLTR8
- inflammation, neutropenia, bone marrow failure, and lymphoproliferation caused by TLR8
description: >-
  Immunodeficiency 98 with autoinflammation is caused by gain-of-function variants
  in TLR8, the X-linked endosomal sensor of single-stranded RNA degradation
  products. TLR8 is expressed mainly by myeloid cells and signals through NF-kB to
  produce proinflammatory cytokines. The disease-causing variants make the
  receptor hypersensitive to ligand rather than constitutively active, so patient
  cells over-respond to stimulation.

  The clinical picture pairs two things that usually pull in opposite directions:
  immunodeficiency - severe refractory neutropenia, recurrent infection, impaired
  B-cell maturation - and autoinflammation, with activated T cells, raised serum
  cytokines and lymphoproliferation. Bone marrow characteristically shows severe
  myeloid hypoplasia with activated T-cell infiltrates. Disease is refractory to
  granulocyte colony-stimulating factor and corticosteroids, and allogeneic
  haematopoietic cell transplantation is the only intervention shown to resolve
  the phenotype.

  Two features of this disease are unusual enough to be the reason it is worth a
  separate entry rather than a line in a TLR-signalling review. First, most
  patients are somatic mosaics with variant allele fractions between 7 and 26 per
  cent, and the phenotype is full-blown anyway - so a minority clone of
  hypersensitive cells is sufficient, and the disease would be missed by any
  workflow assuming germline heterozygosity. Second, TLR8 turns out to act inside
  the erythroid lineage as well, blocking EPO signalling by a mechanism that has
  been worked out in detail, which makes the anaemia a second molecular arm rather
  than a consequence of the marrow inflammation.
disease_term:
  preferred_term: immunodeficiency 98 with autoinflammation, X-linked
  term:
    id: MONDO:0024777
    label: immunodeficiency 98 with autoinflammation, X-linked
parents:
- inborn error of immunity
- bone marrow failure syndrome
- autoinflammatory syndrome
references:
- reference: PMID:33512449
  title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
- reference: PMID:41370196
  title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
- reference: PMID:36119097
  title: "Gain-of-function defects in toll-like receptor 8 shed light on the interface between immune system and bone marrow failure disorders."
inheritance:
- name: X-linked dominant, frequently somatic mosaic
  description: >-
    TLR8 is at Xp22.2. The disease was first described in males, but a female
    patient with a germline variant has since been reported, which establishes the
    mode as X-linked dominant rather than X-linked recessive. Most patients carry
    the variant as a post-zygotic somatic mosaic rather than in the germline, and
    mosaicism has been demonstrated outside the haematopoietic compartment in skin
    fibroblasts - so the mutational event is early and not confined to blood.
  inheritance_term:
    preferred_term: X-linked dominant inheritance
    term:
      id: HP:0001423
      label: X-linked dominant inheritance
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TLR8 GOF is an X-linked dominant disorder that should be considered in male and female patients with cytopenia, particularly severe neutropenia, lymphoproliferation with immune dysregulation, increased LGLs, and new to this cohort, red cell aplasia."
    explanation: >-
      States the inheritance mode explicitly, and the female patient is what changed it
      from the X-linked recessive assumption of the original male-only cohort.
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment."
    explanation: >-
      Establishes that the mosaicism is developmental rather than a clonal
      haematopoietic event, which matters for how and where to test for it.
pathophysiology:
- name: TLR8 Gain-of-Function Variant
  description: >-
    The initiating lesion. Missense variants in TLR8 confer gain of function on the
    encoded receptor. In most patients the variant is present as a somatic mosaic at
    a low variant allele fraction rather than in every cell, which is recorded here
    in genetic_context because it is the defining molecular feature of the disease
    rather than an incidental finding in a few cases.
  biological_scale: MOLECULAR
  genetic_context:
    functional_impact_category: GAIN_OF_FUNCTION
    variant_origin: SOMATIC
  downstream:
  - target: Hypersensitivity of the Endosomal ssRNA Sensor
    causal_link_type: DIRECT
    description: >-
      The variants do not make the receptor constitutively active; they lower its
      threshold, so patient cells over-respond when ligand is present.
    evidence:
    - reference: PMID:41370196
      reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "All TLR8 variants led to a gain-of-function (GOF) of the encoded protein, with patient-derived cells exhibiting hypersensitivity to ligand stimulation, resulting in increased NF-κB activation and cytokine production."
      explanation: >-
        The whole molecular chain in one sentence - gain of function, expressed as
        ligand hypersensitivity, producing NF-kB activation and cytokine output.
  evidence:
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype."
    explanation: >-
      Records both the mosaicism and the inference the authors draw from it - that a
      minority clone suffices, which is what makes the mechanism dominant.
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All variants conferred gain of function to TLR8 protein"
    explanation: Establishes the direction of the functional effect for every variant described.
  - reference: PMID:41729082
    reference_title: "Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect."
    explanation: A further gain-of-function allele, characterised in two male siblings with recurrent infection and systemic inflammation.
  - reference: PMID:41729082
    reference_title: "Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation."
    explanation: >-
      The counterintuitive half of the mechanism - there is less mutant protein, not
      more. Recorded because it rules out the obvious reading that gain of function here
      means gain of receptor.
  - reference: PMID:41729082
    reference_title: "Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution."
    explanation: >-
      The proposed reconciliation: the variant stabilises the active conformation rather
      than increasing receptor number. Graded COMPUTATIONAL because it is a modelling
      prediction, not a structure.
- name: Hypersensitivity of the Endosomal ssRNA Sensor
  description: >-
    TLR8 sits in the endosome and recognises single-stranded RNA degradation
    products, signalling through NF-kB. A hypersensitive receptor converts ordinary
    ligand exposure - which for an endosomal RNA sensor is routine - into a
    disproportionate signal. Myeloid cells differentiated from patient-derived
    induced pluripotent stem cells show the increased responsiveness directly, which
    matters because it locates the defect in the cell rather than in the patient's
    inflammatory milieu.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: toll-like receptor signaling pathway
    term:
      id: GO:0002224
      label: toll-like receptor signaling pathway
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: TIRAP-MyD88 Adaptor Assembly and IRAK Activation
    causal_link_type: DIRECT
    description: >-
      An activated TLR8 dimer recruits its adaptors. This is the step the receptor's
      signal actually passes through, and it is separated out because it is where the
      human and mouse pathways diverge.
    evidence:
    - reference: PMID:41159953
      reference_title: "A novel TIRAP-MyD88 inhibitor blocks TLR7- and TLR8-induced type I IFN responses."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "P7-Pen blocked TIRAP recruitment to the TLR8-MyD88 complex, leading to reduced late-stage IRAK1 activation, Akt and IKKα/β phosphorylation, and downstream IRF5 dimerization and nuclear translocation."
      explanation: >-
        The step order, established by blocking it: TIRAP joins the TLR8-MyD88 complex,
        and removing it costs IRAK1 activation and everything downstream. INDIRECT
        because it is shown in healthy human monocytes rather than in TLR8-GOF cells.
  evidence:
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8."
    explanation: >-
      Demonstrates the cellular phenotype in a patient-derived system independent of
      the patient's circulating inflammatory environment.
  - reference: PMID:21949866
    reference_title: "Comparative analysis of species-specific ligand recognition in Toll-like receptor 8 signaling: a hypothesis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "The primary sequences of rodent and non-rodent TLR8s are similar, but the antiviral compound (R848) that activates the TLR8 pathway is species-specific."
    explanation: >-
      Why a human patient-derived system is the right model and a rodent one would not
      be: the receptor does not respond to the same ligands across species. Graded
      COMPUTATIONAL because the mechanistic account is homology modelling and docking;
      the species difference in R848 response it starts from is an established
      experimental fact.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "Toll-like receptor 8 (TLR8) is an endosomal pattern recognition receptor primarily expressed by myeloid cells that recognizes microbial single-stranded RNA degradation products, with activation ultimately resulting in the production of NF-κB–dependent cytokines and proinflammatory signature."
    explanation: >-
      Describes the normal function the variants exaggerate. BACKGROUND: introduction
      physiology in a human clinical cohort study, not a result of it. OTHER is kept
      rather than raised to a study type, because the sentence is textbook receptor
      biology that describes no single study - which is a different reason for OTHER
      than the review item below, and the pair is only distinguishable now that
      `quote_role` says which is which.
  - reference: PMID:25599397
    reference_title: "Toll-like receptor 8 senses degradation products of single-stranded RNA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TLR8 recognized two degradation products of ssRNA—uridine and a short oligonucleotide—at two distinct sites: uridine bound the site on the dimerization interface where small chemical ligands are recognized, whereas short oligonucleotides bound a newly identified site on the concave surface of the TLR8 horseshoe structure."
    explanation: >-
      Defines what the receptor actually senses, at structural resolution. The uridine
      site sits on the dimerization interface, which is the surface the A518T variant is
      modelled to stabilise - so the ligand chemistry and the disease mechanism meet at
      the same place.
  - reference: PMID:25599397
    reference_title: "Toll-like receptor 8 senses degradation products of single-stranded RNA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Site-directed mutagenesis revealed that both binding sites were essential for activation of TLR8 by ssRNA."
    explanation: Establishes that activation requires both sites, which is what makes the dimer interface a point of control rather than an incidental surface.
- name: TIRAP-MyD88 Adaptor Assembly and IRAK Activation
  description: >-
    The step between the receptor and its transcriptional output, and the reason to
    curate it separately is that it is where this disease's species problem lives.

    TLR8 signals through MyD88, and recent work shows TIRAP - long thought to serve only
    plasma-membrane TLRs - is also recruited to the endosomal TLR8-MyD88 complex, where
    it is required for late IRAK1 activation, IKK phosphorylation and IRF5 nuclear
    translocation. A peptide that disrupts the TIRAP-MyD88 interaction blocks
    TLR8-induced IFN-beta and IL-12 in human monocytes and whole blood, and fails
    entirely against murine TLR7, because TIRAP is not recruited to MyD88 in mouse
    macrophages after ligand stimulation.

    That last observation matters for this entry specifically. The entry's argument
    against a mouse model rests on species-specific ligand recognition at the receptor;
    this adds a second, independent divergence one step downstream, in the adaptor
    complex itself. IRAK-2 shows the same pattern from the other direction: human IRAK-2
    is required for TLR8-mediated NF-kB and p38 activation in primary human cells, where
    the inbred mouse knockout said it was not needed.

    Note the gain-of-function claim here is inferred, not measured. No study has shown
    the adaptor complex assembling excessively in TLR8-GOF patient cells; what is
    established is that the step is required, and that the receptor above it is
    hypersensitive.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: MyD88-dependent toll-like receptor signaling pathway
    term:
      id: GO:0002755
      label: MyD88-dependent toll-like receptor signaling pathway
    modifier: INCREASED
  downstream:
  - target: Excess NF-kB-Dependent Cytokine Production
    causal_link_type: DIRECT
    description: >-
      Adaptor assembly and IRAK activation are what convert receptor engagement into
      IKK phosphorylation and NF-kB-dependent transcription.
    evidence:
    - reference: PMID:21606490
      reference_title: "Human interleukin-1 receptor-associated kinase-2 is essential for Toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alpha."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "siRNA knockdown of IRAK-2 expression in human peripheral blood mononuclear cells showed a role for human IRAK-2 in both TLR4- and TLR8-mediated early NFκB and p38 MAPK activation and in induction of TNF mRNA."
      explanation: >-
        The requirement for an IRAK kinase in TLR8-driven NF-kB activation, in primary
        human cells. INDIRECT because the cells are healthy donors', not patients'.
    - reference: PMID:41370196
      reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "patient-derived cells exhibiting hypersensitivity to ligand stimulation, resulting in increased NF-κB activation and cytokine production"
      explanation: >-
        Connects the receptor-level hypersensitivity to the pathway-level output in
        patient cells. Re-homed onto this edge when the adaptor node was inserted, since
        the claim it carries is receptor engagement producing NF-kB output, which is this
        edge rather than the recruitment step above it.
  evidence:
  - reference: PMID:41159953
    reference_title: "A novel TIRAP-MyD88 inhibitor blocks TLR7- and TLR8-induced type I IFN responses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In primary human monocytes and a whole blood model, P7-Pen inhibited TLR7- and TLR8-induced expression and secretion of IRF5-regulated cytokines IFNβ, IL-12p40, and IL-12p70, without effect on TNF or IL-6."
    explanation: >-
      That the adaptor step is required for part of the TLR8 cytokine output, and which
      part: the IRF5-regulated arm rather than TNF or IL-6. Worth noting because the
      patient cell readout used elsewhere in this entry is IL-6.
  - reference: PMID:41159953
    reference_title: "A novel TIRAP-MyD88 inhibitor blocks TLR7- and TLR8-induced type I IFN responses."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Notably, P7-Pen failed to inhibit murine TLR7 responses, which correlated with a lack of TIRAP recruitment to MyD88 in mouse macrophages following TLR7 ligand stimulation, highlighting species-specific differences in TLR signaling mechanisms."
    explanation: >-
      A second species divergence, one step below the ligand-recognition difference this
      entry already records. It strengthens the argument against a knock-in mouse model
      rather than restating it.
  - reference: PMID:21606490
    reference_title: "Human interleukin-1 receptor-associated kinase-2 is essential for Toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alpha."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "These data conflict with findings from the in-bred Irak2(-/-) mice but concur with what has been seen in wild-derived mice for TLR2."
    explanation: >-
      The same divergence from the kinase side: what the mouse knockout said about
      IRAK-2 does not hold in human cells. Recorded because this entry's no-mouse
      argument is a substantive claim and deserves more than one line of support.
- name: Excess NF-kB-Dependent Cytokine Production
  description: >-
    The proinflammatory state. Patients show activated T cells and elevated serum
    cytokines. This node is the shared upstream of the marrow, lymphoid and humoral
    consequences below, which is why they branch from it rather than from each other.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: positive regulation of canonical NF-kappaB signal transduction
    term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
    modifier: INCREASED
  - preferred_term: cytokine production
    term:
      id: GO:0001816
      label: cytokine production
    modifier: INCREASED
  downstream:
  - target: Myeloid Hypoplasia and Bone Marrow Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The marrow shows myeloid hypoplasia alongside activated T-cell infiltrates. How
      the inflammatory state suppresses granulopoiesis - whether through the T-cell
      infiltrate, a cytokine effect on progenitors, or both - is not established in
      these patients.
    evidence:
    - reference: PMID:41370196
      reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bone marrow characteristically demonstrated severe myeloid hypoplasia and activated T-cell infiltrates and/or aggregates."
      explanation: >-
        Puts the hypoplasia and the T-cell infiltrate in the same marrow, which is the
        observation the edge rests on without establishing which drives which.
  - target: Lymphoproliferation with Immune Dysregulation
    causal_link_type: DIRECT
    description: >-
      Activated T cells and raised cytokines are the proximate description of the
      lymphoproliferative phenotype.
  - target: Impaired B-Cell Maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Humoral defects accompany the inflammatory phenotype. The paper reports the
      association rather than a mechanism connecting the two.
    evidence:
    - reference: PMID:33512449
      reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation"
      explanation: >-
        States the association between the inflammatory phenotype and the B-cell defect,
        in the associative language the source itself uses.
  evidence:
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines"
    explanation: The immunophenotype that defines this node in patients.
- name: Myeloid Hypoplasia and Bone Marrow Failure
  description: >-
    The dominant clinical problem. Neutropenia is universal and usually severe, and is
    refractory to the treatments that work in other neutropenias. Anaemia and
    thrombocytopenia are common, so the failure is not confined to the granulocytic
    line. An increased number of large granular lymphocytes was found in half the
    expanded cohort.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had neutropenia, most with severe neutropenia refractory to medical therapy. Anemia and thrombocytopenia were common."
    explanation: The cytopenia profile across the full reported cohort, and its refractoriness.
- name: Lymphoproliferation with Immune Dysregulation
  description: >-
    The autoinflammatory arm. Lymphoproliferation was among the founding cohort's
    defining features and remains in the diagnostic description of the expanded one.
    Coexisting with the immunodeficiency, it is what makes the disease a combined
    picture rather than a simple bone marrow failure syndrome.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8)."
    explanation: The founding clinical description, listing lymphoproliferation alongside the immunodeficiency features.
- name: Impaired B-Cell Maturation
  description: >-
    The humoral arm. B-cell maturation is impaired and humoral immune defects are part
    of the founding phenotype, contributing to the infectious susceptibility alongside
    the neutropenia.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure"
    explanation: The authors' summary of the disease, naming the B- and T-cell defects as components.
- name: TLR8-Driven Blockade of EPO Signaling in Erythroid Progenitors
  description: >-
    A second, mechanistically separate arm, and the one that is worked out in most
    molecular detail. TLR8 is expressed in the erythroid lineage, and activating it
    impairs erythropoiesis from the progenitor stage onward while inhibiting it
    enhances erythropoiesis. The mechanism is specific: TLR8 activation blocks
    annexin A2-mediated plasma membrane localisation of STAT5, which disrupts
    erythropoietin signalling. This is an erythroid-intrinsic effect rather than a
    consequence of the marrow inflammation, which is why it is modelled as its own
    branch from the receptor node rather than downstream of the cytokine node.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  biological_processes:
  - preferred_term: erythropoietin-mediated signaling pathway
    term:
      id: GO:0038162
      label: erythropoietin-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: erythrocyte differentiation
    term:
      id: GO:0030218
      label: erythrocyte differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:38971858
    reference_title: "Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells."
    explanation: The specific molecular mechanism by which TLR8 activation impairs erythropoiesis.
  - reference: PMID:38971858
    reference_title: "Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage."
    explanation: >-
      Establishes both the expression and the bidirectional dependence - inhibition
      improves erythropoiesis, which is what makes the effect causal rather than
      correlative.
mechanistic_hypotheses:
- hypothesis_group_id: low_vaf_mosaic_sufficiency
  hypothesis_label: How a somatic clone at 7-26 per cent variant allele fraction produces the full phenotype
  status: EMERGING
  description: >-
    Eight of the ten reported patients are somatic mosaics with peripheral blood
    variant allele fractions between 7 and 26 per cent. A minority of hypersensitive
    cells is therefore sufficient to produce severe, refractory, transplant-requiring
    disease. The original authors read this as evidence of a dominant mechanism.

    What "dominant" means here is the open part, but the authors are not neutral
    between the two readings and this entry should not present them as though they
    were. They call the neutropenia likely cell-extrinsic, on the grounds that patients
    with the variant in a small fraction of cells carry a large burden of disease, and
    they make a sharper version of the same argument for the lymphoid arm: T and B cells
    do not express TLR8 at all, so whatever is dysregulating them cannot be acting
    inside them.

    They also name candidates for the intermediate, which is the step the pathograph
    leaves as INDIRECT_UNKNOWN_INTERMEDIATES. By analogy with the neutropenia of large
    granular lymphocyte leukaemia, the proposals are high soluble Fas ligand triggering
    apoptosis of neutrophil and myeloid progenitors, and direct destruction by
    infiltrating T cells. Soluble Fas ligand has been measured as elevated in these
    patients, so the first is a candidate with a measurement behind it rather than a
    guess.

    What remains genuinely open is whether either candidate is doing the work. A
    cell-autonomous account would require the mutant clone to have a competitive
    advantage that the data do not establish; the cell-extrinsic account fits the
    observed picture and explains why transplantation with full donor chimerism resolves
    the phenotype, but neither candidate intermediate has been tested in these patients.

    Two practical consequences follow regardless of which is right. A germline-only
    variant calling pipeline at standard heterozygous thresholds will miss most of
    these patients, and a negative blood test does not exclude the disease, since
    mosaicism has been found in fibroblasts.
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight patients had somatic mosaicism with peripheral blood variant allele fractions of 7% to 26%, and age of disease onset of 9 months to 28 years."
    explanation: The observation the hypothesis is about - low variant allele fractions with full disease.
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic mosaicism is a prominent molecular mechanism of this new disease."
    explanation: The authors' framing of mosaicism as a defining feature rather than an incidental one.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients are surviving at 1 to 3 years after HCT with full donor myeloid and T-cell chimerism, and resolution of disease phenotype."
    explanation: >-
      Replacing the haematopoietic compartment resolves the disease, which is consistent
      with the non-cell-autonomous reading but does not by itself distinguish the two.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The etiology of the severe neutropenia remains incompletely elucidated, but is likely cell-extrinsic given the significant burden of disease in patients with mosaicism in a small fraction of cells"
    explanation: The authors' stated lean, and the argument they give for it.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The nature of T- and B-cell dysregulation is unclear, but is expected to be cell-extrinsic given that T and B cells do not express TLR8."
    explanation: >-
      The cleanest form of the argument. For the lymphoid arm it is not a weighing of
      evidence but an expression fact: the affected cells do not carry the receptor.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the hypotheses for neutropenia include high soluble Fas ligand triggering apoptosis of neutrophil and/or myeloid progenitors and direct destruction by infiltrating T cells"
    explanation: >-
      The named candidate intermediates for the edge the pathograph marks as having
      unknown intermediates.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also previously demonstrated elevated levels of proinflammatory cytokines, the B-cell survival factor B-cell activating factor, and soluble Fas ligand."
    explanation: >-
      The measurement behind the first candidate. INDIRECT because elevated soluble Fas
      ligand in these patients does not establish that it is what kills the progenitors.
  - reference: PMID:36119097
    reference_title: "Gain-of-function defects in toll-like receptor 8 shed light on the interface between immune system and bone marrow failure disorders."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "TLR8-GOF joins a growing list of (interface) disorders that can cause disease both with germline and somatic (mosaic) genetic variants."
    explanation: >-
      Places the mosaicism in a class rather than treating it as a peculiarity of this
      gene, which is what makes the low-variant-allele-fraction question a general one.
      REVIEW_SYNTHESIS: the publication is indexed as a Review and this sentence is its
      synthesis across that literature.
- hypothesis_group_id: conformational_gain_not_receptor_gain
  hypothesis_label: Whether gain of function here is conformational stabilisation rather than more receptor
  status: EMERGING
  description: >-
    The A518T allele produces more NF-kB activation and more cytokine from *less*
    protein: turnover assays show reduced abundance of the mutant, through faster
    proteasomal degradation. So whatever "gain of function" means in this disease, it is
    not gain of receptor.

    The proposal is that the substitution stabilises the *active* TLR8 homodimer
    interface - computational modelling predicts additional water-mediated hydrogen
    bonds there - so each remaining receptor spends more of its time in the signalling
    conformation. That is consistent with the ligand-hypersensitivity phenotype the
    founding cohort reported, and it would explain why a somatic clone at low variant
    allele fraction suffices, since the effect is per-receptor rather than per-cell.

    It is one allele, and the structural claim is a prediction rather than a solved
    structure. Whether the other reported variants share the mechanism has not been
    tested; they were characterised as gain of function by reporter activity, which does
    not distinguish more receptor from better receptor.
  evidence:
  - reference: PMID:41729082
    reference_title: "Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation."
    explanation: The observation the hypothesis exists to explain - less protein with more signal.
  - reference: PMID:41729082
    reference_title: "Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in"
    explanation: >-
      The authors' summary, calling the mutation ligand-specific - which is the
      conformational reading rather than an abundance one. Truncated at a line boundary
      in the cached record.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "The results demonstrate that CU-CPT9a inhibited WT TLR8 activity, but cells with the p.P432L variant were resistant to CU-CPT9a treatment (Figure 2G)."
    explanation: >-
      Independent support for the conformational reading, from a drug experiment rather
      than from structure. CU-CPT9a binds TLR8 in its inactive conformation, so an
      inhibitor that works on wild-type and fails on the variant implies the variant is
      not occupying that conformation. Marked INDIRECT because the inference runs through
      the inhibitor's stated binding mode rather than being measured directly, and
      because the variant tested is p.P432L while the hypothesis was framed around A518T.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "CU-CPT9a is a selective inhibitor of TLR8 signaling that binds to TLR8 in its inactive conformation"
    explanation: The binding mode the previous item's inference depends on, stated by the same authors.
phenotypes:
- category: Hematological
  name: Severe refractory neutropenia
  description: >-
    Present in every reported patient and usually severe. Its refractoriness to
    granulocyte colony-stimulating factor and corticosteroids is diagnostically useful
    as well as clinically important, since it separates this from the neutropenias
    those agents treat.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
    temporality: CHRONIC
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had neutropenia, most with severe neutropenia refractory to medical therapy."
    explanation: Universal presence and refractoriness in the full cohort.
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation."
    explanation: The same finding in the original cohort, alongside the transplant decision it drove.
- category: Hematological
  name: Bone marrow myeloid hypoplasia
  description: >-
    The marrow finding, with activated T-cell infiltrates alongside the hypoplasia.
    This combination is what identifies the marrow failure as immune-mediated rather
    than as a primary stem cell defect.
  phenotype_term:
    preferred_term: Bone marrow hypocellularity
    term:
      id: HP:0005528
      label: Bone marrow hypocellularity
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone marrow characteristically demonstrated severe myeloid hypoplasia and activated T-cell infiltrates and/or aggregates."
    explanation: The characteristic marrow histology.
- category: Hematological
  name: Thrombocytopenia
  description: >-
    Universal in the reported cohort - all ten patients - and mild to moderate in every
    one of them, which is a different claim from the "common" the abstract makes. The
    paper defines its bands, so mild and moderate here mean platelet counts of 100 to
    150 and 50 to 100 x 10^9/L respectively.

    Curated separately from the anaemia below because the two cytopenias run
    differently: thrombocytopenia is present in everyone and stays moderate, while the
    anaemia is present in eight and is severe in three. A single bundled entry could
    not say either of those things, and bound only one of the two terms.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    severity: MODERATE
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 10 patients had mild to moderate thrombocytopenia; 5 patients had mild to moderate anemia; and 3 patients had severe anemia, including patient 10, who presented at age 2 weeks with pure red cell aplasia."
    explanation: >-
      The full-text frequency statement, which gives 10 of 10 for thrombocytopenia and
      the severity split for the anaemia curated below.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild, moderate, and severe thrombocytopenia were defined as platelet counts 100 × 109/L to 150 × 109/L, 50 × 109/L to 100 × 109/L, and <50 × 109/L, respectively."
    explanation: >-
      The definitions behind the severity qualifier, so "mild to moderate" is a platelet
      range rather than a clinical impression.
- category: Hematological
  name: Anemia
  description: >-
    Present in eight of the ten reported patients and severe in three of them. The
    erythroid arm of the disease has its own molecular mechanism, so the anaemia here is
    not simply a second consequence of the marrow inflammation - the most severe end of
    it is the pure red cell aplasia curated below.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "5 patients had mild to moderate anemia; and 3 patients had severe anemia"
    explanation: The severity split, which the abstract's "common" does not carry.
- category: Immunological
  name: Hypogammaglobulinemia
  description: >-
    Six of ten patients, and all six required immunoglobulin replacement, so this is the
    phenotype behind one of the treatments curated below rather than a laboratory
    observation alone. It sits with the impaired B-cell maturation node: low or absent
    switched memory B cells is the mechanism, and low serum immunoglobulin is what that
    produces.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients had hypogammaglobulinemia requiring immunoglobulin replacement."
    explanation: The frequency and, in the same sentence, the treatment it drove.
- category: Immunological
  name: Lymphadenopathy
  description: >-
    Every reported patient had lymphadenopathy, splenomegaly, or both. Recorded as its
    own phenotype rather than folded into the Lymphoproliferation entry above because
    the two make different claims: that entry binds HP:0005523, a disorder-level term,
    while this is the organ finding a clinician examines for.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, all patients had evidence of lymphoproliferation with lymphadenopathy and/or splenomegaly."
    explanation: >-
      Universal in the cohort. The "and/or" is why lymphadenopathy and splenomegaly are
      curated as two entries rather than one combined finding.
- category: Immunological
  name: Splenomegaly
  description: >-
    The other half of the universal lymphoproliferative finding. The cohort table
    records hepatosplenomegaly in every patient, so the enlargement is not confined to
    the spleen, but splenomegaly is what the prose states and is what is bound here.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients had evidence of lymphoproliferation with lymphadenopathy and/or splenomegaly"
    explanation: The same universal statement, cited here for the splenic half.
- category: Mucocutaneous
  name: Oral ulcers
  description: >-
    Seven of ten patients. Worth having explicitly because it is a visible,
    non-haematological feature in a disease otherwise defined by marrow findings, and
    because recurrent oral ulceration with neutropenia is the presentation that sends a
    patient to a general clinic rather than to immunology.
  phenotype_term:
    preferred_term: Oral ulcer
    term:
      id: HP:0000155
      label: Oral ulcer
    temporality: RECURRENT
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most (n = 7) patients had a history of oral ulcers, and all patients had a history of bacterial and/or fungal infection, which were often severe."
    explanation: The frequency, alongside the universal infection history already curated separately.
- category: Hematological
  name: CD8-positive CD57-positive large granular lymphocytes in marrow
  description: >-
    Present in five of ten patients, and the reason it matters is diagnostic rather
    than mechanistic: two patients in the cohort were treated for large granular
    lymphocyte leukaemia before TLR8 gain of function was discovered. The authors
    propose it as a trigger for TLR8 sequencing in its own right, particularly in
    paediatric or young adult patients, which makes it a finding that redirects a
    diagnosis rather than one that follows it.
  phenotype_term:
    preferred_term: CD8+/CD57+ large granular lymphocytes
    term:
      id: HP:0004332
      label: Abnormal lymphocyte morphology
  review_notes: >-
    Bound to a parent term deliberately. HPO has no term for a large granular
    lymphocyte, so the most specific accurate binding available is the abnormal
    lymphocyte morphology parent, with the immunophenotype carried in
    `preferred_term`. NCIT does have the concept - NCIT:C12921 Large Granular
    Lymphocyte - but it is a cell type rather than a phenotypic abnormality and
    PhenotypeTerm is HP-rooted, so it cannot fill this slot. No term beats a wrong one.
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "several (n = 5) patients had CD8+/CD57+ large granular lymphocytes (LGLs)"
    explanation: The frequency, from the bone marrow findings section.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients received treatment for LGL leukemia (1 with oligoclonal LGLs and 1 with polyclonal LGLs) before discovery of TLR8 GOF."
    explanation: >-
      The misdiagnosis this finding caused in the cohort itself, which is why the
      authors raise it as a sequencing trigger.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "many patients had CD8+/CD57+ LGLs present, which may be an additional clinical phenotype to consider for TLR8 sequencing, especially in pediatric or young adult patients"
    explanation: The authors' recommendation, which is the practical use of this phenotype.
- category: Hematological
  name: Pure red cell aplasia
  description: >-
    A presentation new to the expanded cohort, found in the first reported female
    patient, who presented in infancy with a germline TLR8 variant. It is the clinical
    counterpart of the erythroid-intrinsic mechanism curated in the pathophysiology.
  phenotype_term:
    preferred_term: Pure red cell aplasia
    term:
      id: HP:0012410
      label: Pure red cell aplasia
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify the first female patient with TLR8 GOF who presented during infancy with pure red cell aplasia due to a germ line TLR8 variant"
    explanation: The single case establishing this presentation, and the one that established female involvement.
- category: Immunological
  name: Lymphoproliferation
  description: >-
    Lymphoproliferation with immune dysregulation, one of the founding features and
    part of the description used to define who should be tested.
  phenotype_term:
    preferred_term: Lymphoproliferative disorder
    term:
      id: HP:0005523
      label: Lymphoproliferative disorder
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Toll-like receptor 8 (TLR8) gain-of-function (GOF) somatic variants were recently identified as causing severe neutropenia, lymphoproliferation, and immune dysregulation."
    explanation: Names lymphoproliferation among the disease's defining features.
- category: Immunological
  name: Recurrent infections
  description: >-
    Infectious susceptibility follows from the neutropenia and the humoral defect
    together. It was among the founding cohort's presenting features.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects"
    explanation: Records infection among the presenting features of the original cohort.
- category: Hematological
  name: Autoimmune myelofibrosis
  description: >-
    An expansion of the phenotypic spectrum from a single case: a 25-year-old man with
    eight years of chronic neutropenia, previously diagnosed with Behcet disease, in
    whom exome sequencing found a TLR8 variant and the diagnosis was revised to
    autoimmune myelofibrosis secondary to TLR8 gain of function. Recorded as a
    reported association from one patient, not as an established feature.
  phenotype_term:
    preferred_term: Myelofibrosis
    term:
      id: HP:0011974
      label: Myelofibrosis
  evidence:
  - reference: PMID:42023410
    reference_title: "Autoimmune myelofibrosis with a TLR8 gain-of-function defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge, this is the first reported association between TLR8-GOF mutation and AIMF, expanding the phenotypic spectrum of TLR8-related disorders."
    explanation: >-
      The authors' own characterisation of the finding as a first report, which is why
      this phenotype is curated with that qualification rather than as established.
genetic:
- name: TLR8
  association: Causal
  gene_term:
    preferred_term: TLR8
    term:
      id: hgnc:15632
      label: TLR8
  notes: >-
    TLR8 is at Xp22.2. Disease-causing variants are missense and gain of function.
    Most are somatic, present as post-zygotic mosaics at peripheral blood variant
    allele fractions of 7 to 26 per cent and detectable in skin fibroblasts as well as
    blood; germline variants are reported, including in the first described female
    patient.

    The dominant recurrent position is p.P432. Eight of the ten reported patients carry
    a variant there - six p.P432L, plus the novel p.P432Q and p.P432R - and the authors
    call it a hot spot for somatic variation, particularly during embryogenesis. The
    two novel alleles were functionally validated: neither is constitutively active, and
    both show increased NF-kB activity after stimulation with the TLR8-specific ligand
    TL8-506, which is the same ligand-hypersensitivity signature as p.P432L. Outside the
    hot spot, p.F494L and a germline p.G572D are each reported once, the latter in a
    patient with autoimmune myelofibrosis.

    Age of onset spans 9 months to 28 years. Because most cases are mosaic, variant
    calling at standard germline heterozygous thresholds will miss them.
  evidence:
  - reference: PMID:33512449
    reference_title: "Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8)"
    explanation: Establishes TLR8 as the causal gene and names its product.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel missense variants in the TLR8 gene, located on the short arm of chromosome X (Xp22.2), were recently identified in 6 unrelated male patients with severe neutropenia, lymphoproliferation, and immune dysregulation, known as INFLTR8 (inflammation, neutropenia, bone marrow failure, and lymphoproliferation caused by TLR8)."
    explanation: Gives the cytogenetic location and the acronym the disease is also known by.
  - reference: PMID:42023410
    reference_title: "Autoimmune myelofibrosis with a TLR8 gain-of-function defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing revealed a TLR8-G572D mutation, leading to a diagnosis of autoimmune myelofibrosis (AIMF) secondary to TLR8 gain of function (GOF)."
    explanation: A further variant and the presentation it was found in.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight patients had mutations at the same amino acid location, 6 with the previously reported p.P432L variant and 2 with novel variants (p.P432Q and p.P432R)."
    explanation: >-
      The hotspot, with the allele breakdown. Note for anyone working from the
      deep-research report for this entry: that report names Phe494 and Gly572 as the
      hotspots, sourced from ClinVar, and the primary literature disagrees. Each of those
      is a single case; p.P432 is eight of ten.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting that the position p.P432 in TLR8 is a hot spot for somatic variation, particularly during embryogenesis, and has significant impact on TLR8 function"
    explanation: The authors' interpretation, including when in development they think the variants arise.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Neither variant was constitutively active, and both demonstrated increased NF-κB activity following stimulation with the TLR8-specific chemical ligand TL8-506, similar to the previously identified p.P432L variant and consistent with GOF (Figure 1B)."
    explanation: >-
      Functional validation of the two novel hotspot alleles, and the detail that makes
      this a ligand-hypersensitivity gain rather than a constitutive one - the receptor
      still needs its ligand.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ten patients in the expanded cohort, which incorporates the original six. Further
    single cases have been reported since. The disease was first described in 2021, so
    the reported count reflects how recently it was recognised at least as much as how
    rare it is - a point the mosaic molecular mechanism sharpens, since routine
    germline pipelines would not have found these patients.
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the expanded clinical and laboratory phenotype and management of 10 patients, including the original cohort of 6 male patients."
    explanation: The cohort size and its relationship to the founding series.
animal_models:
- name: Human TLR8 transgenic mouse crossed onto a lupus background
  species: Mouse
  genotype: Transgenic expression of human TLR8, crossed with a lupus-prone strain
  publication: PMID:41370196
  description: >-
    The humanised route around this disease's species problem. A knock-in mouse
    carrying the homologous substitution would not help, because murine TLR8 does not
    recognise the same ligands - that objection stands. Putting the human receptor into
    a mouse sidesteps it, and that experiment has been done: mice transgenic for human
    TLR8, crossed onto a lupus background, develop fatal anaemia driven by myeloid cell
    dysregulation.

    The authors of the patient cohort cite it as indicating a potential mechanism for
    the pure red cell aplasia in their own patients, which is why it is curated here
    rather than treated as unrelated lupus work. It converges on the erythroid arm this
    entry models, and by a myeloid route rather than an erythroid-intrinsic one, which
    is a different account from the erythroid-intrinsic TLR8 signalling reported in
    inherited anaemia.

    Two things it is not. It is not a model of TLR8 gain of function - the transgene is
    wild-type human TLR8, and what is varied is dose and background, not receptor
    activity. And the anaemia arises on a lupus-prone background that contributes its
    own autoimmunity, so the phenotype cannot be attributed to TLR8 alone.
  modeled_mechanisms:
  - target: TLR8-Driven Blockade of EPO Signaling in Erythroid Progenitors
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Produces the organism-level outcome this arm ends in - fatal anaemia - and
      attributes it to myeloid dysregulation. It does not reproduce the node itself,
      which is a molecular claim about EPO receptor signalling in erythroid progenitors.
    limitations: >-
      The transgene is wild-type human TLR8, not a gain-of-function variant, so the model
      tests the consequence of human TLR8 activity in a mouse rather than the consequence
      of this disease's variants. The lupus-prone background contributes autoimmunity of
      its own and is required for the phenotype. Transgenic expression is not the mosaic,
      low-variant-allele-fraction state patients are in. And the mechanism reported is
      myeloid dysregulation, whereas the node it is linked to is erythroid-intrinsic.
    divergences:
    - divergence_type: CONTESTED_ASSUMPTION
      materiality: QUALIFYING
      description: >-
        The model assumes that expressing human TLR8 at transgenic levels in a mouse is
        equivalent to a hypersensitive human TLR8 in a subset of human myeloid cells. The
        equivalence is between quantity of normal receptor and quality of abnormal
        receptor, and this entry's own conformational-gain hypothesis argues those are
        different lesions.
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model's quantity is fatal anaemia in a whole animal. The node's quantity is
        blocked EPO receptor signalling in erythroid progenitors. The model reports the
        outcome and not the mechanism, and reaches it by a myeloid route rather than the
        erythroid-intrinsic one the node describes.
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        A lupus-prone inbred background is not the genetic context of these patients, and
        the phenotype requires it. No anaemia is reported from the human TLR8 transgene
        alone.
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "a recent study that crossed transgenic mice expressing human TLR8 with lupus mice demonstrated that expression of human TLR8 in lupus mice induces fatal anemia via myeloid cell dysregulation,16 indicating a potential mechanism in our patients."
    explanation: >-
      The model and the authors' own reason for raising it, in one sentence. INDIRECT
      because the inference to the patients is theirs and is offered as potential.
clinical_trials:
- name: NCT04339777
  phase: PHASE_II
  status: RECRUITING
  description: >-
    A phase II allogeneic haematopoietic stem cell transplant protocol for inborn errors
    of immunity, on which one patient in the reported cohort (patient 8) was
    transplanted. It is not a TLR8-specific trial - the eligible population is primary
    immunodeficiency or primary immune regulatory disorder where standard management has
    failed or does not exist - which is the usual route to transplant for a disease with
    ten reported patients.
  target_phenotypes:
  - preferred_term: Severe refractory neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: clinicaltrials:NCT04339777
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To see if stem cell transplant can be successfully performed in people with primary immunodeficiency disease and cure them."
    explanation: The trial's stated objective, which is the intervention this entry curates as the only effective one.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 8 underwent HCT on a clinical trial (ClinicalTrials.gov identifier: NCT04339777)."
    explanation: The link between this trial and the cohort, naming the patient transplanted on it.
diagnosis:
- name: Targeted deep sequencing for low-variant-allele-fraction somatic TLR8 variants
  description: >-
    The diagnostic problem in this disease is not recognising the phenotype, it is
    detecting the variant. Eight of ten patients are somatic mosaics with peripheral
    blood variant allele fractions between 7 and 26 per cent, and a germline exome or
    genome pipeline calling at standard heterozygous thresholds will filter those out.
    The authors state the remedy directly: a high index of suspicion, and targeted deep
    sequencing when standard analysis is negative.

    Two details change the threshold for reaching for it. In female patients the
    fraction is expected to be lower still, because there are two X chromosomes to
    dilute it - which is precisely the group least likely to be suspected in what was
    described as a male disease. And a negative blood test does not exclude the
    diagnosis, since the mosaicism has been found in skin fibroblasts as well.
  diagnosis_term:
    preferred_term: targeted deep sequencing
    term:
      id: NCIT:C101293
      label: Next Generation Sequencing
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A high index of suspicion is necessary, as somatic mutations may be missed on standard exome and genome analysis, especially in female patients where VAFs may be lower due to the presence of 2 X chromosomes."
    explanation: The reason standard sequencing fails here, and the group it fails hardest in.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alternative methodologies to identify variants, such as targeted deep sequencing, may be required."
    explanation: The recommended alternative, stated by the authors as a methodology rather than a suggestion.
  - reference: PMID:36119097
    reference_title: "Gain-of-function defects in toll-like receptor 8 shed light on the interface between immune system and bone marrow failure disorders."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "This not only has repercussions for the diagnostic workup of these disorders, inasmuch that routine genetic testing may miss somatic variants, but has therapeutic implications as well, for example, with the approach to curative treatment, such as hematopoietic stem cell transplantation."
    explanation: >-
      The same problem stated from the review literature, and generalized: TLR8 gain of
      function is one of a growing set of disorders caused by both germline and somatic
      variants, for which routine testing is systematically blind.
- name: Bone marrow biopsy with immunophenotyping
  description: >-
    The marrow is where this disease looks like itself: myeloid hypoplasia to
    agranulocytosis with predominantly CD8-positive T-cell infiltrates or aggregates,
    and in half the cohort CD8-positive CD57-positive large granular lymphocytes. No
    patient showed dysplasia, which matters because the differential includes marrow
    failure syndromes that do.

    The finding to be careful with is the negative one. The first reported female
    patient had myeloid predominance with erythroid hypoplasia and lacked the inverted
    CD4:CD8 ratio and memory skewing seen in the others, and the authors say plainly
    that absent characteristic findings do not exclude the diagnosis. So the biopsy
    supports the diagnosis and cannot rule it out.
  diagnosis_term:
    preferred_term: bone marrow biopsy
    term:
      id: NCIT:C15193
      label: Bone Marrow Biopsy
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients had marked myeloid hypoplasia to agranulocytosis, and the presence of predominantly CD8+ T-cell lymphoid infiltrates or aggregates."
    explanation: The characteristic marrow picture.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no evidence of dysplasia on any of the bone marrow biopsies."
    explanation: >-
      A negative that does diagnostic work: it separates this from the myelodysplastic
      end of the marrow-failure differential.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Nevertheless, the absence of characteristic findings on bone marrow biopsy and immune phenotyping does not preclude a diagnosis of TLR8 GOF."
    explanation: >-
      Evidence against treating the biopsy as a rule-out test. Recorded as REFUTE against
      that use of it, not against its value when positive.
treatments:
- name: Allogeneic Hematopoietic Cell Transplantation
  description: >-
    The only intervention shown to resolve the disease. Seven of ten reported patients
    were transplanted; five are surviving at one to three years with full donor
    myeloid and T-cell chimerism and resolution of the phenotype. The counterfactual is
    stark - both patients who presented in childhood and were not transplanted died of
    the disease. It is not a benign option: post-transplant cytopenia of unclear
    aetiology and graft-versus-host disease were both common.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: TLR8 Gain-of-Function Variant
    description: >-
      Replacing the haematopoietic compartment removes the mutant clone from blood and
      marrow. Note that it does not remove it from other tissues, since the mosaicism
      extends to fibroblasts - so this addresses the compartment that produces the
      disease rather than the variant itself.
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients are surviving at 1 to 3 years after HCT with full donor myeloid and T-cell chimerism, and resolution of disease phenotype."
    explanation: The efficacy result, with chimerism as the mechanistic correlate of the clinical resolution.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High rates of post-HCT cytopenia of unclear etiology and graft-versus-host disease were observed."
    explanation: The toxicity side of the same cohort, recorded so the treatment is not read as straightforwardly successful.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 2 patients who presented during childhood and did not undergo HCT ultimately died from disease."
    explanation: The untransplanted outcome, which is what makes the case for transplantation despite its toxicity.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although this hypothesis is unproven, it may be prudent to avoid high-dose busulfan for patients with TLR8 GOF due to concerns for increased risk of chemotherapy-related toxicity."
    explanation: >-
      The conditioning recommendation, which is the one piece of actionable detail on
      how to do this transplant rather than whether to. Note the authors' own hedge -
      the mechanism they propose for it, that TLR8-GOF tissue-resident cells surviving
      conditioning are primed to over-respond to tissue injury, is unproven.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, the patient (patient 2) who received high-dose busulfan developed severe VOD and multisystem organ failure after HCT followed by secondary graft failure."
    explanation: >-
      The single case behind the recommendation. One patient, which is why it is recorded
      as prudence rather than as a contraindication.
- name: Granulocyte Colony-Stimulating Factor and Corticosteroids
  description: >-
    Recorded because they do not work. Both are standard for the presentations this
    disease mimics - chronic neutropenia and immune-mediated cytopenia - and the
    neutropenia is refractory to both. That refractoriness is a diagnostic signal as
    much as a therapeutic failure.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: filgrastim
      term:
        id: NCIT:C1474
        label: Filgrastim
  target_mechanisms:
  - target: Myeloid Hypoplasia and Bone Marrow Failure
    description: >-
      Both agents act on the marrow failure node, and both fail there - which locates
      the problem upstream of anything a growth factor or a broad immunosuppressant
      can reach.
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The neutropenia was refractory to granulocyte-colony stimulating factor (G-CSF) and corticosteroids, and 3 patients underwent allogeneic hematopoietic cell transplant (HCT)."
    explanation: >-
      Direct evidence against these agents as treatments for this disease. Recorded as
      REFUTE rather than omitted because "tried and failed" is a finding a curator or a
      clinician needs, and because the refractoriness is itself diagnostically useful.
- name: TLR8 Inhibition
  description: >-
    Preclinical, and the evidence now comes from two directions that need separating.

    In patient cells. Three inhibitors were tested in iPSC-derived macrophages carrying
    the p.P432L variant, the commonest one in this disease. Chloroquine, which raises
    endosomal pH, and CPG-52364, a small-molecule TLR7/8 inhibitor, both suppressed IL-6
    production from the gain-of-function receptor. CU-CPT9a did not: it inhibited
    wild-type TLR8 and the p.P432L cells were resistant to it. That split is
    informative beyond the drug screen, because CU-CPT9a works by binding TLR8 in its
    inactive conformation - so a variant that resists it is a variant that is not
    spending its time in that conformation, which is what the conformational-gain
    hypothesis in this entry predicts.

    In other erythroid systems. TLR8 inhibition also improves erythropoiesis in
    RPS19-haploinsufficient cells and in CD34-positive cells from healthy donors and
    from patients with inherited non-haemolytic anaemia. That work was done in the
    context of inherited anaemia rather than in TLR8 gain-of-function patients, so it
    supports the erythroid arm by analogy rather than directly.

    Neither line has reached a patient. There are no clinical data for any TLR8
    inhibitor in this disease, and the one endosomal-signalling inhibitor that was given
    to a patient - hydroxychloroquine, in one case - had no effect on the neutrophil
    count.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: TLR8-Driven Blockade of EPO Signaling in Erythroid Progenitors
    description: >-
      Inhibition acts on the receptor node directly, which is the one point in the
      erythroid arm upstream of the STAT5 mislocalisation.
  evidence:
  - reference: PMID:38971858
    reference_title: "Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TLR8 inhibition improves erythropoiesis in RPS19+/- HuDEP2 cells and CD34+ cells from healthy donors and inherited non-hemolytic anemic patients."
    explanation: >-
      The rescue result. Note the cell systems named are not from TLR8 gain-of-function
      patients, which is the limitation recorded in the description.
  - reference: PMID:38971858
    reference_title: "Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia."
    explanation: The authors' own framing of the therapeutic implication as something to explore rather than established.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CHQ and CPG-52364 both inhibited IL-6 production by macrophages expressing WT and GOF TLR8 (Figure 2H-I)."
    explanation: >-
      The positive result, and the only inhibitor data generated in cells carrying a
      disease-causing TLR8 variant rather than in a surrogate system.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "The results demonstrate that CU-CPT9a inhibited WT TLR8 activity, but cells with the p.P432L variant were resistant to CU-CPT9a treatment (Figure 2G)."
    explanation: >-
      Evidence against one of the three agents specifically. Recorded as REFUTE rather
      than omitted because a selective TLR8 inhibitor that fails on the disease variant
      is exactly what a reader reaching for this strategy needs to know.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Hydroxychloroquine, which is thought to inhibit endosomal TLR signaling,10 was also trialed in 1 patient, again without effect."
    explanation: >-
      The one time an endosomal TLR inhibitor reached a patient in this cohort. A single
      case, and negative, which is why the description calls the strategy preclinical
      despite the in vitro results above.
- name: Immunoglobulin Replacement
  description: >-
    Given to the six of ten patients with hypogammaglobulinemia. Unlike the other
    medical therapies in this entry it is not being tried against the neutropenia; it
    replaces a deficiency the disease produces, and the cohort report records it as
    administered rather than as trialled. It does nothing for the marrow failure.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Impaired B-Cell Maturation
    description: >-
      Substitutes exogenous antibody for the antibody the impaired B-cell compartment
      cannot produce. It is pure replacement: the maturation defect is untouched.
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients had hypogammaglobulinemia requiring immunoglobulin replacement."
    explanation: The therapy and its indication in one sentence, in six of ten patients.
- name: Sirolimus, Mycophenolate Mofetil and JAK Inhibitors
  description: >-
    Recorded for the same reason G-CSF and corticosteroids are: they were tried and
    none of them worked. Sirolimus in four patients, mycophenolate mofetil in two, JAK
    inhibitors in two, all without response, and a further patient received
    azathioprine, methotrexate, cyclophosphamide and rituximab over three to four
    months with no improvement in neutrophil count.

    The pattern is the finding. These agents span mTOR, purine synthesis, JAK-STAT and
    B-cell depletion, and the neutropenia is indifferent to all of them. That is what
    makes transplantation the only intervention in this entry with a positive result,
    and it is a substantive claim about where the lesion sits rather than a list of
    disappointments.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
  target_mechanisms:
  - target: Excess NF-kB-Dependent Cytokine Production
    description: >-
      All of these are aimed, directly or indirectly, at the inflammatory output of this
      node. Their uniform failure is evidence that suppressing the output downstream does
      not reach the receptor-level lesion that generates it.
  evidence:
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Other therapies that were trialed in >1 patient included sirolimus (n = 4), mycophenolate mofetil (n = 2), and JAK inhibitors (n = 2), all without response."
    explanation: >-
      Direct evidence against three drug classes in this disease, with the numbers
      treated. Recorded as REFUTE for the same reason the G-CSF entry is.
  - reference: PMID:41370196
    reference_title: "Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient received alemtuzumab for suspected evolving T-cell LGL leukemia, and 1 patient received azathioprine, methotrexate, cyclophosphamide, and rituximab therapy for 3 to 4 months with no improvement in neutrophil count."
    explanation: >-
      The single-patient failures, including the one given four agents in sequence. Kept
      with the multi-patient failures above because the claim is about the class of
      approach rather than about any one drug.
notes: >-
  Why this is a Disease entry and not a line in a TLR-signalling module. The
  combination of immunodeficiency with autoinflammation from a single sensor's gain
  of function, arising predominantly as a somatic mosaic, is a specific pathograph
  rather than an instance of a general pattern. The erythroid arm is a second,
  independently characterised mechanism from the same receptor.

  On the somatic variant_origin. The pathophysiology's initiating node carries
  variant_origin: SOMATIC because that is the majority molecular mechanism - eight of
  ten patients. Germline variants are also reported, including in the first female
  patient, and the disease is the same. The slot is single-valued, so the majority
  case is recorded there and the germline route is described in the inheritance and
  genetic blocks.

  Evidence that this entry deliberately records as negative. Granulocyte
  colony-stimulating factor and corticosteroids are curated as a treatment with
  REFUTE evidence rather than left out, because their failure is a diagnostic signal
  and because a reader looking for what to try should find out here that those were
  tried. The same applies to the transplant toxicity, which is recorded alongside the
  efficacy rather than after it.

  Why there is no knock-in mouse. TLR8 ligand recognition is species-specific: the
  antiviral compound R848 activates the human receptor but not the rodent one, and the
  sequence variation responsible localises to LRR14-15. A mouse carrying the homologous
  substitution would therefore not be sensing the same things, which is a stronger
  objection than the usual mouse-versus-human caveat. The divergence is not confined to
  the receptor either: TIRAP is recruited to the TLR8-MyD88 complex in human monocytes
  and not to MyD88 in mouse macrophages, and human IRAK-2 is required for TLR8-driven
  NF-kB activation where the mouse knockout said it was not. Both are curated on the
  adaptor node.

  The objection is to a knock-in, and the humanised route gets around it, so the
  animal_models section is not empty: a human TLR8 transgenic crossed onto a lupus
  background is curated there, with fidelity LOW and the reasons stated. It is a real
  model of a converging phenotype rather than a model of this disease, and the earlier
  version of this note overstated the absence by not distinguishing the two routes.

  The patient-derived iPSC myeloid differentiation in the founding paper remains the
  system that carries the weight, and it is curated on the sensor node.

  What is thin. This disease was first described in 2021 and the literature is a
  founding cohort, an expanded cohort that contains it, and a small number of single
  cases. Several claims here rest on ten patients or fewer, and two phenotypes
  (autoimmune myelofibrosis, pure red cell aplasia) rest on one patient each and are
  flagged as such in their own descriptions.
📚

References & Deep Research

References

3
PMID:33512449
Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.
No top-level findings curated for this source.
PMID:41370196
Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function.
No top-level findings curated for this source.
PMID:36119097
Gain-of-function defects in toll-like receptor 8 shed light on the interface between immune system and bone marrow failure disorders.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review round 1: address all eight blocking findings and four suggestions on PR #11799 · 2026-09-13T22:46:27Z · View source

Addressed the ai4c-reviewer CHANGES_REQUESTED review on PR #11799 in a single push. The reviewer's root-cause diagnosis was right: PMID_41370196 is a full-text cache with Tables 1 and 2, and the entry was quoting only its abstract. Snippets went from 45 to 86. Finding 1, omitted phenotypes. Added hypogammaglobulinemia, lymphadenopathy, splenomegaly, oral ulcers and CD8+/CD57+ large granular lymphocytes. The reviewer's suggested HP:0002720 for hypogammaglobulinemia is wrong: that term is Decreased circulating IgA concentration. Bound HP:0004313 Decreased circulating immunoglobulin concentration instead, which carries Hypogammaglobulinemia as an exact synonym, verified against OLS. LGLs have no HPO term. Bound the HP:0004332 Abnormal lymphocyte morphology parent with the immunophenotype in preferred_term and a review_notes recording that NCIT:C12921 exists but is a cell type rather than a phenotypic abnormality and cannot fill an HP-rooted slot. Finding 2, bundled cytopenias. Split into Thrombocytopenia (HP:0001873, universal at 10 of 10, severity MODERATE, with the paper's own platelet-count band definitions as a second evidence item) and Anemia (HP:0001903, 5 mild-moderate and 3 severe). Finding 3, TLR8 inhibition. Rewrote the description around the inhibitor experiment in patient p.P432L iPSC-derived macrophages. Chloroquine and CPG-52364 inhibited the GOF receptor; CU-CPT9a did not, and that failure is curated as REFUTE. Added the CU-CPT9a result and the inhibitor's stated binding mode as INDIRECT support on the conformational_gain_not_receptor_gain hypothesis, since an inhibitor that binds the inactive conformation failing on the variant is what that hypothesis predicts. Also added the single-patient hydroxychloroquine failure as REFUTE. Finding 4, no diagnosis section. Added two entries: targeted deep sequencing for low-VAF somatic variants, citing the authors' high-index-of-suspicion statement, the lower-VAF-in-females detail and the alternative-methodologies sentence, plus PMID:36119097 generalizing the problem; and bone marrow biopsy with immunophenotyping, including the no-dysplasia negative that separates this from the myelodysplastic differential, and a REFUTE item against using the biopsy as a rule-out test. Finding 5, missing treatments. Added immunoglobulin replacement (6 of 10 patients, NCIT:C62710) and a combined entry for sirolimus, mycophenolate mofetil and JAK inhibitors with REFUTE evidence, plus the single-patient azathioprine/methotrexate/cyclophosphamide/rituximab failure. Added the busulfan-avoidance recommendation and the patient-2 VOD case to the HCT entry. Finding 6, wrong hotspot. Rewrote genetic.notes around p.P432 (8 of 10 patients: 6 p.P432L, plus novel p.P432Q and p.P432R), with three new evidence items including the functional validation showing neither novel allele is constitutively active. Recorded in an explanation that the deep-research report names Phe494/Gly572 from ClinVar and the primary literature disagrees, so the report is not followed. Finding 7, clinical trial. Fetched NCT04339777 and added a clinical_trials entry, noting it is a general inborn-errors-of-immunity transplant protocol rather than a TLR8-specific trial. Finding 8, no animal model. Added the human TLR8 transgenic crossed onto a lupus background, with relationship PARTIALLY_RECAPITULATES, fidelity LOW, and three typed divergences: CONTESTED_ASSUMPTION (transgenic quantity of normal receptor is not the same lesion as a hypersensitive one), PROXY_QUANTITY (fatal anaemia in a whole animal versus blocked EPO signalling in erythroid progenitors, reached by a myeloid route), and POPULATION_MISMATCH (the lupus background is required). Narrowed the notes claim from 'no animal model' to 'no knock-in mouse' and stated that the earlier version overstated the absence. Suggestion 9, adaptor step. Added a TIRAP-MyD88 Adaptor Assembly and IRAK Activation pathophysiology node between the sensor and the cytokine output, citing PMID:41159953 and PMID:21606490. Both carry a second species divergence one step below ligand recognition, which strengthens the entry's no-mouse argument rather than restating it. The node's description records that the gain-of-function claim there is inferred rather than measured in patient cells. Inserting the node produced a duplicate evidence key on the sensor node's downstream edge; the pre-existing evidence item was re-homed onto the new adaptor-to-cytokine edge rather than deleted, and the explanation records the move. Suggestion 10, cell-extrinsic lean. Rewrote the low_vaf_mosaic_sufficiency description to record the authors' stated position rather than presenting the two accounts as equally open, including the clean form of the argument for the lymphoid arm (T and B cells do not express TLR8), and the named candidate intermediates for the edge left as INDIRECT_UNKNOWN_INTERMEDIATES. Suggestion 11, reference consumption. PMID:36119097, PMID:41159953 and PMID:21606490 are now cited. Suggestion 12, references block. Confirmed by PubMed esearch that no GeneReviews chapter exists for TLR8 or immunodeficiency 98, and added a top-level references block with the founding cohort, the expanded cohort and the interface-disorders review. Validation: schema, term and reference validation all pass; snippets verified 86/86 (was 45/45). All nine offline gates run. Cache diff is additive: two term rows, two enum rows, a full-text upgrade to PMID_36119097, and the new NCT cache file.

Create: Immunodeficiency_98_With_Autoinflammation (MONDO:0024777) · 2026-09-13T21:55:16Z · View source

De novo curation of TLR8 gain-of-function disease (IMD98 / INFLTR8). Deep research: one openscientist report, committed alongside. Report reference validation resolved 13/13 citations with confabulation_rate 0.0 and 13/13 quotes valid; term validation returned needs_review: true on 7 label mismatches, all table-parsing artefacts. just preflight-dr returns PASS with OMIM agreement (301078 on both sides) and TLR8 mentioned 81 times. Worth recording that the report's relevance metric reads on_topic 4 of relevance_assessed 13 with off_topic null and no off_topic_references, so nine references are undecided rather than off topic; that is the accounting gap issue #9339 describes, and it would be a misreading to treat the low on_topic count as a relevance failure. No GeneReviews chapter exists for this disease; the PubMed search was run and returned nothing, which is expected for a disease first described in 2021. The entry models two mechanistically separate arms from the same receptor: the myeloid NF-kB/cytokine arm producing marrow failure, lymphoproliferation and the B-cell defect, and an erythroid-intrinsic arm in which TLR8 activation blocks annexin A2-mediated STAT5 membrane localisation and disrupts EPO signalling. Three mechanistic_hypotheses blocks: how a somatic clone at 7-26 per cent variant allele fraction produces full disease, and whether gain of function here is conformational stabilisation of the active homodimer rather than more receptor - the A518T allele signals more from less protein, since it turns over faster. Granulocyte colony-stimulating factor and corticosteroids are curated as a treatment with REFUTE evidence rather than omitted, because their failure is diagnostically useful. No animal_models section: TLR8 ligand recognition is species-specific and R848 does not activate the rodent receptor, which is recorded in notes as the reason rather than left as an absence. One error of my own was caught by the reference validator: a reference_title completed from a truncated search listing as 'a hypothetical model' where the cached title says 'a hypothesis'. Validation: schema, term and reference checks pass with 45/45 snippets verified; all five offline gates pass.

OpenScientist ▸
Key Findings
openscientist-autonomous 7 citations 2026-09-13T21:09:35.190292

Key Findings

Finding 1 — IMD98 is an X-linked dominant disorder caused by TLR8 gain-of-function variants

The founding study (Aluri et al., 2021) identified six unrelated males with a shared syndrome of neutropenia, recurrent infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure, all carrying one of three different variants in the X-linked gene TLR8. Critically, five of the six patients carried somatic (mosaic) variants with less than 30 % mosaicism, establishing a dominant disease mechanism operating even at low variant allele burden. All identified variants conferred gain of function.

"We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8)." — PMID: 33512449

"5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype" — PMID: 33512449

The 2026 expansion (Arnold et al.) broadened the phenotype to 10 patients and, importantly, described the first female patient, who presented during infancy with pure red cell aplasia due to a germline TLR8 variant. Peripheral-blood VAF ranged from 7–26 %, and onset spanned 9 months to 28 years. The female germline case, together with the predominance of affected males and the dominant behavior of low-VAF mosaic variants, is consistent with X-linked dominant inheritance.

"We identify the first female patient with TLR8 GOF who presented during infancy with pure red cell aplasia due to a germ line TLR8 variant" — PMID: 41370196

Finding 2 — TLR8 is an endosomal ssRNA sensor signaling via MyD88/NF-κB; GOF causes constitutive proinflammatory signaling

TLR8 is a pattern-recognition receptor localized to the endosome that senses degradation products of single-stranded RNA. Crystallographic work (Tanji et al., 2013, 2015) demonstrated that TLR8 is a leucine-rich-repeat horseshoe that exists as a preformed dimer; agonist binding at two distinct sites reorganizes the dimer so that the two C-terminal TIR domains are brought into proximity, enabling downstream signaling.

"Upon ligand stimulation, the TLR8 dimer was reorganized such that the two C termini were brought into proximity." — PMID: 23520111

"TLR8 recognized two degradation products of ssRNA—uridine and a short oligonucleotide—at two distinct sites" — PMID: 25599397

In IMD98, GOF variants confer increased or constitutive responsiveness. Aluri et al. showed that patient iPSC-derived myeloid cells had increased responsiveness to TLR8 stimulation and a proinflammatory phenotype, with activated T cells, elevated serum cytokines, and impaired B-cell maturation — directly linking TLR8 GOF to the autoinflammatory and immune-dysregulatory clinical picture.

"immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation" — PMID: 33512449

Finding 3 — Clinical phenotype: refractory neutropenia, marrow myeloid hypoplasia, LGL expansion, lymphoproliferation; HCT is curative

Arnold et al. (2026, n = 10) provide the most detailed natural-history and management data. All patients had neutropenia, most severe and refractory to medical therapy; anemia and thrombocytopenia were common. Bone marrow characteristically demonstrated severe myeloid hypoplasia and activated T-cell infiltrates and/or aggregates. An increased number of large granular lymphocytes (LGLs) was identified in 5 of 10 patients. Eight patients had somatic mosaicism (VAF 7–26 %), and onset ranged from 9 months to 28 years.

"All patients had neutropenia, most with severe neutropenia refractory to medical therapy. Anemia and thrombocytopenia were common. Bone marrow characteristically demonstrated severe myeloid hypoplasia and activated T-cell infiltrates and/or aggregates." — PMID: 41370196

"An increased number of large granular lymphocytes (LGLs) was identified in 5 patients." — PMID: 41370196

Prognosis is grave without definitive therapy, but allogeneic HCT is curative. Seven patients underwent transplant with high rates of post-HCT cytopenia and GVHD; five are surviving 1–3 years post-HCT with full donor chimerism and phenotype resolution. The two childhood-onset patients who did not undergo HCT died of disease.

"Five patients are surviving at 1 to 3 years after HCT with full donor myeloid and T-cell chimerism, and resolution of disease phenotype. The 2 patients who presented during childhood and did not undergo HCT ultimately died from disease." — PMID: 41370196

Finding 4 — Specific TLR8 GOF variants (e.g., A518T) stabilize the active dimer and enhance NF-κB-driven cytokine secretion

Skenteris et al. (2026) characterized a novel hemizygous missense variant, A518T, in two male siblings with recurrent infections and systemic inflammation. Functional studies confirmed the GOF mechanism at the signaling level: the variant enhanced NF-κB activation and increased proinflammatory cytokine secretion versus wild-type upon stimulation. Computational modeling provided a structural rationale — the substitution introduces additional water-mediated hydrogen bonds that stabilize the active TLR8 homodimer interface. Interestingly, protein assays showed reduced mutant abundance due to faster turnover/proteasomal degradation, indicating the GOF is not simply a consequence of increased protein levels but of altered signaling per molecule.

"Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect." — PMID: 41729082

"Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution." — PMID: 41729082

Broader X-chromosome immunology literature (Miquel et al., 2023) places these observations in context: TLR7 and TLR8, encoded at the Xp locus, are causal in sex-biased autoimmunity via gene-dosage effects or gain-of-function mutations.

Finding 5 — Mouse TLR8 is a poor model; human downstream signaling uses MyD88-TIRAP-IRAK-IRF5/NF-κB

A recurring theme with therapeutic and experimental implications is that mouse TLR8 does not faithfully model human TLR8. Although rodent and non-rodent TLR8 primary sequences are similar, the antiviral compound R848 that activates the TLR8 pathway is species-specific, with sequence variation concentrated near the ligand-binding site (LRR14–15).

"The primary sequences of rodent and non-rodent TLR8s are similar, but the antiviral compound (R848) that activates the TLR8 pathway is species-specific." — PMID: 21949866

Human TLR8 signals through a TIRAP-MyD88 complex that drives IRAK1/Akt/IKK activity and IRF5 dimerization for IRF5-regulated cytokines (IFNβ, IL-12); this TIRAP requirement is not recapitulated in mouse. Human IRAK-2 (which, unlike mouse, has no inhibitory splice variants) is required for TLR8-mediated NF-κB/p38 activation and TNF induction. Tissue-expression studies further show TLR8 protein strongly expressed in human but essentially undetectable in mouse pancreatic islets.

"P7-Pen failed to inhibit murine TLR7 responses, which correlated with a lack of TIRAP recruitment to MyD88 in mouse macrophages" — PMID: 41159953

Finding 6 — ClinVar catalogs recurrent pathogenic TLR8 variants at hotspot codons Phe494 and Gly572

ClinVar (transcript NM_138636.5) curates several disease-associated TLR8 variants to "Immunodeficiency 98 with autoinflammation, X-linked," revealing mutational hotspots:

Variant (protein) cDNA ClinVar classification Notes
p.Leu433Phe c.1299G>C Pathogenic
p.Phe494Tyr c.1481T>A Likely pathogenic Hotspot codon 494
p.Phe494Leu c.1482C>A Pathogenic Hotspot codon 494
p.Gly572Val c.1715G>T Pathogenic Condition: autoimmune hemolytic anemia; systemic autoinflammation
p.Gly572Asp c.1715G>A Pathogenic Hotspot codon 572
p.Glu133fs c.396del Likely pathogenic Frameshift
p.Ser31Pro / p.Gln110Glu / p.Pro432Leu — VUS Uncertain significance

Recurrent substitutions at Phe494 and Gly572 indicate mutational hotspots. TLR8 has 314 total ClinVar records, including large Xp deletions unrelated to IMD98.

Finding 7 — TLR8 is strongly constrained against missense variation in gnomAD

gnomAD (GRCh38) constraint metrics for TLR8 (ENSG00000101916; NCBI 51311; HGNC:15632; chrX:12,906,620–12,923,169; Xp22.2) support a pathogenic missense/GOF mechanism:

  • Missense Z-score = 3.49 (strong missense constraint; observed/expected = 0.71, 90 % CI 0.66–0.76)
  • LoF pLI = 0.92, oe_lof = 0.27 (observed 5 vs expected 18.5 LoF variants)

The IMD98 pathogenic variants (Leu433Phe, Phe494Tyr/Leu, A518T, Gly572Val/Asp) are private/ultra-rare and absent or vanishingly rare in gnomAD — consistent with severe, highly penetrant GOF alleles under strong negative selection.

Finding 8 — Verified disease identifiers and cross-references

Per EBI OLS4 (MONDO ontology) for MONDO:0024777 "immunodeficiency 98 with autoinflammation, X-linked":

Resource Identifier
MONDO MONDO:0024777
OMIM 301078
Orphanet 675628
Disease Ontology (DOID) 0061068
GARD 0027130
MedGen C1805285 (UID 1805285)
UMLS C5676883
Gene TLR8 · HGNC:15632 · ENSG00000101916 · NCBI Gene 51311 · Xp22.2

Synonyms: IMD98; X-linked immunodeficiency with autoinflammation; "inflammation, neutropenia, bone marrow failure, and lymphoproliferation caused by TLR8."

Section-by-Section Report

1. Disease Information

IMD98 is a rare monogenic inborn error of immunity that manifests as a combined bone-marrow-failure + autoinflammation syndrome. Onset of recurrent infections with lymphoproliferation and autoinflammation typically occurs in the first decade of life; mostly males are affected, and carrier females may have mild symptoms. Immune dysregulation includes hypogammaglobulinemia and reduced memory B cells, skewed T-cell subsets, increased proinflammatory cytokines, activated T cells and monocytes, and autoimmune cytopenias including neutropenia. Identifiers are listed in Finding 8. Information is derived from aggregated disease-level resources (OMIM, Orphanet, MONDO) and individual-patient case series (Aluri 2021; Arnold 2026; Skenteris 2026) rather than EHR-scale data — the disease is ultra-rare (≈16 reported patients total across the primary literature).

2. Etiology

Causal factor: monogenic — gain-of-function missense variants in TLR8. Variants arise as germline (including the first female case) or, more commonly, low-level somatic mosaic events (VAF ~7–30 %). Genetic risk factors: hemizygous male sex (single X); recurrent hotspot variants at Phe494 and Gly572; other pathogenic alleles Leu433Phe and A518T. Modifier genes: none formally established; downstream signaling components (MyD88, TIRAP, IRAK1/2, IRF5) are mechanistic candidates. Environmental risk/protective factors and gene–environment interactions: none established; TLR8 endogenous ligands are ssRNA degradation products, and infection-associated RNA could plausibly amplify signaling, but this is not demonstrated. No protective alleles are described.

3. Phenotypes

Phenotype Type HPO suggestion Frequency / notes
Neutropenia (severe, refractory) Lab abnormality HP:0001875 / HP:0000823 All patients (10/10 Arnold)
Anemia Lab abnormality HP:0001903 Common
Thrombocytopenia Lab abnormality HP:0001873 Common
Bone marrow myeloid hypoplasia Lab/histology HP:0005528 (BMF) Characteristic
Recurrent infections Symptom HP:0002719 Core feature
Lymphoproliferation Clinical sign HP:0002732 / HP:0002716 Core feature
Increased large granular lymphocytes Lab abnormality — 5/10
Hypogammaglobulinemia / reduced memory B cells Lab abnormality HP:0002720 Present
Systemic autoinflammation / elevated cytokines Lab/symptom HP:0002090-adjacent Present
Autoimmune cytopenias (e.g., AIHA, pure red cell aplasia) Lab abnormality HP:0001890 Present; PRCA in female germline case

Onset: first decade in most, but range 9 months–28 years. Severity: severe and often refractory. Progression: progressive without treatment, frequently fatal. QoL impact: substantial — recurrent infections, transfusion/G-CSF dependence, marrow failure, and transplant morbidity.

4. Genetic / Molecular Information

Causal gene: TLR8 (HGNC:15632; Xp22.2). Pathogenic variants: missense predominate (Leu433Phe, Phe494Tyr/Leu, A518T, Gly572Val/Asp) plus a likely-pathogenic frameshift (Glu133fs); classifications per ACMG/ClinVar range from Pathogenic to VUS (Finding 6). Allele frequency: private/ultra-rare, absent or vanishingly rare in gnomAD (Finding 7). Somatic vs germline: both — most patients mosaic (VAF 7–30 %), minority germline. Functional consequence: gain of function via stabilization of the active dimer (Findings 2, 4). Modifier genes / epigenetics / chromosomal abnormalities: not established for IMD98 (note: large Xp deletions in ClinVar are unrelated to this GOF disease).

5. Environmental Information

No environmental, lifestyle, or infectious causal agents are established. TLR8's physiologic ligands are ssRNA degradation products (uridine + short oligonucleotides), so RNA from infections is a plausible but unproven amplifier of GOF signaling. The disease is fundamentally genetically determined.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. A germline or somatic mosaic GOF missense variant in TLR8 (e.g., Phe494, Gly572, Leu433Phe, A518T) arises → leads to an amino-acid substitution in the endosomal TLR8 ectodomain/dimer interface.
  2. The substitution stabilizes the active TLR8 homodimer (demonstrated computationally and functionally for A518T; inferred structurally for hotspot residues) → results in increased/constitutive receptor activation independent of, or hypersensitive to, ssRNA ligand.
  3. Active TLR8 dimer brings the two C-terminal TIR domains into proximity → recruits the TIRAP–MyD88 adaptor complex (human-specific requirement).
  4. MyD88 → activates IRAK1/IRAK2 → IKK/NF-κB and IRF5 dimerization → drives transcription of proinflammatory cytokines.
  5. Excess cytokine output → produces systemic autoinflammation, activated T cells and monocytes, and (branch A) marrow suppression → severe refractory neutropenia, myeloid hypoplasia, anemia, thrombocytopenia; and (branch B) immune dysregulation → impaired B-cell maturation, hypogammaglobulinemia, reduced memory B cells, lymphoproliferation, LGL expansion, autoimmune cytopenias.
  6. Untreated → progresses to bone marrow failure and death (inferred from fatal untreated childhood cases); replacing the mutant hematopoietic compartment by allogeneic HCT → resolves the phenotype.

Molecular pathways: endosomal TLR → MyD88/TIRAP → IRAK → NF-κB (GO:0034163 regulation of TLR8 signaling; GO:0043123 positive regulation of NF-κB) and IRF5. Cellular processes: inflammation, myeloid differentiation arrest, T-cell activation. Protein dysfunction: GOF via dimer-interface stabilization. Immune involvement: simultaneous immunodeficiency (humoral defect) and autoinflammation. Cell types (CL): neutrophils/myeloid progenitors (CL:0000775 / CL:0000037 HSC), T cells (CL:0000084), monocytes (CL:0000576), large granular lymphocytes/NK-T. Subcellular compartment: endosome (GO:0005768).

7. Anatomical Structures Affected

Primary organ: bone marrow (UBERON:0002371) and the hematopoietic/immune system (UBERON:0002390 / UBERON:0000178 blood). Secondary: lymphoid organs — spleen and lymph nodes (lymphoproliferation; UBERON:0002106, UBERON:0000029). Body system: hematopoietic/immune. Tissue/cell level: myeloid lineage (hypoplasia), activated T-cell infiltrates, LGLs, B cells (impaired maturation). Subcellular: endosomal membrane (TLR8 localization). Lateralization: systemic/bilateral (not focal).

8. Temporal Development

Onset: pediatric in most (first decade), range 9 months–28 years; germline female case in infancy. Pattern: chronic-progressive with autoinflammatory features; refractory to standard therapy. Course: progressive marrow failure and infection; often fatal without HCT. Remission: treatment-induced (transplant), with full donor chimerism and phenotype resolution; no spontaneous remission described. Critical period: early definitive treatment (HCT) before irreversible marrow failure/complications.

9. Inheritance and Population

Inheritance: X-linked dominant. Predominantly affected males (hemizygous); the first female patient had a germline variant with infantile presentation; carrier females may be mildly symptomatic. Somatic mosaic variants behave dominantly even at low VAF. Penetrance/expressivity: high penetrance in males; variable expressivity/onset. Epidemiology: ultra-rare — ~16 patients in the literature; true prevalence/incidence unknown (not quantified in registries). Founder effects/consanguinity: none (mostly de novo/mosaic). Carrier frequency: not established. Sex ratio: strongly male-predominant.

10. Diagnostics

Genetic testing is definitive, but must account for somatic mosaicism: deep next-generation sequencing (high read depth) of TLR8 on peripheral blood and, ideally, on affected tissue (bone marrow/sorted myeloid cells) is required, because low-VAF variants can be missed by standard germline WES/panels. Recommended approach: targeted TLR8 sequencing / IEI-BMF gene panels with high-depth NGS and mosaicism-aware variant calling; WES/WGS with careful low-VAF analysis. Supporting labs: CBC (neutropenia, anemia, thrombocytopenia), bone marrow biopsy (myeloid hypoplasia, activated T-cell infiltrates, LGLs), immunoglobulins (hypogammaglobulinemia), B-cell memory subsets, cytokine profiling, T-cell activation markers. Functional confirmation: NF-κB reporter / cytokine-secretion assays in HEK293 or patient iPSC-derived myeloid cells demonstrate GOF. Differential diagnosis: other IEI/BMF "interface disorders," severe congenital neutropenia, T-LGL leukemia, autoimmune lymphoproliferative syndrome, other autoinflammatory syndromes; UNC93B1-GOF (which enhances TLR7/TLR8 signaling causing SLE/chilblain lupus, PMID 38869500) is a mechanistically related differential.

11. Outcome / Prognosis

Without treatment: poor — the two untreated childhood-onset patients died of disease. With allogeneic HCT: curative in the majority — 5 of 7 transplanted patients surviving 1–3 years with full donor myeloid and T-cell chimerism and resolution of phenotype, though with high rates of post-HCT cytopenia and GVHD. Prognostic factors: early definitive therapy; transplant-related complications are the main threat to survival after HCT. Morbidity: transfusion/growth-factor dependence, infection burden, transplant morbidity.

12. Treatment

  • Definitive/curative: allogeneic hematopoietic cell transplantation (NCIT: Allogeneic Hematopoietic Stem Cell Transplantation) — the only established cure; replaces the mutant hematopoietic compartment.
  • Supportive: G-CSF (variable response; neutropenia often refractory), transfusions, antimicrobial prophylaxis, immunoglobulin replacement for humoral defect.
  • Immunomodulation / precision candidates (rational, mechanism-based): because signaling flows through TLR8 → MyD88 → IRAK → NF-κB/IRF5, targeted inhibition (e.g., IRAK inhibitors, JAK inhibitors for cytokine-driven inflammation, or TLR7/8 antagonists / TIRAP-MyD88 inhibitors such as the P7-Pen tool compound, PMID 41159953) is a plausible bridge-to-transplant or steroid-sparing strategy — investigational only.
  • Pharmacogenomics/gene therapy/RNA therapy: none established.

13. Prevention

No primary prevention exists for a de novo/mosaic monogenic GOF disorder. Secondary prevention: early genetic diagnosis (mosaicism-aware sequencing) enables timely HCT before irreversible marrow failure. Genetic counseling: recurrence risk is generally low for somatic mosaic/de novo variants but non-negligible for germline cases (X-linked dominant); counseling and, where a germline variant is identified, cascade/prenatal testing are appropriate. Tertiary prevention: infection prophylaxis and transplant-complication management.

14. Other Species / Natural Disease

No naturally occurring animal disease equivalent is described. Comparative genomics shows TLR8 is broadly conserved across mammals, yet human and mouse TLR8 diverge functionally (species-specific R848 responsiveness and downstream TIRAP requirement; Finding 5), and TLR8 protein is strongly expressed in human but not mouse pancreatic islets. Orthologs exist (mouse Tlr8, NCBI Gene 170744) but do not model the human GOF disease. No zoonotic or cross-species transmission (non-infectious genetic disease).

15. Model Organisms

Mouse is a poor model for reasons above. The principal experimental systems are: (1) patient iPSC-derived myeloid cells, which recapitulate increased TLR8 responsiveness and the proinflammatory phenotype; and (2) HEK293 NF-κB reporter assays transfected with WT vs mutant TLR8 to quantify GOF (used for A518T and other variants). These capture the signaling GOF and cytokine output but do not fully reproduce the in vivo marrow-failure/lymphoproliferation phenotype. Humanized or knock-in models are not established and would need to address human-specific TLR8 ligand recognition and TIRAP-dependent signaling.

Mechanistic Model / Interpretation

 TLR8 GOF missense variant (germline or somatic mosaic, VAF ~7–30%)
   │  hotspots: Phe494, Gly572; also Leu433Phe, Ala518Thr
   ▼
 Stabilized ACTIVE TLR8 homodimer in the endosome
   │  (extra water-mediated H-bonds at dimer interface; A518T shown)
   ▼
 C-terminal TIR domains juxtaposed → TIRAP–MyD88 recruitment (human-specific)
   ▼
 IRAK1/IRAK2 → IKK/NF-κB  +  IRF5 dimerization
   ▼
 Excess proinflammatory cytokines / systemic autoinflammation
   ├──────────────► Branch A: Bone marrow suppression
   │                 → severe refractory neutropenia, myeloid hypoplasia,
   │                   anemia, thrombocytopenia, activated-T/LGL marrow infiltrates
   └──────────────► Branch B: Immune dysregulation
     → impaired B-cell maturation, hypogammaglobulinemia,
       reduced memory B cells, lymphoproliferation,
       autoimmune cytopenias (e.g., PRCA, AIHA)
   ▼
 Untreated → progressive BMF → death
 Allogeneic HCT → replace mutant hematopoietic compartment → phenotype resolves

Upstream vs downstream: the mutation and dimer stabilization are the upstream drivers; NF-κB/IRF5-driven cytokine excess is the central node; marrow failure and humoral defects are downstream manifestations. The mosaic-yet-dominant behavior implies that even a minority of hematopoietic cells bearing the GOF allele can drive a systemic inflammatory milieu sufficient to suppress normal marrow — explaining why HCT (eliminating the mutant clone) is curative.

Evidence Base

PMID Title (abbrev.) Role in this report
33512449 Immunodeficiency and bone marrow failure with mosaic and germline TLR8 GOF Founding cohort; gene discovery; mosaicism; GOF; proinflammatory phenotype (F1, F2)
41370196 Clinical characteristics, management, and HCT of patients with TLR8 GOF Expanded cohort (n=10); phenotype, LGLs, HCT outcomes, first female (F1, F3)
41729082 Structural modeling and functional characterization of a novel GOF TLR8 variant A518T functional + structural GOF evidence (F4)
23520111 Structural reorganization of the TLR8 dimer by agonists Activation mechanism GOF dysregulates (F2)
25599397 TLR8 senses degradation products of ssRNA TLR8 ligand biology (F2)
21949866 Species-specific ligand recognition in TLR8 Mouse is a poor model (F5)
41159953 TIRAP-MyD88 inhibitor blocks TLR7/8 IFN responses Human-specific TIRAP-MyD88-IRF5 pathway; species difference (F5)
21606490 Human IRAK-2 essential for TLR-mediated TNF regulation Human IRAK-2 requirement in TLR8 signaling (F5)
28028829 Localization of nucleic-acid-sensing TLRs in human/mouse pancreas TLR8 human vs mouse expression difference (F5)
36119097 GOF defects in TLR8 — interface disorders Framing as BMF/IEI interface disorder; diagnostics/therapeutics
36641351 Influence of X chromosome in sex-biased autoimmune diseases TLR7/8 Xp locus causal via dosage/GOF (F4 context)
38869500 GOF UNC93B1 variants cause SLE/chilblain lupus Mechanistically related TLR7/8 hyperactivation; differential dx
27742543 TLR7 dual receptor structure Comparative structural context for TLR7/8 activation

Evidence source types: human clinical (33512449, 41370196), in vitro functional/structural (41729082, 23520111, 25599397, 21606490, 41159953), comparative/computational (21949866, 28028829, 36641351). Ontology cross-references (MONDO/OMIM/Orphanet/DOID/GARD/MedGen/UMLS) and constraint metrics (gnomAD) are from curated databases (Findings 6–8).

Limitations and Knowledge Gaps

  • Small n. The entire evidence base rests on ~16 reported patients across three primary case series; prevalence, incidence, penetrance, and full phenotypic spectrum remain uncertain.
  • Registry-level epidemiology absent. No cases-per-100,000 estimates; the disease is too new and rare.
  • Mosaicism complicates diagnosis and prevalence estimation — low-VAF cases are likely under-ascertained by standard testing.
  • No faithful animal model. Species-specific TLR8 biology means in vivo mechanistic and preclinical therapeutic studies are constrained to human cell/iPSC systems.
  • Variant-level genotype–phenotype correlation (e.g., whether Phe494 vs Gly572 vs A518T differ in severity or onset) is not yet defined.
  • Non-transplant targeted therapies (IRAK/JAK/TLR8 inhibitors) are rational but unproven in this disease.
  • Modifier genes, epigenetics, and environmental triggers are unstudied.

Proposed Follow-up Experiments / Actions

  1. Establish an international IMD98/TLR8-GOF registry to define natural history, genotype–phenotype correlations, and true epidemiology, with standardized deep-sequencing (mosaicism-aware) diagnostic protocols.
  2. Systematic functional characterization of all reported and future TLR8 variants in a uniform NF-κB reporter + cytokine-secretion + dimer-stability platform (extending the A518T approach) to build an ACMG-grade functional evidence resource.
  3. Preclinical testing of targeted signal-pathway inhibitors (IRAK1/4 inhibitors, JAK inhibitors, TIRAP-MyD88 or TLR8 antagonists) in patient iPSC-derived myeloid cells as bridge-to-transplant / steroid-sparing candidates.
  4. Develop a humanized TLR8 knock-in mouse (accounting for human ligand recognition and TIRAP dependence) to model marrow failure/lymphoproliferation in vivo.
  5. Single-cell multi-omics of patient marrow to map the mutant-clone-driven inflammatory circuit and identify the cell populations mediating myeloid suppression.
  6. Optimize HCT protocols to reduce the high post-transplant cytopenia and GVHD rates observed in the cohort.
  7. Prospective evaluation of biomarkers (cytokine signatures, activated-T/LGL burden, VAF dynamics) for diagnosis, prognosis, and treatment-response monitoring.

Report compiled from 9 confirmed findings and 18 reviewed papers over 5 investigation iterations. All mechanistic and clinical claims are cited to primary literature (PMIDs) or curated databases (ClinVar, gnomAD, EBI OLS4/MONDO).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 13
Quoted claims found in source 13
Quoted claims not found in source 0
References weighed for topical relevance 13
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 25
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 7
Terms named correctly 0
Terms named as a different term 7

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0024777 (3 mentions) - the report calls it "MONDO"; MONDO calls it immunodeficiency 98 with autoinflammation, X-linked
  • HP:0001903 (1 mention) - the report calls it "Lab abnormality"; HP calls it Anemia
  • HP:0001873 (1 mention) - the report calls it "Lab abnormality"; HP calls it Thrombocytopenia
  • HP:0005528 (1 mention) - the report calls it "BMF"; HP calls it Bone marrow hypocellularity
  • HP:0002719 (1 mention) - the report calls it "Symptom"; HP calls it Recurrent infections
  • HP:0002720 (1 mention) - the report calls it "Lab abnormality"; HP calls it Decreased circulating IgA concentration
  • HP:0001890 (1 mention) - the report calls it "Lab abnormality"; HP calls it Autoimmune hemolytic anemia