Immunodeficiency 15A

Mendelian MONDO:0032599 Pathograph 22 Show in embeddings browser Immunodeficiency Disease

Immunodeficiency 15A (IMD15A, OMIM 618204) is an autosomal dominant inborn error of immunity caused by heterozygous gain-of-function missense variants in IKBKB, which encodes IKK2 - the kinase that phosphorylates IkappaB-alpha and so releases NF-kappaB into the nucleus. The established disease alleles sit in the kinase domain; variants elsewhere in the protein have been reported in a patient with a different, autoinflammatory presentation and a different genotype, and are treated separately below. The direction is the surprising part. NF-kappaB drives lymphocyte activation, so more of it ought to mean more immunity; instead these patients are immunodeficient. Constitutive IKK2 activity uncouples NF-kappaB from receptor engagement, and lymphocyte development and selection depend on reading the difference between signal and baseline. Naive T cells from these patients hyperproliferate to a stimulus that normally moves few cells, yet far fewer cells survive the culture; B cells activate abnormally and fail to make immunoglobulin. The entry records the reconciliation of activation with deficiency as an open question rather than asserting one, because the defining study does the same. It is the mirror image of a disease caused by the same gene in the other direction: biallelic loss-of-function IKBKB variants cause IMD15B, a severe combined immunodeficiency with normal lymphocyte counts. Both directions produce immune deficiency by different cellular routes.

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1
Mappings
1
Inheritance
7
Pathophys.
13
Phenotypes
1
Gaps
22
Pathograph
1
Genes
1
Medical Actions
1
Differentials
2
Models
1
Deep Research
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Classifications

IUIS Category
combined immunodeficiency
🔗

Mappings

MONDO
MONDO:0032599 immunodeficiency 15a
skos:exactMatch MONDO
The entry curates exactly the MONDO concept, which cross-references OMIM:618204 and Orphanet:700205 and carries the causal gene relation to IKBKB.
👪

Inheritance

1
Autosomal dominant HP:0000006
A single heterozygous kinase-domain variant is sufficient. The founding kindreds carried a de novo variant; later families show transmission, with clinical severity varying widely between and within families.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (2 references)
PMID:30337470 SUPPORT Human Clinical
"The IKBKB mutation was not found in either parent, and after excluding nonpaternity with high confidence, we concluded that the mutation had arisen de novo in the proband."
Establishes the heterozygous, de novo origin of the founding IMD15A allele.
PMID:36378426 SUPPORT Human Clinical
"Heterozygous missense gain-of-function (GOF) variants in the same gene cause an autosomal dominant immunodeficiency disorder characterized by recurrent sinopulmonary infections, immune dysregulation, inflammation, epithelial defects, and lymphopenia"
States the autosomal dominant inheritance and the core clinical phenotype of the heterozygous gain-of-function disorder curated here.
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Discussions and Knowledge Gaps

1
How does a variant that increases NF-kappaB signalling - and demonstrably lowers the lymphocyte activation threshold - produce immune deficiency rather than autoimmunity or lymphoproliferation?
OPEN QUESTION OPEN activation_versus_deficiency_paradox
Attached to
pathophysiology#Lowered Lymphocyte Activation Threshold pathophysiology#Increased Regulatory T Cell Output
This is the central unresolved question of the disorder, and the paper that defined IMD15A names it as unresolved rather than settling it. Two candidate answers are on the table. The first is regulatory: FOXP3 is under canonical NF-kappaB control, regulatory T cells and per-cell FOXP3 are increased, and in the mouse the increase is already present in the thymus - so a hyperactivating allele might expand the suppressive compartment faster than the effector one. The second is attritional: patient cells proliferate more but end up fewer, so chronic hyperactivation may simply consume the naive pool. The two are not exclusive, and the evidence does not currently separate them. The regulatory explanation also has a counterexample within the founding report itself - one of the two probands had a late-onset combined immunodeficiency with normal regulatory T cells.
Show evidence (3 references)
PMID:30337470 SUPPORT Other
"In both human and mouse, we observed pathological immune activation, but this finding needs to be reconciled with clinical manifestation of mild immune deficiency."
The authors state the paradox explicitly and as unreconciled, which is why this is recorded as an open question rather than a mechanism.
PMID:30337470 SUPPORT Other
"One possible explanation is the increase in thymic T reg cells, observed in the mouse model, and increased FOXP3 expression in the proband."
The regulatory hypothesis, offered by the authors as one possibility. Graded OTHER rather than split: the sentence is a single interpretive claim that happens to cite a mouse observation and a human one together, so neither MODEL_ORGANISM nor HUMAN_CLINICAL describes it, and splitting it would mean quoting half a hypothesis.
PMID:30337470 SUPPORT Human Clinical
"Patient B.II.1, however, had a late-onset combined immunodeficiency alone and presented with normal T reg cells."
Supports the question remaining open, by cutting against the leading answer: one affected patient had the deficiency without the regulatory T cell expansion. `supports` here is scoped to the discussion's claim - that the reconciliation is unresolved - which this observation strengthens rather than contradicts.
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Pathophysiology

7
IKBKB Kinase Domain Gain-of-Function Variant
A heterozygous missense variant in the IKK2 kinase domain. The founding allele, p.Val203Ile, sits in the activating pocket at a residue conserved to Drosophila; p.Lys171Arg lies in the activation loop and p.Met65Thr has also been reported. The protein is expressed normally - what changes is that its kinase activity no longer waits for an upstream signal. p.Glu518Lys and p.Thr559Met are deliberately excluded from this node. They lie between the leucine-zipper and NEMO-binding regions rather than in the kinase domain, and were reported in trans in one patient, so they are neither the same protein region nor the same genotype as the dominant single-allele disease this node describes.
Genetic context IKBKB hgnc:5960 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns IKBKB (hgnc:5960). hgnc:5960 is a gene from the HUGO Gene Nomenclature Committee. allele_type: SNV variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Heterozygous germline missense variants in the IKK2 kinase domain, acting through increased kinase activity rather than loss of protein.
Downstream
Constitutive IkappaB-alpha Phosphorylation The variant kinase phosphorylates its substrate more, and for longer, than wild type at equal protein levels - and does so at rest as well as after stimulation.
Show evidence (4 references)
PMID:30337470 SUPPORT Human Clinical
"identified a novel heterozygous de novo IKBKB missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects"
Identifies the founding variant and the phenotype it segregates with in two independent kindreds.
PMID:30337470 SUPPORT In Vitro
"Valine 203 is conserved to at least Drosophila melanogaster (Fig. 1 d), is located within the active site of IKK2 (Fig. 1, e and f), on the second lobe of the kinase domain"
Locates the variant in the kinase active site and records its conservation, the structural basis for a gain-of-function effect.
PMID:40403933 SUPPORT Human Clinical
"Whole-exome sequencing revealed 2 gain-of-function variants in the IKBKB gene, of which one was a novel variant."
Extends the allelic series beyond the founding variant, supporting this node's description as a class of kinase-domain variants.
+ 1 more reference
Constitutive IkappaB-alpha Phosphorylation
IkappaB-alpha is phosphorylated at rest as well as after stimulation, so the brake that normally holds NF-kappaB in the cytoplasm is partially released all the time. In the mouse knock-in this is dose-dependent: homozygotes phosphorylate more than heterozygotes, and both more than wild type.
IkappaB kinase activity GO:0008384 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves IkappaB kinase activity (GO:0008384), qualified as gain of function. GO:0008384 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Animal models
Ikbkb V203I CRISPR knock-in mouse Mouse recapitulates Splenocytes show constitutive IkappaB-alpha phosphorylation at baseline and prolonged phosphorylation after stimulation, with homozygotes exceeding heterozygotes.
Downstream
Enhanced Canonical NF-kappaB Signalling
Show evidence (2 references)
PMID:30337470 SUPPORT Model Organism
"Analysis of isolated splenocytes revealed constitutive IκBα phosphorylation, with evidence of a gene dose effect: phosphorylation was greater in cells with homozygous mutation compared with heterozygotes, both at baseline"
Reports constitutive substrate phosphorylation and its allele-dose dependence in the knock-in mouse.
PMID:30337470 SUPPORT In Vitro
"we observed increased IκBα phosphorylation at baseline and after activation of PBMCs obtained from the proband"
The same resting-state phosphorylation in the patient's own cells, so this node does not rest on model-organism evidence alone.
Enhanced Canonical NF-kappaB Signalling
Downstream of the released brake, phospho-p65 rises and NF-kappaB-dependent transcription increases - measurably even in unstimulated cells, and more so after activation. The pathway is not merely more responsive; its resting set point has moved.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves canonical NF-kappaB signal transduction (GO:0007249), qualified as gain of function. GO:0007249 is a biological process from the Gene Ontology. ⇑ GAIN OF FUNCTION
Animal models
Ikbkb K171R knock-in mouse Mouse recapitulates The authors report that the mouse immunologic phenotype parallels the human one.
Downstream
Lowered Lymphocyte Activation Threshold
Increased Regulatory T Cell Output
Eczematoid dermatitis The autoinflammatory skin disease is attributed to the same pathway hyperactivation, but the cells and cytokines between the signalling change and the skin lesion are not established in this disorder. Drawn as an inferential edge rather than a direct one.
Show evidence (3 references)
PMID:30337470 SUPPORT In Vitro
"we observed increased phospho-p65, particularly in the T cell compartment, and an increase in abundance of phospho-p65 after activation out to 60 min"
Measures the NF-kappaB subunit phosphorylation this node describes, and locates the effect preferentially in T cells.
PMID:30337470 SUPPORT In Vitro
"Even in the absence of stimulation, IKBKBV203I resulted in enhanced luciferase activity compared to the WT allele, and this response was enhanced after TNF stimulation."
Shows the shifted resting set point - increased NF-kappaB-dependent transcription with no stimulus at all - which is the distinguishing claim of this node.
PMID:40403933 SUPPORT In Vitro
"Altered NF-κB signaling was evidenced by phosphoflow experiments."
Independent confirmation of altered NF-kappaB signalling in the larger patient cohort.
Lowered Lymphocyte Activation Threshold
Naive T cells respond to stimuli that normally move few cells, and proliferate more than control cells - but the cultures end up with far fewer cells, consistent with substantial death. Activation and attrition are the same phenomenon here, not competing ones.
Downstream
Naive T Cell Depletion
Impaired B Cell Differentiation
Show evidence (2 references)
PMID:30337470 SUPPORT In Vitro
"we stimulated cells with CD3 only (rather than CD2, CD3, and CD28), which normally induces only a small proportion of cells to enter cycle, and observed a substantial proliferative response in cells from the proband, but not in controls"
Demonstrates the reduced activation threshold directly: a deliberately weak stimulus produces a response only in patient cells.
PMID:30337470 SUPPORT In Vitro
"although we observed an enhanced proliferative response, there were far fewer cells present in cultures at time of analysis, consistent with substantial cell death"
The attrition that accompanies the enhanced response, and the link from hyperactivation to lymphocyte loss.
Naive T Cell Depletion
The naive compartment is preferentially lost in both CD4 and CD8 lineages, with a compensating shift toward effector and effector-memory phenotypes. The reservoir of cells able to respond to a new antigen shrinks, which is what makes this an immunodeficiency rather than an autoimmune disease.
CD4-positive, alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology. CD8-positive, alpha-beta T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
Animal models
Ikbkb V203I CRISPR knock-in mouse Mouse recapitulates Mutant mice show a relative and absolute deficiency of splenic T cells in both CD4 and CD8 compartments, again dose-graded.
Downstream
Decreased naive T cell proportion
Decreased total lymphocyte count
Combined immunodeficiency
Chronic mucocutaneous candidiasis Mucosal antifungal defence depends on T cell help; the intermediate steps between a depleted naive T cell pool and Candida susceptibility are not established in this disorder.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"Probands in both kindreds exhibited deficiencies of CD4+ and CD8+ T cells, with a significant reduction in naive T cells in both compartments"
Reports the naive-predominant T cell deficiency in both independent kindreds.
Impaired B Cell Differentiation
B cells sit on the same lowered threshold - unstimulated patient B cells show NF-kappaB phosphorylation comparable to CD40-stimulated controls - and then fail at the step that matters: they do not proliferate normally, do not make immunoglobulin, and do not accumulate a memory compartment or differentiate into plasmablasts.
memory B cell CL:0000787 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves memory B cell (CL:0000787). CL:0000787 is a cell type from the Cell Ontology.
Downstream
Decreased proportion of memory B cells
Decreased circulating immunoglobulin concentration
Decreased specific antibody response to vaccination
Combined immunodeficiency
Recurrent respiratory infections Failure to make specific antibody is the proximate cause of the sinopulmonary infection burden.
Show evidence (3 references)
PMID:30337470 SUPPORT In Vitro
"B cells failed to proliferate normally and exhibited a defect in immunoglobulin production after CD40 or CpG stimulation"
The functional B cell failure this node asserts, measured against two independent stimuli.
PMID:30337470 SUPPORT Human Clinical
"The probands were also found to exhibit a significant deficiency of memory B cells (Freiburg class Ib)"
Reports the memory B cell deficiency that follows from the differentiation block.
PMID:40403933 SUPPORT In Vitro
"Although still normal in their proliferative capacity, B and T cells show defective activation at day 3 (CD70, CD25, and CD40L expression) and impaired B-cell differentiation into plasmablasts."
Independent cohort evidence for the differentiation block, and a useful nuance: this series found proliferative capacity preserved while activation and plasmablast differentiation failed.
Increased Regulatory T Cell Output
Regulatory T cells and FOXP3 expression per cell are increased, and in the mouse the increase is already present in the thymus, implying it arises during development rather than as a peripheral response. FOXP3 is itself under canonical NF-kappaB control, which makes this a direct consequence of the pathway change rather than a coincidence. It is the leading candidate explanation for how a hyperactivating variant produces deficiency - see the open question recorded in `discussions`.
Show evidence (3 references)
PMID:30337470 SUPPORT Model Organism
"A similar increase in T reg cells was observed within thymus of mutant mice, suggesting that the defect arises during T reg cell development"
Places the regulatory T cell increase in the thymus, supporting a developmental rather than reactive origin.
PMID:30337470 SUPPORT Other
"FOXP3 expression is known to be regulated by canonical NF-κB signaling"
Supplies the mechanistic link from the pathway change to the regulatory T cell phenotype. Graded OTHER because it is the authors summarising established literature, not an observation made in their patients.
PMID:30337470 SUPPORT Human Clinical
"The proband exhibited an increase in circulating T reg cells."
The human observation behind this node, so the claim does not rest on the mouse alone.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 15A Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Blood 5
Decreased total lymphocyte count HP:0001888 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total lymphocyte count (HP:0001888). HP:0001888 is a phenotype from the Human Phenotype Ontology.
No frequency band is asserted. The two available series disagree by design rather than by conflict - one reports fixed lymphopenia in a single kindred, the other an age-dependent decline across four - so any single band would misdescribe one of them.
Show evidence (2 references)
PMID:30337470 SUPPORT Human Clinical
"Initial cellular analysis of peripheral blood mononuclear cells (PMBCs) isolated from the proband and both children revealed lymphopenias."
Reports lymphopenia across three affected members of one kindred.
PMID:40403933 SUPPORT Human Clinical
"While lymphocyte cell numbers are generally normal at young ages, most adult patients exhibit strongly reduced B- and T-cell numbers."
Establishes that the lymphopenia is age-dependent, which is why no frequency band is set for this phenotype.
Decreased naive T cell proportion HP:0031397 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased naive T cell proportion (HP:0031397). HP:0031397 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"Probands in both kindreds exhibited deficiencies of CD4+ and CD8+ T cells, with a significant reduction in naive T cells in both compartments"
Reports the naive T cell reduction in both CD4 and CD8 lineages.
Decreased proportion of memory B cells Decreased memory B cell proportion HP:0030374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased memory B cell proportion (HP:0030374). HP:0030374 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"The probands were also found to exhibit a significant deficiency of memory B cells (Freiburg class Ib)"
Reports the memory B cell deficiency, classified by Freiburg criteria.
Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"He was noted to have hypogammaglobulinemia at age 18 yr and subcutaneous abscesses at age 28 yr."
Hypogammaglobulinaemia in the second kindred's proband.
Autoimmune hemolytic anemia HP:0001890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune hemolytic anemia (HP:0001890). HP:0001890 is a phenotype from the Human Phenotype Ontology.
Attributed to this disorder with less confidence than the infection phenotype, for three compounding reasons. The reported infant carried two IKBKB variants in trans - E518K from the mother, T559M from the father, both parents asymptomatic - so the genotype is compound heterozygous rather than the dominant single allele that defines IMD15A. Only T559M behaved as gain-of-function when transduced into Jurkat cells; E518K showed no significant change. And both variants lie between the leucine-zipper and NEMO-binding regions rather than in the kinase domain where the established disease alleles sit.
Show evidence (1 reference)
PMID:36378426 SUPPORT Human Clinical
"Beginning at 6 weeks of age, he developed recurrent self-limiting episodes of rash, fever, and auto-immune hemolytic anemia (AIHA)."
Names autoimmune haemolytic anaemia directly, which is the phenotype bound here; the paper's summary sentence says "autoimmune cytopenias", a genus that also covers the anti-neutrophil antibodies it reports.
Ear 1
Recurrent otitis media HP:0000403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent otitis media (HP:0000403). HP:0000403 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"The proband had two children (aged 2 and 5 yr), and both suffered with recurrent otitis media and sinusitis, but no inflammation or ectodermal dysplasia."
Recurrent otitis media in the two affected children of the first proband, and a useful illustration of the intrafamilial variability recorded under inheritance.
Immune 5
Combined immunodeficiency HP:0005387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Combined immunodeficiency (HP:0005387). HP:0005387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects"
Names the combined T and B cell deficiency in both founding kindreds.
Recurrent respiratory infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Sequelae: Bronchiectasis Recurrent otitis media
Show evidence (2 references)
PMID:36378426 SUPPORT Human Clinical
"cause an autosomal dominant immunodeficiency disorder characterized by recurrent sinopulmonary infections, immune dysregulation, inflammation, epithelial defects, and lymphopenia"
Lists recurrent sinopulmonary infection among the defining features of the dominant gain-of-function disorder.
PMID:30337470 SUPPORT Human Clinical
"a 33-yr-old male proband with a history of recurrent respiratory infections, otitis media, and tonsillitis since childhood"
The second kindred's presenting infection history.
Decreased specific antibody response to vaccination HP:0032140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased specific antibody response to vaccination (HP:0032140). HP:0032140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"she had mild hypogammaglobulinemia and defective specific antibody responses to pneumococcal vaccination"
Records the defective vaccine response alongside only mild hypogammaglobulinaemia.
Eczematoid dermatitis HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eczematoid dermatitis (HP:0000964). HP:0000964 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"a patient who presented with recurrent respiratory tract infections, severe and atypical eczema, dental abnormalities consistent with ectodermal dysplasia (without conical teeth), hidradenitis suppurativa and subcutaneous abscesses, mucocutaneous candidiasis, and premature cataracts"
The founding proband's presentation, which includes the eczema recorded here.
Chronic mucocutaneous candidiasis HP:0002728 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic mucocutaneous candidiasis (HP:0002728). HP:0002728 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"hidradenitis suppurativa and subcutaneous abscesses, mucocutaneous candidiasis, and premature cataracts"
Mucocutaneous candidiasis in the founding proband, indicating a defect in mucosal antifungal defence alongside the bacterial susceptibility.
Integument 1
Ectodermal dysplasia HP:0000968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ectodermal dysplasia (HP:0000968). HP:0000968 is a phenotype from the Human Phenotype Ontology.
No frequency is asserted. The evidence is two independently ascertained patients; that establishes the association without supporting a band.
Show evidence (2 references)
PMID:32554083 SUPPORT Human Clinical
"We identified in an adult with ectodermal dysplasia and immunodeficiency a germline, gain-of-function mutation, K171R, in IKBKB."
An IKBKB gain-of-function patient ascertained through the combination of ectodermal dysplasia and immunodeficiency.
PMID:30337470 SUPPORT Human Clinical
"dental abnormalities consistent with ectodermal dysplasia (without conical teeth)"
The founding proband's ectodermal finding, named as such, in a second independently ascertained patient.
Respiratory 1
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30337470 SUPPORT Human Clinical
"Further investigations revealed bronchiectasis (Fig. 1 c) and hepatosplenomegaly (Table S1)."
Reports bronchiectasis in the second kindred's proband.
🧬

Genetic Associations

1
IKBKB
Gene: IKBKB hgnc:5960 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IKBKB (hgnc:5960). hgnc:5960 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant
Show evidence (4 references)
PMID:30337470 SUPPORT In Vitro
"IKBKB encodes IKK2, which activates NF-κB signaling. IKK2V203I results in enhanced NF-κB signaling, as well as T and B cell functional defects."
States the gene-disease relationship and the direction of the functional effect.
PMID:30337470 SUPPORT INDIRECT Other
"two instances of the same mutation arising as a somatic variant in brain tumors have been reported (Fukumura et al., 2016). Consistent with our findings, this somatic variant was reported to confer gain of function."
Independent, non-germline corroboration that this exact substitution is activating.
PMID:40403933 SUPPORT Human Clinical
"Genetic variants (p.V203I and p.M65T) in the patients were identified by whole-exome sequencing."
Sources the p.Met65Thr allele recorded in the series above.
+ 1 more reference
💊

Medical Actions

1
Immunoglobulin Replacement Therapy
Action: intravenous immunoglobulin therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intravenous immunoglobulin therapy (NCIT:C121331). NCIT:C121331 is a clinical intervention from the NCI Thesaurus. Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331
Agent: human immunoglobulin G NCIT:C80829 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses human immunoglobulin G (NCIT:C80829). NCIT:C80829 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Prophylactic immunoglobulin for the antibody defect. Reported in one gain-of-function patient started at 9 months, with improvement in skin disease and in the frequency of febrile autoimmune flares, and withdrawn at age 3 when he proved to have neither an infectious history nor hypogammaglobulinaemia. That single course is the extent of the published IMD15A treatment experience - see the entry `notes`.
Mechanism Target:
Impaired B Cell Differentiation — Replaces the antibody the patient's own B cells fail to produce. It substitutes for the failed output; it does not correct the differentiation block.
Target Phenotypes: Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36378426 SUPPORT Human Clinical
"He was started on prophylactic intravenous immunoglobulin (IVIG) 0.5 g/kg infusions at 9 months for infection prophylaxis given his history and genetic findings suggestive of combined immunodeficiency in the literature"
The one published account of immunoglobulin replacement in an IKBKB gain-of-function patient, including the dose and the indication.
🔬

Diagnosis

1
Exome or gene-panel sequencing with functional confirmation
There is no screening test and no characteristic routine-laboratory signature - counts can be normal in childhood - so the diagnosis is made by sequencing in a patient investigated for unexplained antibody or combined deficiency. Because gain-of-function missense variants are not self-evidently pathogenic, reported cases have been confirmed functionally, by NF-kappaB reporter assay or phospho-flow showing increased pathway activity.
Show evidence (2 references)
PMID:40403933 SUPPORT Human Clinical
"Genetic variants (p.V203I and p.M65T) in the patients were identified by whole-exome sequencing."
The sequencing route by which reported patients were diagnosed.
PMID:40403933 SUPPORT In Vitro
"An NF-κB reporter assay was performed to investigate NF-κB activity."
The functional confirmation step used to establish that a candidate variant is gain-of-function.
📈

Progression

1
Progression to combined immunodeficiency in adulthood
The immune defect is not static. Lymphocyte numbers are generally normal in childhood and fall in adults, so a patient can look immunologically unremarkable early and meet criteria for combined immunodeficiency decades later. This is why the disorder is missed: the diagnostic features accumulate after the age at which inborn errors are usually sought.
Show evidence (2 references)
PMID:40403933 SUPPORT Human Clinical
"While lymphocyte cell numbers are generally normal at young ages, most adult patients exhibit strongly reduced B- and T-cell numbers."
Directly reports the age-dependent decline in lymphocyte numbers that defines this phase.
PMID:40403933 SUPPORT Human Clinical
"These findings coincide with autoinflammatory skin manifestations, systemic infections with progressive lymphopenia, and potentially fatal diseases occurring later in life."
Records the late-onset severity, including fatal outcomes, that makes the progressive course clinically consequential.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population estimate exists. The published experience is 16 patients from 4 unrelated families in the largest series, plus scattered single cases, so the count is recorded rather than a rate and no numeric band is asserted. ULTRA_RARE is the qualitative tier, which the schema defines by threshold rather than by magnitude and pairs explicitly with CASES_IN_LITERATURE; it presupposes no numeric estimate, so recording it is not in tension with declining a rate.
Show evidence (1 reference)
PMID:40403933 SUPPORT Human Clinical
"We describe the clinical heterogeneity in 16 patients from 4 unrelated families with missense variants in the kinase domain of IKK2 encoded by IKBKB."
The largest reported cohort, and the basis for describing this as an ultra-rare disorder known from a handful of families.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 15A:

Immunodeficiency 15B
Overlapping Features The same gene in the opposite direction: biallelic loss-of-function IKBKB variants, causing a severe combined immunodeficiency of infancy. The cellular phenotype is the mirror image - where IMD15A lowers the activation threshold and depletes naive cells, IMD15B leaves lymphocytes numerically normal but frozen in a naive, unresponsive state.
Distinguishing Features
  • Biallelic loss of function rather than heterozygous gain of function
  • Onset in infancy rather than progression across decades
  • Lymphocytes numerically normal but almost exclusively naive, with absent regulatory and gamma-delta T cells
  • Normal T-cell receptor excision circles, so newborn TREC screening does not detect it
Show evidence (3 references)
PMID:24369075 SUPPORT Human Clinical
"All patients carried a homozygous duplication--c.1292dupG in exon 13 of IKBKB, which encodes IκB kinase 2 (IKK2, also known as IKKβ)--leading to loss of expression of IKK2, a component of the IKK-nuclear factor κB (NF-κB) pathway."
Establishes the loss-of-function mechanism that distinguishes IMD15B from the gain-of-function disorder curated here.
PMID:24369075 SUPPORT Human Clinical
"The patients had hypogammaglobulinemia or agammaglobulinemia, and their peripheral-blood B cells and T cells were almost exclusively of naive phenotype. Regulatory T cells and γδ T cells were absent."
The mirror-image cellular phenotype: naive-frozen lymphocytes with absent regulatory T cells, against IMD15A's naive depletion and increased regulatory T cells.
PMID:30391351 SUPPORT Human Clinical
"T-cell receptor excision circles were normal, meaning newborn screening by TREC analysis would miss IKBKB cases."
Normal T-cell receptor excision circles mean the newborn TREC screen that detects most severe combined immunodeficiencies does not pick up IMD15B. No TREC data have been reported for IMD15A, so no claim is made about the screen's behaviour in this entry's disease.
🐁

Animal Models

2
Ikbkb V203I CRISPR knock-in mouse
Built specifically to test causation for the human allele: the orthologous codon change was introduced into mouse Ikbkb by CRISPR/Cas9, so the mouse carries the same amino acid substitution as the patients rather than a convenient approximation. Heterozygotes and homozygotes were born at expected Mendelian ratios, and phenotypes are graded by allele dose.
Species
Mouse
Genotype
Ikbkb p.Val203Ile knock-in (heterozygous and homozygous)
Publication
PMID:30337470
Pathograph links
Constitutive IkappaB-alpha Phosphorylation recapitulates fidelity: high observes: molecular Splenocytes show constitutive IkappaB-alpha phosphorylation at baseline and prolonged phosphorylation after stimulation, with homozygotes exceeding heterozygotes.
Limitations: The published characterisation emphasises young animals at baseline; whether the model reproduces the decades-long progressive course seen in adult patients has not been reported.
Readouts
Splenocyte phospho-IkappaB-alpha to total IkappaB-alpha ratio
Direction: INCREASED
Interpretation: Biochemical correlate of unregulated IKK2 activity, graded by allele dose.
Show evidence (1 reference)
PMID:30337470 SUPPORT Model Organism
"Analysis of isolated splenocytes revealed constitutive IκBα phosphorylation, with evidence of a gene dose effect: phosphorylation was greater in cells with homozygous mutation compared with heterozygotes, both at baseline"
Reports the measurement behind this readout.
Show evidence (1 reference)
PMID:30337470 SUPPORT Model Organism
"Mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes."
The authors' own assessment of fidelity, and the basis for the HIGH rating on this link.
Naive T Cell Depletion recapitulates fidelity: moderate observes: cellular Mutant mice show a relative and absolute deficiency of splenic T cells in both CD4 and CD8 compartments, again dose-graded.
Limitations: The compartment shift is not identical to the human one. Humans lose naive T cells specifically; mice show an increase in the CD44+CD62L-low effector subset, which is the mouse counterpart of the same redistribution rather than the same measurement. The mouse also loses CD8 cells preferentially, which the human data do not show.
Readouts
Splenic CD3+ T cell proportion and absolute count
Direction: DECREASED
Interpretation: Peripheral T cell deficiency matching the human lymphopenia.
Show evidence (1 reference)
PMID:30337470 SUPPORT Model Organism
"we observed that mice heterozygous and homozygous for IkbkbV203I exhibited a relative deficiency of T cells"
Reports the T cell deficiency measured in this model.
Show evidence (1 reference)
PMID:30337470 SUPPORT Model Organism
"In mice, we observed greater reduction in CD8+ T cells (Fig. 4 g)."
Supports the model's T cell phenotype while recording the CD8 bias that distinguishes it from the human presentation.
Show evidence (1 reference)
PMID:30337470 SUPPORT Model Organism
"to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in Ikbkb using CRISPR/Cas9"
Establishes what this model is and why it was made - an orthologous knock-in built to prove causation for the human variant.
Ikbkb K171R knock-in mouse
A second orthologous knock-in, for the activation-loop allele rather than the active-site one. Its value is corroborative: two independently reported human alleles, in different parts of the kinase, each modelled in mouse, each reproducing the human immune phenotype.
Species
Mouse
Genotype
Ikbkb p.Lys171Arg knock-in
Publication
PMID:32554083
Pathograph links
Enhanced Canonical NF-kappaB Signalling recapitulates fidelity: moderate observes: organism The authors report that the mouse immunologic phenotype parallels the human one.
Limitations: The available description is a brief abstract, so which specific immunological features were compared, and how closely, cannot be read off the record. The fidelity rating is held at MODERATE for that reason rather than because a discrepancy was reported.
Show evidence (1 reference)
PMID:32554083 SUPPORT Model Organism
"The K171R mouse immunologic phenotype parallels human, suggesting IKBKB K171R underlies a novel immunodeficiency syndrome."
The authors' assessment that this model reproduces the human immune phenotype for the activation-loop allele.
{ }

Source YAML

click to show 
name: Immunodeficiency 15A
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
description: >
  Immunodeficiency 15A (IMD15A, OMIM 618204) is an autosomal dominant inborn
  error of immunity caused by heterozygous gain-of-function missense variants
  in IKBKB, which encodes IKK2 - the kinase that phosphorylates
  IkappaB-alpha and so releases NF-kappaB into the nucleus. The established
  disease alleles sit in the kinase domain; variants elsewhere in the protein
  have been reported in a patient with a different, autoinflammatory
  presentation and a different genotype, and are treated separately below.

  The direction is the surprising part. NF-kappaB drives lymphocyte
  activation, so more of it ought to mean more immunity; instead these
  patients are immunodeficient. Constitutive IKK2 activity uncouples
  NF-kappaB from receptor engagement, and lymphocyte development and
  selection depend on reading the difference between signal and baseline.
  Naive T cells from these patients hyperproliferate to a stimulus that
  normally moves few cells, yet far fewer cells survive the culture; B cells
  activate abnormally and fail to make immunoglobulin. The entry records the
  reconciliation of activation with deficiency as an open question rather
  than asserting one, because the defining study does the same.

  It is the mirror image of a disease caused by the same gene in the other
  direction: biallelic loss-of-function IKBKB variants cause IMD15B, a
  severe combined immunodeficiency with normal lymphocyte counts. Both
  directions produce immune deficiency by different cellular routes.
disease_term:
  preferred_term: immunodeficiency 15a
  term:
    id: MONDO:0032599
    label: immunodeficiency 15a
synonyms:
- IMD15A
- IKBKB gain-of-function combined immunodeficiency
- IKK2 gain-of-function immune deficiency
parents:
- Immunodeficiency Disease
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      IUIS phenotypic classification Table 1 (combined immunodeficiencies).
      IMD15A is a combined T and B cell defect, which is the basis for the
      assignment.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee."
      explanation: >-
        The IUIS classification this assignment is made against.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0032599
      label: immunodeficiency 15a
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >
      The entry curates exactly the MONDO concept, which cross-references
      OMIM:618204 and Orphanet:700205 and carries the causal gene relation
      to IKBKB.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >
    A single heterozygous kinase-domain variant is sufficient. The founding
    kindreds carried a de novo variant; later families show transmission,
    with clinical severity varying widely between and within families.
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The IKBKB mutation was not found in either parent, and after excluding nonpaternity with high confidence, we concluded that the mutation had arisen de novo in the proband."
    explanation: >
      Establishes the heterozygous, de novo origin of the founding IMD15A
      allele.
  - reference: PMID:36378426
    reference_title: "A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous missense gain-of-function (GOF) variants in the same gene cause an autosomal dominant immunodeficiency disorder characterized by recurrent sinopulmonary infections, immune dysregulation, inflammation, epithelial defects, and lymphopenia"
    explanation: >
      States the autosomal dominant inheritance and the core clinical
      phenotype of the heterozygous gain-of-function disorder curated here.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    No population estimate exists. The published experience is 16 patients
    from 4 unrelated families in the largest series, plus scattered single
    cases, so the count is recorded rather than a rate and no numeric band
    is asserted. ULTRA_RARE is the qualitative tier, which the schema
    defines by threshold rather than by magnitude and pairs explicitly with
    CASES_IN_LITERATURE; it presupposes no numeric estimate, so recording it
    is not in tension with declining a rate.
  evidence:
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the clinical heterogeneity in 16 patients from 4 unrelated families with missense variants in the kinase domain of IKK2 encoded by IKBKB."
    explanation: >
      The largest reported cohort, and the basis for describing this as an
      ultra-rare disorder known from a handful of families.
progression:
- phase: Progression to combined immunodeficiency in adulthood
  notes: >
    The immune defect is not static. Lymphocyte numbers are generally normal
    in childhood and fall in adults, so a patient can look immunologically
    unremarkable early and meet criteria for combined immunodeficiency
    decades later. This is why the disorder is missed: the diagnostic
    features accumulate after the age at which inborn errors are usually
    sought.
  evidence:
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While lymphocyte cell numbers are generally normal at young ages, most adult patients exhibit strongly reduced B- and T-cell numbers."
    explanation: >
      Directly reports the age-dependent decline in lymphocyte numbers that
      defines this phase.
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings coincide with autoinflammatory skin manifestations, systemic infections with progressive lymphopenia, and potentially fatal diseases occurring later in life."
    explanation: >
      Records the late-onset severity, including fatal outcomes, that makes
      the progressive course clinically consequential.
pathophysiology:
- name: IKBKB Kinase Domain Gain-of-Function Variant
  description: >
    A heterozygous missense variant in the IKK2 kinase domain. The founding
    allele, p.Val203Ile, sits in the activating pocket at a residue conserved
    to Drosophila; p.Lys171Arg lies in the activation loop and p.Met65Thr has
    also been reported. The protein is expressed normally - what changes is
    that its kinase activity no longer waits for an upstream signal.

    p.Glu518Lys and p.Thr559Met are deliberately excluded from this node.
    They lie between the leucine-zipper and NEMO-binding regions rather than
    in the kinase domain, and were reported in trans in one patient, so they
    are neither the same protein region nor the same genotype as the
    dominant single-allele disease this node describes.
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: IKBKB
      term:
        id: hgnc:5960
        label: IKBKB
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >
      Heterozygous germline missense variants in the IKK2 kinase domain,
      acting through increased kinase activity rather than loss of protein.
  downstream:
  - target: Constitutive IkappaB-alpha Phosphorylation
    causal_link_type: DIRECT
    description: >
      The variant kinase phosphorylates its substrate more, and for longer,
      than wild type at equal protein levels - and does so at rest as well as
      after stimulation.
    evidence:
    - reference: PMID:30337470
      reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "After stimulation with TNF, we observed increased and prolonged IκBα phosphorylation, despite similar levels of WT and mutant allele IKK2 expression"
      explanation: >
        Shows the variant allele driving more substrate phosphorylation at
        equal protein levels. This is the stimulated arm of the claim; the
        resting arm is the patient-PBMC baseline measurement cited below.
    - reference: PMID:30337470
      reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we observed increased IκBα phosphorylation at baseline and after activation of PBMCs obtained from the proband"
      explanation: >
        The resting arm, in the patient's own cells: substrate
        phosphorylation is elevated before any stimulus, which is what makes
        the effect receptor-uncoupled rather than merely exaggerated.
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a novel heterozygous de novo IKBKB missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects"
    explanation: >
      Identifies the founding variant and the phenotype it segregates with in
      two independent kindreds.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Valine 203 is conserved to at least Drosophila melanogaster (Fig. 1 d), is located within the active site of IKK2 (Fig. 1, e and f), on the second lobe of the kinase domain"
    explanation: >
      Locates the variant in the kinase active site and records its
      conservation, the structural basis for a gain-of-function effect.
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing revealed 2 gain-of-function variants in the IKBKB gene, of which one was a novel variant."
    explanation: >
      Extends the allelic series beyond the founding variant, supporting this
      node's description as a class of kinase-domain variants.
  - reference: PMID:32554083
    reference_title: "Heterozygous IKKβ activation loop mutation results in a complex immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified in an adult with ectodermal dysplasia and immunodeficiency a germline, gain-of-function mutation, K171R, in IKBKB."
    explanation: >
      A further germline gain-of-function allele, this one in the IKK2
      activation loop rather than the active site, in a patient whose
      presentation combines immunodeficiency with ectodermal features.
- name: Constitutive IkappaB-alpha Phosphorylation
  description: >
    IkappaB-alpha is phosphorylated at rest as well as after stimulation, so
    the brake that normally holds NF-kappaB in the cytoplasm is partially
    released all the time. In the mouse knock-in this is dose-dependent:
    homozygotes phosphorylate more than heterozygotes, and both more than
    wild type.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: IkappaB kinase activity
    term:
      id: GO:0008384
      label: IkappaB kinase activity
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: Enhanced Canonical NF-kappaB Signalling
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of isolated splenocytes revealed constitutive IκBα phosphorylation, with evidence of a gene dose effect: phosphorylation was greater in cells with homozygous mutation compared with heterozygotes, both at baseline"
    explanation: >
      Reports constitutive substrate phosphorylation and its allele-dose
      dependence in the knock-in mouse.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we observed increased IκBα phosphorylation at baseline and after activation of PBMCs obtained from the proband"
    explanation: >
      The same resting-state phosphorylation in the patient's own cells, so
      this node does not rest on model-organism evidence alone.
- name: Enhanced Canonical NF-kappaB Signalling
  description: >
    Downstream of the released brake, phospho-p65 rises and NF-kappaB-dependent
    transcription increases - measurably even in unstimulated cells, and more
    so after activation. The pathway is not merely more responsive; its
    resting set point has moved.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: GAIN_OF_FUNCTION
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  downstream:
  - target: Lowered Lymphocyte Activation Threshold
  - target: Increased Regulatory T Cell Output
  - target: Eczematoid dermatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The autoinflammatory skin disease is attributed to the same pathway
      hyperactivation, but the cells and cytokines between the signalling
      change and the skin lesion are not established in this disorder. Drawn
      as an inferential edge rather than a direct one.
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we observed increased phospho-p65, particularly in the T cell compartment, and an increase in abundance of phospho-p65 after activation out to 60 min"
    explanation: >
      Measures the NF-kappaB subunit phosphorylation this node describes,
      and locates the effect preferentially in T cells.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Even in the absence of stimulation, IKBKBV203I resulted in enhanced luciferase activity compared to the WT allele, and this response was enhanced after TNF stimulation."
    explanation: >
      Shows the shifted resting set point - increased NF-kappaB-dependent
      transcription with no stimulus at all - which is the distinguishing
      claim of this node.
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Altered NF-κB signaling was evidenced by phosphoflow experiments."
    explanation: >
      Independent confirmation of altered NF-kappaB signalling in the larger
      patient cohort.
- name: Lowered Lymphocyte Activation Threshold
  description: >
    Naive T cells respond to stimuli that normally move few cells, and
    proliferate more than control cells - but the cultures end up with far
    fewer cells, consistent with substantial death. Activation and attrition
    are the same phenomenon here, not competing ones.
  biological_scale: CELLULAR
  downstream:
  - target: Naive T Cell Depletion
  - target: Impaired B Cell Differentiation
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we stimulated cells with CD3 only (rather than CD2, CD3, and CD28), which normally induces only a small proportion of cells to enter cycle, and observed a substantial proliferative response in cells from the proband, but not in controls"
    explanation: >
      Demonstrates the reduced activation threshold directly: a deliberately
      weak stimulus produces a response only in patient cells.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "although we observed an enhanced proliferative response, there were far fewer cells present in cultures at time of analysis, consistent with substantial cell death"
    explanation: >
      The attrition that accompanies the enhanced response, and the link from
      hyperactivation to lymphocyte loss.
- name: Naive T Cell Depletion
  description: >
    The naive compartment is preferentially lost in both CD4 and CD8
    lineages, with a compensating shift toward effector and effector-memory
    phenotypes. The reservoir of cells able to respond to a new antigen
    shrinks, which is what makes this an immunodeficiency rather than an
    autoimmune disease.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  downstream:
  - target: Decreased naive T cell proportion
  - target: Decreased total lymphocyte count
  - target: Combined immunodeficiency
  - target: Chronic mucocutaneous candidiasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Mucosal antifungal defence depends on T cell help; the intermediate
      steps between a depleted naive T cell pool and Candida susceptibility
      are not established in this disorder.
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Probands in both kindreds exhibited deficiencies of CD4+ and CD8+ T cells, with a significant reduction in naive T cells in both compartments"
    explanation: >
      Reports the naive-predominant T cell deficiency in both independent
      kindreds.
- name: Impaired B Cell Differentiation
  description: >
    B cells sit on the same lowered threshold - unstimulated patient B cells
    show NF-kappaB phosphorylation comparable to CD40-stimulated controls -
    and then fail at the step that matters: they do not proliferate normally,
    do not make immunoglobulin, and do not accumulate a memory compartment or
    differentiate into plasmablasts.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  downstream:
  - target: Decreased proportion of memory B cells
  - target: Decreased circulating immunoglobulin concentration
  - target: Decreased specific antibody response to vaccination
  - target: Combined immunodeficiency
  - target: Recurrent respiratory infections
    causal_link_type: DIRECT
    description: >
      Failure to make specific antibody is the proximate cause of the
      sinopulmonary infection burden.
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "B cells failed to proliferate normally and exhibited a defect in immunoglobulin production after CD40 or CpG stimulation"
    explanation: >
      The functional B cell failure this node asserts, measured against two
      independent stimuli.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands were also found to exhibit a significant deficiency of memory B cells (Freiburg class Ib)"
    explanation: >
      Reports the memory B cell deficiency that follows from the
      differentiation block.
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although still normal in their proliferative capacity, B and T cells show defective activation at day 3 (CD70, CD25, and CD40L expression) and impaired B-cell differentiation into plasmablasts."
    explanation: >
      Independent cohort evidence for the differentiation block, and a useful
      nuance: this series found proliferative capacity preserved while
      activation and plasmablast differentiation failed.
- name: Increased Regulatory T Cell Output
  description: >
    Regulatory T cells and FOXP3 expression per cell are increased, and in
    the mouse the increase is already present in the thymus, implying it
    arises during development rather than as a peripheral response. FOXP3 is
    itself under canonical NF-kappaB control, which makes this a direct
    consequence of the pathway change rather than a coincidence. It is the
    leading candidate explanation for how a hyperactivating variant produces
    deficiency - see the open question recorded in `discussions`.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A similar increase in T reg cells was observed within thymus of mutant mice, suggesting that the defect arises during T reg cell development"
    explanation: >
      Places the regulatory T cell increase in the thymus, supporting a
      developmental rather than reactive origin.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FOXP3 expression is known to be regulated by canonical NF-κB signaling"
    explanation: >
      Supplies the mechanistic link from the pathway change to the regulatory
      T cell phenotype. Graded OTHER because it is the authors summarising
      established literature, not an observation made in their patients.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband exhibited an increase in circulating T reg cells."
    explanation: >
      The human observation behind this node, so the claim does not rest on
      the mouse alone.
  notes: >
    The increase was seen in one of the two founding probands and not the
    other, so it is not a constant feature of the disorder.
phenotypes:
- category: Immunologic
  name: Combined immunodeficiency
  description: >
    A combined T and B cell defect. Notably it is functional before it is
    numerical - activation and differentiation fail while counts are still
    normal in childhood.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  diagnostic: true
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects"
    explanation: Names the combined T and B cell deficiency in both founding kindreds.
- category: Immunologic
  name: Recurrent respiratory infections
  description: >
    Recurrent sinopulmonary infection is the usual presenting complaint, from
    childhood in some patients and adulthood in others.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  sequelae:
  - target: Bronchiectasis
    description: >
      Repeated lower respiratory infection is what damages the airways; the
      bronchiectasis is a consequence of the infection burden rather than an
      independent feature.
  - target: Recurrent otitis media
  evidence:
  - reference: PMID:36378426
    reference_title: "A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cause an autosomal dominant immunodeficiency disorder characterized by recurrent sinopulmonary infections, immune dysregulation, inflammation, epithelial defects, and lymphopenia"
    explanation: >
      Lists recurrent sinopulmonary infection among the defining features of
      the dominant gain-of-function disorder.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 33-yr-old male proband with a history of recurrent respiratory infections, otitis media, and tonsillitis since childhood"
    explanation: The second kindred's presenting infection history.
- category: Respiratory
  name: Bronchiectasis
  description: >
    Structural airway damage following years of recurrent infection, and one
    of the findings that prompts investigation in adults.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further investigations revealed bronchiectasis (Fig. 1 c) and hepatosplenomegaly (Table S1)."
    explanation: Reports bronchiectasis in the second kindred's proband.
- category: Otologic
  name: Recurrent otitis media
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband had two children (aged 2 and 5 yr), and both suffered with recurrent otitis media and sinusitis, but no inflammation or ectodermal dysplasia."
    explanation: >
      Recurrent otitis media in the two affected children of the first
      proband, and a useful illustration of the intrafamilial variability
      recorded under inheritance.
- category: Hematologic
  name: Decreased total lymphocyte count
  description: >
    Lymphopenia that is fixed in some patients and progressive in others;
    the larger series found counts normal in childhood and reduced in adults.
  phenotype_term:
    preferred_term: Decreased total lymphocyte count
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial cellular analysis of peripheral blood mononuclear cells (PMBCs) isolated from the proband and both children revealed lymphopenias."
    explanation: Reports lymphopenia across three affected members of one kindred.
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While lymphocyte cell numbers are generally normal at young ages, most adult patients exhibit strongly reduced B- and T-cell numbers."
    explanation: >
      Establishes that the lymphopenia is age-dependent, which is why no
      frequency band is set for this phenotype.
  notes: >
    No frequency band is asserted. The two available series disagree by
    design rather than by conflict - one reports fixed lymphopenia in a
    single kindred, the other an age-dependent decline across four - so any
    single band would misdescribe one of them.
- category: Immunologic
  name: Decreased naive T cell proportion
  phenotype_term:
    preferred_term: Decreased naive T cell proportion
    term:
      id: HP:0031397
      label: Decreased naive T cell proportion
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Probands in both kindreds exhibited deficiencies of CD4+ and CD8+ T cells, with a significant reduction in naive T cells in both compartments"
    explanation: Reports the naive T cell reduction in both CD4 and CD8 lineages.
- category: Immunologic
  name: Decreased proportion of memory B cells
  phenotype_term:
    preferred_term: Decreased memory B cell proportion
    term:
      id: HP:0030374
      label: Decreased memory B cell proportion
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands were also found to exhibit a significant deficiency of memory B cells (Freiburg class Ib)"
    explanation: Reports the memory B cell deficiency, classified by Freiburg criteria.
- category: Immunologic
  name: Decreased circulating immunoglobulin concentration
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was noted to have hypogammaglobulinemia at age 18 yr and subcutaneous abscesses at age 28 yr."
    explanation: Hypogammaglobulinaemia in the second kindred's proband.
- category: Immunologic
  name: Decreased specific antibody response to vaccination
  description: >
    Antibody function fails independently of antibody quantity - the first
    proband's hypogammaglobulinaemia was mild, but her specific responses
    were defective.
  phenotype_term:
    preferred_term: Decreased specific antibody response to vaccination
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she had mild hypogammaglobulinemia and defective specific antibody responses to pneumococcal vaccination"
    explanation: >
      Records the defective vaccine response alongside only mild
      hypogammaglobulinaemia.
- category: Dermatologic
  name: Eczematoid dermatitis
  description: >
    Severe and atypical eczema in the founding proband; the larger series
    describes autoinflammatory skin disease more broadly, and one reported
    infant had a neutrophilic dermatosis resembling Sweet syndrome.
  phenotype_term:
    preferred_term: Eczematoid dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a patient who presented with recurrent respiratory tract infections, severe and atypical eczema, dental abnormalities consistent with ectodermal dysplasia (without conical teeth), hidradenitis suppurativa and subcutaneous abscesses, mucocutaneous candidiasis, and premature cataracts"
    explanation: >
      The founding proband's presentation, which includes the eczema recorded
      here.
- category: Immunologic
  name: Chronic mucocutaneous candidiasis
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hidradenitis suppurativa and subcutaneous abscesses, mucocutaneous candidiasis, and premature cataracts"
    explanation: >
      Mucocutaneous candidiasis in the founding proband, indicating a defect
      in mucosal antifungal defence alongside the bacterial susceptibility.
- category: Integumentary
  name: Ectodermal dysplasia
  description: >
    Ectodermal features accompany the immune phenotype in more than one
    reported patient: the founding proband had dental abnormalities
    described as consistent with ectodermal dysplasia, and a separate adult
    carrying an activation-loop allele was ascertained through ectodermal
    dysplasia with immunodeficiency. Ectodermal dysplasia with
    immunodeficiency is a recognised presentation of NF-kappaB pathway
    disorders more broadly, so the pairing is unlikely to be incidental -
    but the developmental step linking IKK2 activity to ectodermal appendage
    formation is not evidenced in this entry, and no causal edge is drawn to
    this phenotype for that reason.
  phenotype_term:
    preferred_term: Ectodermal dysplasia
    term:
      id: HP:0000968
      label: Ectodermal dysplasia
  evidence:
  - reference: PMID:32554083
    reference_title: "Heterozygous IKKβ activation loop mutation results in a complex immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified in an adult with ectodermal dysplasia and immunodeficiency a germline, gain-of-function mutation, K171R, in IKBKB."
    explanation: >
      An IKBKB gain-of-function patient ascertained through the combination
      of ectodermal dysplasia and immunodeficiency.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dental abnormalities consistent with ectodermal dysplasia (without conical teeth)"
    explanation: >
      The founding proband's ectodermal finding, named as such, in a second
      independently ascertained patient.
  notes: >
    No frequency is asserted. The evidence is two independently ascertained
    patients; that establishes the association without supporting a band.
- category: Hematologic
  name: Autoimmune hemolytic anemia
  description: >
    Autoimmune cytopenia, reported in an infant who presented with
    autoinflammation rather than infection - the dysregulation arm of the
    phenotype rather than the deficiency arm. The genotype is a caveat and
    not a footnote: that infant carried two IKBKB variants in trans, one
    inherited from each asymptomatic parent, which is a compound
    heterozygous genotype rather than the single dominant allele that
    defines IMD15A.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:36378426
    reference_title: "A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beginning at 6 weeks of age, he developed recurrent self-limiting episodes of rash, fever, and auto-immune hemolytic anemia (AIHA)."
    explanation: >
      Names autoimmune haemolytic anaemia directly, which is the phenotype
      bound here; the paper's summary sentence says "autoimmune cytopenias",
      a genus that also covers the anti-neutrophil antibodies it reports.
  notes: >
    Attributed to this disorder with less confidence than the infection
    phenotype, for three compounding reasons. The reported infant carried
    two IKBKB variants in trans - E518K from the mother, T559M from the
    father, both parents asymptomatic - so the genotype is compound
    heterozygous rather than the dominant single allele that defines IMD15A.
    Only T559M behaved as gain-of-function when transduced into Jurkat
    cells; E518K showed no significant change. And both variants lie between
    the leucine-zipper and NEMO-binding regions rather than in the kinase
    domain where the established disease alleles sit.
genetic:
- name: IKBKB
  gene_term:
    preferred_term: IKBKB
    term:
      id: hgnc:5960
      label: IKBKB
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >
    Encodes IKK2 (IKK-beta), the catalytic subunit that, with IKK1 and NEMO,
    phosphorylates IkappaB-alpha and releases NF-kappaB. Reported IMD15A
    alleles are heterozygous kinase-domain missense variants - p.Val203Ile
    in the active site, p.Lys171Arg in the activation loop, and p.Met65Thr -
    acting by increased kinase activity at normal protein levels. The
    p.Glu518Lys and p.Thr559Met variants reported in one autoinflammatory
    patient lie between the leucine-zipper and NEMO-binding regions, outside
    the kinase domain, and were carried in trans; they are not part of this
    allele series. The same residue, V203, has been reported as a somatic
    gain-of-function variant in central nervous system B cell lymphoma,
    which is independent corroboration of the biochemical direction.
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "IKBKB encodes IKK2, which activates NF-κB signaling. IKK2V203I results in enhanced NF-κB signaling, as well as T and B cell functional defects."
    explanation: >
      States the gene-disease relationship and the direction of the
      functional effect.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "two instances of the same mutation arising as a somatic variant in brain tumors have been reported (Fukumura et al., 2016). Consistent with our findings, this somatic variant was reported to confer gain of function."
    directness: INDIRECT
    explanation: >
      Independent, non-germline corroboration that this exact substitution is
      activating.
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic variants (p.V203I and p.M65T) in the patients were identified by whole-exome sequencing."
    explanation: Sources the p.Met65Thr allele recorded in the series above.
  - reference: PMID:32554083
    reference_title: "Heterozygous IKKβ activation loop mutation results in a complex immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified in an adult with ectodermal dysplasia and immunodeficiency a germline, gain-of-function mutation, K171R, in IKBKB."
    explanation: Sources the p.Lys171Arg activation-loop allele recorded in the series above.
  notes: >
    Biallelic loss-of-function IKBKB variants cause a different disease,
    IMD15B, and are not curated in this entry; see
    `differential_diagnoses`.
animal_models:
- name: Ikbkb V203I CRISPR knock-in mouse
  species: Mouse
  genotype: Ikbkb p.Val203Ile knock-in (heterozygous and homozygous)
  publication: PMID:30337470
  description: >
    Built specifically to test causation for the human allele: the orthologous
    codon change was introduced into mouse Ikbkb by CRISPR/Cas9, so the mouse
    carries the same amino acid substitution as the patients rather than a
    convenient approximation. Heterozygotes and homozygotes were born at
    expected Mendelian ratios, and phenotypes are graded by allele dose.
  modeled_mechanisms:
  - target: Constitutive IkappaB-alpha Phosphorylation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >
      Splenocytes show constitutive IkappaB-alpha phosphorylation at baseline
      and prolonged phosphorylation after stimulation, with homozygotes
      exceeding heterozygotes.
    limitations: >
      The published characterisation emphasises young animals at baseline;
      whether the model reproduces the decades-long progressive course seen
      in adult patients has not been reported.
    readouts:
    - name: Splenocyte phospho-IkappaB-alpha to total IkappaB-alpha ratio
      target: Constitutive IkappaB-alpha Phosphorylation
      direction: INCREASED
      interpretation: >
        Biochemical correlate of unregulated IKK2 activity, graded by allele
        dose.
      evidence:
      - reference: PMID:30337470
        reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Analysis of isolated splenocytes revealed constitutive IκBα phosphorylation, with evidence of a gene dose effect: phosphorylation was greater in cells with homozygous mutation compared with heterozygotes, both at baseline"
        explanation: Reports the measurement behind this readout.
    evidence:
    - reference: PMID:30337470
      reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes."
      explanation: >
        The authors' own assessment of fidelity, and the basis for the HIGH
        rating on this link.
  - target: Naive T Cell Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >
      Mutant mice show a relative and absolute deficiency of splenic T cells
      in both CD4 and CD8 compartments, again dose-graded.
    limitations: >
      The compartment shift is not identical to the human one. Humans lose
      naive T cells specifically; mice show an increase in the
      CD44+CD62L-low effector subset, which is the mouse counterpart of the
      same redistribution rather than the same measurement. The mouse also
      loses CD8 cells preferentially, which the human data do not show.
    readouts:
    - name: Splenic CD3+ T cell proportion and absolute count
      target: Naive T Cell Depletion
      direction: DECREASED
      interpretation: >
        Peripheral T cell deficiency matching the human lymphopenia.
      evidence:
      - reference: PMID:30337470
        reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we observed that mice heterozygous and homozygous for IkbkbV203I exhibited a relative deficiency of T cells"
        explanation: Reports the T cell deficiency measured in this model.
    evidence:
    - reference: PMID:30337470
      reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In mice, we observed greater reduction in CD8+ T cells (Fig. 4 g)."
      explanation: >
        Supports the model's T cell phenotype while recording the CD8 bias
        that distinguishes it from the human presentation.
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in Ikbkb using CRISPR/Cas9"
    explanation: >
      Establishes what this model is and why it was made - an orthologous
      knock-in built to prove causation for the human variant.
- name: Ikbkb K171R knock-in mouse
  species: Mouse
  genotype: Ikbkb p.Lys171Arg knock-in
  publication: PMID:32554083
  description: >
    A second orthologous knock-in, for the activation-loop allele rather than
    the active-site one. Its value is corroborative: two independently
    reported human alleles, in different parts of the kinase, each modelled
    in mouse, each reproducing the human immune phenotype.
  modeled_mechanisms:
  - target: Enhanced Canonical NF-kappaB Signalling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >
      The authors report that the mouse immunologic phenotype parallels the
      human one.
    limitations: >
      The available description is a brief abstract, so which specific
      immunological features were compared, and how closely, cannot be read
      off the record. The fidelity rating is held at MODERATE for that reason
      rather than because a discrepancy was reported.
    evidence:
    - reference: PMID:32554083
      reference_title: "Heterozygous IKKβ activation loop mutation results in a complex immunodeficiency syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The K171R mouse immunologic phenotype parallels human, suggesting IKBKB K171R underlies a novel immunodeficiency syndrome."
      explanation: >
        The authors' assessment that this model reproduces the human immune
        phenotype for the activation-loop allele.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >
    Prophylactic immunoglobulin for the antibody defect. Reported in one
    gain-of-function patient started at 9 months, with improvement in skin
    disease and in the frequency of febrile autoimmune flares, and withdrawn
    at age 3 when he proved to have neither an infectious history nor
    hypogammaglobulinaemia. That single course is the extent of the published
    IMD15A treatment experience - see the entry `notes`.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: human immunoglobulin G
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  target_mechanisms:
  - target: Impaired B Cell Differentiation
    description: >
      Replaces the antibody the patient's own B cells fail to produce. It
      substitutes for the failed output; it does not correct the
      differentiation block.
  target_phenotypes:
  - preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:36378426
    reference_title: "A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was started on prophylactic intravenous immunoglobulin (IVIG) 0.5 g/kg infusions at 9 months for infection prophylaxis given his history and genetic findings suggestive of combined immunodeficiency in the literature"
    explanation: >
      The one published account of immunoglobulin replacement in an IKBKB
      gain-of-function patient, including the dose and the indication.
  notes: >
    Single-patient experience, in the autoinflammation-predominant end of the
    spectrum rather than the classic infection-predominant one, and in a
    patient whose two IKBKB variants were carried in trans rather than as a
    single dominant allele. It is recorded because it is the only quotable
    treatment account for this disorder, not because it establishes a
    standard of care.
diagnosis:
- name: Exome or gene-panel sequencing with functional confirmation
  description: >
    There is no screening test and no characteristic routine-laboratory
    signature - counts can be normal in childhood - so the diagnosis is made
    by sequencing in a patient investigated for unexplained antibody or
    combined deficiency. Because gain-of-function missense variants are not
    self-evidently pathogenic, reported cases have been confirmed
    functionally, by NF-kappaB reporter assay or phospho-flow showing
    increased pathway activity.
  evidence:
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic variants (p.V203I and p.M65T) in the patients were identified by whole-exome sequencing."
    explanation: The sequencing route by which reported patients were diagnosed.
  - reference: PMID:40403933
    reference_title: "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "An NF-κB reporter assay was performed to investigate NF-κB activity."
    explanation: >
      The functional confirmation step used to establish that a candidate
      variant is gain-of-function.
differential_diagnoses:
- name: Immunodeficiency 15B
  description: >
    The same gene in the opposite direction: biallelic loss-of-function IKBKB
    variants, causing a severe combined immunodeficiency of infancy. The
    cellular phenotype is the mirror image - where IMD15A lowers the
    activation threshold and depletes naive cells, IMD15B leaves lymphocytes
    numerically normal but frozen in a naive, unresponsive state.
  distinguishing_features:
  - Biallelic loss of function rather than heterozygous gain of function
  - Onset in infancy rather than progression across decades
  - Lymphocytes numerically normal but almost exclusively naive, with absent regulatory and gamma-delta T cells
  - Normal T-cell receptor excision circles, so newborn TREC screening does not detect it
  evidence:
  - reference: PMID:24369075
    reference_title: "Deficiency of innate and acquired immunity caused by an IKBKB mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients carried a homozygous duplication--c.1292dupG in exon 13 of IKBKB, which encodes IκB kinase 2 (IKK2, also known as IKKβ)--leading to loss of expression of IKK2, a component of the IKK-nuclear factor κB (NF-κB) pathway."
    explanation: >
      Establishes the loss-of-function mechanism that distinguishes IMD15B
      from the gain-of-function disorder curated here.
  - reference: PMID:24369075
    reference_title: "Deficiency of innate and acquired immunity caused by an IKBKB mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients had hypogammaglobulinemia or agammaglobulinemia, and their peripheral-blood B cells and T cells were almost exclusively of naive phenotype. Regulatory T cells and γδ T cells were absent."
    explanation: >
      The mirror-image cellular phenotype: naive-frozen lymphocytes with
      absent regulatory T cells, against IMD15A's naive depletion and
      increased regulatory T cells.
  - reference: PMID:30391351
    reference_title: "Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T-cell receptor excision circles were normal, meaning newborn screening by TREC analysis would miss IKBKB cases."
    explanation: >
      Normal T-cell receptor excision circles mean the newborn TREC screen
      that detects most severe combined immunodeficiencies does not pick up
      IMD15B. No TREC data have been reported for IMD15A, so no claim is
      made about the screen's behaviour in this entry's disease.
discussions:
- discussion_id: activation_versus_deficiency_paradox
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >
    How does a variant that increases NF-kappaB signalling - and demonstrably
    lowers the lymphocyte activation threshold - produce immune deficiency
    rather than autoimmunity or lymphoproliferation?
  attaches_to:
  - pathophysiology#Lowered Lymphocyte Activation Threshold
  - pathophysiology#Increased Regulatory T Cell Output
  rationale: >
    This is the central unresolved question of the disorder, and the paper
    that defined IMD15A names it as unresolved rather than settling it. Two
    candidate answers are on the table. The first is regulatory: FOXP3 is
    under canonical NF-kappaB control, regulatory T cells and per-cell FOXP3
    are increased, and in the mouse the increase is already present in the
    thymus - so a hyperactivating allele might expand the suppressive
    compartment faster than the effector one. The second is attritional:
    patient cells proliferate more but end up fewer, so chronic
    hyperactivation may simply consume the naive pool. The two are not
    exclusive, and the evidence does not currently separate them. The
    regulatory explanation also has a counterexample within the founding
    report itself - one of the two probands had a late-onset combined
    immunodeficiency with normal regulatory T cells.
  evidence:
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In both human and mouse, we observed pathological immune activation, but this finding needs to be reconciled with clinical manifestation of mild immune deficiency."
    explanation: >
      The authors state the paradox explicitly and as unreconciled, which is
      why this is recorded as an open question rather than a mechanism.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One possible explanation is the increase in thymic T reg cells, observed in the mouse model, and increased FOXP3 expression in the proband."
    explanation: >
      The regulatory hypothesis, offered by the authors as one possibility.
      Graded OTHER rather than split: the sentence is a single interpretive
      claim that happens to cite a mouse observation and a human one
      together, so neither MODEL_ORGANISM nor HUMAN_CLINICAL describes it,
      and splitting it would mean quoting half a hypothesis.
  - reference: PMID:30337470
    reference_title: "Gain-of-function IKBKB mutation causes human combined immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient B.II.1, however, had a late-onset combined immunodeficiency alone and presented with normal T reg cells."
    explanation: >
      Supports the question remaining open, by cutting against the leading
      answer: one affected patient had the deficiency without the regulatory
      T cell expansion. `supports` here is scoped to the discussion's claim -
      that the reconciliation is unresolved - which this observation
      strengthens rather than contradicts.
notes: >
  Curated from a claude_code deep-research report
  (research/Immunodeficiency_15A-deep-research-claude_code.md) together with
  the primary literature. No GeneReviews chapter exists for IKBKB - PubMed
  returns no GeneReviews record for the gene - so the usual GeneReviews
  phenotype baseline is unavailable for this entry and no substitute is
  claimed.

  Treatment coverage is deliberately thin. The research report describes
  immunoglobulin replacement, antimicrobial prophylaxis and haematopoietic
  cell transplantation as management, but the transplant experience it cites
  (PMID:30391351) is a cohort of homozygous c.1292dupG patients - that is
  IMD15B, the loss-of-function disorder - and is recorded here under
  `differential_diagnoses` where it belongs rather than as treatment for
  this disease. The report also notes that systemic IKK2 inhibitors are not
  in clinical use, which would be a useful negative finding, but no cached
  source carries a quotable sentence for it. Only the single documented
  immunoglobulin course in a gain-of-function patient is curated.

  Two additions were considered and declined. A serum biomarker panel is
  quotable from PMID:36378426 - it reports increased pro-inflammatory
  chemokines associated with macrophage recruitment - but that panel was
  measured in the patient with the in-trans E518K/T559M genotype quarantined
  above, so importing it would reintroduce exactly the scope problem the
  rest of the entry avoids. And no causal edge is drawn to `Ectodermal
  dysplasia` or `Autoimmune hemolytic anemia`: the first would assert a
  developmental mechanism this entry does not evidence, the second belongs
  to the compound-heterozygous case.

  Reported features not curated: premature cataracts, hidradenitis
  suppurativa, hepatosplenomegaly, and the CMV colitis reported in an adult.
  Quotable sentences exist for most of these - several are already used as
  snippets elsewhere in this entry - so the reason is not sourcing but
  scope: each is a single-patient observation rather than an established
  feature of the disorder. They appear in the founding case descriptions or
  the research report, and the founding proband's full presentation is
  quoted under the `Eczematoid dermatitis` phenotype, so the record of them
  is not lost.

  The mouse Ikbkb null allele is embryonic lethal at about E14.5 from liver
  degeneration (PMID:10229185), while humans homozygous for a null IKBKB
  allele survive with combined immunodeficiency. That species asymmetry is
  real and interesting, but it concerns the loss-of-function disorder rather
  than this one, so it is noted here rather than modelled as a
  human/model mismatch on an entry about a gain-of-function allele.
📚

References & Deep Research

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)

Record notes

Curated from a claude_code deep-research report (research/Immunodeficiency_15A-deep-research-claude_code.md) together with the primary literature. No GeneReviews chapter exists for IKBKB - PubMed returns no GeneReviews record for the gene - so the usual GeneReviews phenotype baseline is unavailable for this entry and no substitute is claimed. Treatment coverage is deliberately thin. The research report describes immunoglobulin replacement, antimicrobial prophylaxis and haematopoietic cell transplantation as management, but the transplant experience it cites (PMID:30391351) is a cohort of homozygous c.1292dupG patients - that is IMD15B, the loss-of-function disorder - and is recorded here under `differential_diagnoses` where it belongs rather than as treatment for this disease. The report also notes that systemic IKK2 inhibitors are not in clinical use, which would be a useful negative finding, but no cached source carries a quotable sentence for it. Only the single documented immunoglobulin course in a gain-of-function patient is curated. Two additions were considered and declined. A serum biomarker panel is quotable from PMID:36378426 - it reports increased pro-inflammatory chemokines associated with macrophage recruitment - but that panel was measured in the patient with the in-trans E518K/T559M genotype quarantined above, so importing it would reintroduce exactly the scope problem the rest of the entry avoids. And no causal edge is drawn to `Ectodermal dysplasia` or `Autoimmune hemolytic anemia`: the first would assert a developmental mechanism this entry does not evidence, the second belongs to the compound-heterozygous case. Reported features not curated: premature cataracts, hidradenitis suppurativa, hepatosplenomegaly, and the CMV colitis reported in an adult. Quotable sentences exist for most of these - several are already used as snippets elsewhere in this entry - so the reason is not sourcing but scope: each is a single-patient observation rather than an established feature of the disorder. They appear in the founding case descriptions or the research report, and the founding proband's full presentation is quoted under the `Eczematoid dermatitis` phenotype, so the record of them is not lost. The mouse Ikbkb null allele is embryonic lethal at about E14.5 from liver degeneration (PMID:10229185), while humans homozygous for a null IKBKB allele survive with combined immunodeficiency. That species asymmetry is real and interesting, but it concerns the loss-of-function disorder rather than this one, so it is noted here rather than modelled as a human/model mismatch on an entry about a gain-of-function allele.

Create: Immunodeficiency 15A (IKBKB gain-of-function) · 2026-09-04T13:23:47Z · View source

New Mendelian entry for IKBKB gain-of-function combined immunodeficiency (MONDO:0032599), curated from a claude_code deep-research run (research/Immunodeficiency_15A-deep-research-claude_code.md, 370s, 15 web searches, 33 turns) plus the primary literature. No GeneReviews chapter exists for IKBKB - a PubMed search for 'IKBKB GeneReviews[All Fields]' returns nothing - so the mandatory GeneReviews phenotype baseline is unavailable for this entry and no substitute was claimed. The dominant risk on this disease is scope confusion between two disorders caused by the same gene in opposite directions: IMD15A is autosomal dominant gain-of-function (PMID:30337470, PMID:40403933, PMID:36378426), while IMD15B is autosomal recessive loss-of-function (PMID:24369075, PMID:30391351). Every IMD15B source is confined to differential_diagnoses. In particular the research report cited the IKBKB transplant cohort (PMID:30391351) toward treatment, but that cohort is 16 patients homozygous for c.1292dupG - IMD15B - so it is not used as treatment evidence here. Treatment coverage is consequently one documented immunoglobulin course in a single gain-of-function patient, and the entry notes say so rather than padding the section. Report validation: reference validation 8/8 resolved, 0 unresolved, needs_review true on one off-topic flag; term validation 38/41 resolved with 4 mislabelled CURIEs and 1 obsolete. The off-topic flag (PMID:10229185, the IKK-beta knockout mouse) was a false positive from vocabulary mismatch and was read rather than dismissed - it establishes that mouse Ikbkb nulls die at E14.5 while humans homozygous for a null survive with immunodeficiency, recorded in notes as a species asymmetry belonging to the loss-of-function disorder rather than modelled as a human/model mismatch here. Mislabelled CURIEs were rejected: the report offered HP:0001878 labelled 'AIHA' (HP calls it Hemolytic anemia); the entry uses the more specific HP:0001890 Autoimmune hemolytic anemia. HP:0010976 and HP:0002164 were offered with table-cell text as labels and not used. The obsolete GO:0002741 was not used. One label correction found by validation: the local OAK hp build gives HP:0030374 as 'Decreased proportion of memory B cells' while the OLS adapter the validator uses gives 'Decreased memory B cell proportion'; the canonical OLS label is used. Content: a seven-node causal chain from the kinase-domain variant through constitutive IkappaB-alpha phosphorylation and enhanced canonical NF-kappaB signalling to a lowered lymphocyte activation threshold, branching to naive T cell depletion and impaired B cell differentiation, with increased regulatory T cell output as a parallel arm. 12 phenotypes, 1 treatment, 1 animal model (the CRISPR orthologous V203I knock-in) with two pathograph links and readouts, an autosomal dominant inheritance block, a progression record for the age-dependent decline, the IMD15B differential, and an OPEN_QUESTION discussion recording the central unresolved paradox - how a hyperactivating allele produces deficiency - including a REFUTE evidence item for the patient who had the deficiency without the regulatory T cell expansion. Scope discipline: no prevalence band or rate (16 patients from 4 families recorded as CASES_IN_LITERATURE with prevalence_class UNKNOWN); no frequency band on lymphopenia because the two available series describe fixed versus age-dependent patterns and a single band would misdescribe one; single-patient features from the founding case reports (cataracts, hidradenitis suppurativa, hepatosplenomegaly, CMV colitis) left uncurated with the reason recorded. Validation: just validate (schema + terms + 49/49 snippets), just validate-disorders (the batched CI gate), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms-online, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence and check-reference-titles all pass. Weighted compliance 90.4%. The stubs entry was deleted.

Claude Code ▸
Immunodeficiency 15A (IMD15A) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 3 citations 2026-09-04T13:11:24.854307

Immunodeficiency 15A (IMD15A) — Comprehensive Research Report

1. Disease Information

Overview. Immunodeficiency 15A (IMD15A) is an ultra-rare, autosomal dominant inborn error of immunity caused by heterozygous, typically de novo, gain-of-function (GOF) missense variants in IKBKB (encoding IKKβ/IKK2, a core catalytic subunit of the IκB kinase complex that activates canonical NF-κB signaling). It was first delineated as a distinct clinical entity by Cardinez et al. (2018), who identified an identical heterozygous de novo IKBKB c.607G>A (p.Val203Ile) missense mutation in two unrelated kindreds presenting with immune dysregulation, combined T- and B-cell functional deficiency, systemic inflammation, and epithelial defects (PMID:30337470, J Exp Med 2018). Unlike classic combined immunodeficiencies, IMD15A is characterized by relatively late onset (childhood to adulthood), recurrent respiratory infections, progressive lymphopenia, and paradoxical immune activation/dysregulation despite (or because of) enhanced NF-κB signaling.

Key identifiers: - OMIM phenotype: #618204 — IMMUNODEFICIENCY 15A; IMD15A - OMIM gene: 603258 — IKBKB (Inhibitor of Nuclear Factor Kappa B Kinase Subunit Beta) - MONDO: MONDO:0032599 - Gene: IKBKB, HGNC:5960, NCBI Gene ID 3551, chromosome 8p11.21 (chr8:42,271,302–42,332,460, GRCh38) - Inheritance: Autosomal dominant (heterozygous, gain-of-function) - Related/contrasted entity: Immunodeficiency 15B (IMD15B; OMIM #615592) — the autosomal recessive, biallelic loss-of-function IKBKB disorder (severe combined immunodeficiency with normal lymphocyte counts but impaired signaling; Pannicke et al. 2013, N Engl J Med, PMID:24369075) - Synonyms:* IKBKB gain-of-function immunodeficiency; IKK2 gain-of-function disease; IKBKB-related combined immune deficiency (autosomal dominant)

Data provenance. Nearly all current knowledge derives from aggregated case reports/small case series (individual-patient, family-based whole-exome sequencing studies) rather than large disease registries — consistent with an ultra-rare monogenic condition first described in 2018 and still comprising well under 50 published patients worldwide as of the most recent 2025 series.

2. Etiology

Disease causal factor: Purely genetic/monogenic. Heterozygous missense variants in the kinase or activation-loop domains of IKBKB that confer gain of function on IKK2 kinase activity, producing constitutive/enhanced canonical NF-κB pathway signaling.

Genetic risk factors: - The prototypic variant is c.607G>A, p.Val203Ile (V203I), located in the second lobe of the kinase domain active site (Cardinez et al. 2018, PMID:30337470). V203 is highly conserved; the mutant protein retains kinase activity but is predicted to adopt an unstable conformation that disrupts normal tetrameric IKK-complex interactions, producing constitutive activity. - A second locus, the activation-loop region, was implicated by Abbott et al. (2021, J Allergy Clin Immunol, PMID:32554083), describing a heterozygous IKKβ activation-loop mutation causing a complex immunodeficiency syndrome. - A 2025 multi-family series (Körholz et al., J Allergy Clin Immunol, PMID:40403933) reported 16 patients from 4 families carrying missense variants clustered in the IKBKB kinase domain, including one novel GOF variant, establishing that the phenotype spans a spectrum broader than the original V203I report. - All reported IMD15A variants to date arise de novo or segregate as autosomal dominant within affected kindreds; no common population polymorphism reproduces the phenotype (variant is absent/near-absent from gnomAD). - A separate, mechanistically distinct pair of compound-heterozygous IKBKB variants (E518K/T559M, in trans) was reported by a 2022 case (PMID:36378426, J Clin Immunol) causing an autoinflammatory/autoimmune phenotype (recurrent fever, autoimmune hemolytic anemia, Sweet-syndrome-like skin lesions) rather than classical IMD15A — illustrating that different IKBKB GOF alleles produce a phenotypic continuum from autoinflammation to combined immunodeficiency.

Modifier considerations: No modifier genes have been established; phenotypic severity appears to depend on which residue is altered and the degree/duration of NF-κB hyperactivation, with clinical heterogeneity documented even within families carrying the identical variant (age of onset in the 2025 series ranged from infancy — mild nail dysplasia — to 48 years — severe CMV colitis).

Environmental/risk-modifying factors: None specifically established; as an intrinsic immune-signaling disorder, disease expression is likely modulated by cumulative pathogen exposure (viral, bacterial) over the patient's lifetime, consistent with the age-dependent progression documented in longitudinal series.

Protective factors: None reported in the literature to date.

Gene-environment interactions: Not formally studied; the progressive, age-related worsening of lymphopenia and hypogammaglobulinemia suggests a "second-hit" or cumulative-exposure model in which repeated antigen/pathogen encounters exhaust the dysregulated NF-κB-dependent lymphocyte activation/homeostasis machinery, but this remains inferential rather than directly demonstrated (PMID:40403933).

3. Phenotypes

Suggested HP terms are given per phenotype.

Phenotype Type Onset/course Frequency (qualitative) HPO term
Recurrent sinopulmonary/respiratory infections Symptom/sign Childhood–adulthood; progressive Common (majority of patients) HP:0002205 (Recurrent respiratory infections)
Progressive lymphopenia Laboratory abnormality Emerges/worsens with age; normal in youth, reduced in adults Frequent, age-dependent HP:0001888 (Lymphopenia)
Reduced/dysfunctional CD8+ and CD4+ T cells Laboratory abnormality Progressive Frequent HP:0005415 (Decreased circulating total T cell count); HP:0032155
Hypogammaglobulinemia / impaired specific-antibody responses Laboratory abnormality Progressive, adult-onset in milder cases Frequent HP:0002850 (Decreased circulating antibody level); HP:0002846
Impaired B-cell differentiation into plasmablasts Laboratory abnormality Progressive Documented in functional assays HP:0010976
Autoinflammatory skin manifestations (rash, abscesses, Sweet-syndrome-like plaques) Clinical sign Variable onset, can be earliest feature (infancy) Variable HP:0100785 (Recurrent skin infections); HP:0031372
Nail dysplasia Physical manifestation Can present in first year of life Rare/variable HP:0002164
Bronchiectasis Clinical sign (complication) Adult-onset, complication of recurrent infection Reported in a subset HP:0002110
Splenomegaly Physical sign Variable Reported in a subset HP:0001744
Cataracts Physical sign Variable Reported in a subset HP:0000518
Hypodontia Physical manifestation Congenital/developmental Reported in a subset HP:0000668
Recurrent cutaneous abscesses Clinical sign Variable Reported in a subset HP:0031292
Autoimmune cytopenias (e.g., autoimmune hemolytic anemia) — seen in the related E518K/T559M phenotype Clinical sign/lab Infancy onset in that case Case-specific HP:0001878 (AIHA)
Severe/opportunistic infections (e.g., CMV colitis) in adulthood Symptom Adult-onset, can be severe Reported HP:0032101
Epithelial defects Physical manifestation Variable Reported (original 2018 description) —

Quality-of-life impact: No formal EQ-5D/SF-36 data exist for this ultra-rare condition. Qualitatively, disease burden accumulates with age — patients described as asymptomatic or mildly affected in childhood (e.g., isolated nail dysplasia, mild upper respiratory infections) can progress in adulthood to bronchiectasis, severe/opportunistic infection (CMV colitis), and clinically significant lymphopenia/hypogammaglobulinemia requiring immunoglobulin replacement (PMID:40403933), consistent with a progressive, life-course disease trajectory rather than a static congenital immunodeficiency.

4. Genetic/Molecular Information

Causal gene: IKBKB (HGNC:5960; OMIM *603258; NCBI Gene 3551; UniProt O14920).

Reported pathogenic variants (heterozygous, gain-of-function): - c.607G>A (p.Val203Ile) — the founding IMD15A variant, kinase-domain active site, second lobe (Cardinez et al. 2018, PMID:30337470). Predicted to destabilize the normal tetrameric IKK holo-complex interaction while preserving/enhancing catalytic activity. - Activation-loop missense variant(s) — Abbott et al. 2021 (PMID:32554083). - Additional kinase-domain missense variants, including at least one novel GOF allele, reported across 4 families/16 patients (Körholz et al. 2025, PMID:40403933). - E518K / T559M in trans — a distinct compound-heterozygous GOF genotype (between the leucine-zipper and NEMO-binding domains) producing an autoinflammatory/autoimmune-predominant phenotype rather than classic IMD15A (PMID:36378426); T559M was functionally validated as gain-of-function (≈1.5-fold increase in NF-κB luciferase reporter activity in Jurkat cells; increased basal IKKα/β and p65 phosphorylation), while E518K alone showed wild-type-like signaling.

Variant classification (ACMG/AMP framework, as applied in the primary reports): Pathogenic/likely pathogenic on the basis of de novo occurrence, functional (kinase activity, NF-κB reporter, phospho-flow) validation, and — for V203I — an orthologous CRISPR/Cas9 knock-in mouse model that reproduced the human immune-cellular and biochemical phenotype (PMID:30337470).

Population frequency: The causal missense alleles are absent or present only at extremely low frequency in gnomAD (e.g., the unrelated E518K/T559M alleles carried population minor allele frequencies of 8.43×10⁻⁶ and 5.24×10⁻⁵ respectively, per PMID:36378426), consistent with strong purifying selection against IKBKB coding variation generally.

Functional consequence: Gain of function — enhanced/constitutive IKK2 kinase activity, increased basal and stimulus-induced phosphorylation of IκBα and p65/RelA, and increased NF-κB transcriptional reporter activity, contrasted with the biallelic loss-of-function mechanism of IMD15B (complete absence of IKK2 protein; Pannicke et al. 2013, PMID:24369075).

Somatic vs. germline: All reported variants are germline (constitutional), heterozygous, and largely de novo; some kindreds show vertical (autosomal dominant) transmission with variable expressivity.

Modifier genes: None established.

Chromosomal abnormalities: None reported; IMD15A is a single-gene, missense-variant disorder, not a copy-number or structural chromosomal condition.

Epigenetics: No disease-specific epigenetic (DNA methylation/chromatin) studies have been published for IMD15A.

Gene/protein structure relevant to mechanism: IKBKB (chr8p11.21) encodes IKKβ/IKK2, a serine/threonine kinase and the principal catalytic subunit of the canonical IKK complex, together with IKKα (CHUK) and the regulatory scaffold IKKγ (NEMO/IKBKG). IKK2 contains an N-terminal kinase domain (site of the V203I and activation-loop mutations), a ubiquitin-like domain, a scaffold/dimerization (leucine-zipper) domain, and a C-terminal NEMO-binding domain (site of the E518K/T559M variants).

5. Environmental Information

No specific environmental toxin, occupational exposure, or lifestyle factor has been implicated as causal. As with other combined immunodeficiencies, standard childhood/community pathogen exposures (respiratory viruses, encapsulated bacteria, CMV) are the proximate triggers of the clinical infectious phenotype rather than disease causes. No infectious agent is causal to the underlying genetic lesion; CMV colitis has been reported as a severe complication in an affected adult, reflecting acquired opportunistic infection secondary to the immunodeficiency rather than an etiological agent (Körholz et al. 2025, PMID:40403933).

6. Mechanism / Pathophysiology

Causal chain (ordered, from molecular lesion to clinical manifestation):

  1. A heterozygous IKBKB missense variant (e.g., V203I in the kinase domain, or an activation-loop/NEMO-binding-domain variant) alters IKKβ protein conformation, producing a kinase that is catalytically hyperactive or constitutively active while destabilizing normal IKK holo-complex tetramerization (demonstrated: PMID:30337470).
  2. This leads to enhanced basal and stimulus-induced phosphorylation of IκBα (and of p65/RelA) by the mutant IKK complex (demonstrated in patient PBMCs and Jurkat reporter assays: PMID:30337470, PMID:36378426).
  3. Increased IκBα phosphorylation results in accelerated IκBα ubiquitination/proteasomal degradation, releasing NF-κB dimers (p65/p50) from cytoplasmic sequestration (established canonical NF-κB biology, applied here as the disease mechanism).
  4. Liberated NF-κB leads to constitutive/exaggerated nuclear translocation and transcription of NF-κB target genes governing lymphocyte activation, survival, and inflammatory cytokine/chemokine production (elevated MCP-1, MDC, MIP-1α/β, IL-18, IL-16, S100A8 reported in patient serum/PBMC supernatant: PMID:36378426) — this step is directly demonstrated by patient biomarker and mouse-model data.
  5. Chronic/dysregulated NF-κB signaling in developing and mature lymphocytes causes defective T-cell receptor– and B-cell receptor–dependent activation (impaired CD70, CD25, CD40L induction at day 3 of stimulation) and impaired B-cell differentiation into plasmablasts despite preserved proliferative capacity (demonstrated functionally: PMID:40403933) — an apparent paradox in which pathway hyperactivation produces functional lymphocyte hypofunction, likely reflecting exhaustion of negative-feedback capacity (IκBα resynthesis) and/or activation-induced dysregulation rather than simple loss of signal. This link is partly inferred: the downstream mechanistic step from "chronic NF-κB activation" to "functional T/B-cell defect" is documented phenomenologically (the defect is measured) but its precise molecular route (e.g., activation-induced cell death, receptor desensitization, altered thymic/germinal-center selection) is not yet fully resolved in humans.
  6. Over time, this signaling dysregulation leads to progressive peripheral lymphopenia (both T and B lineages) and impaired specific-antibody production/hypogammaglobulinemia, worsening from childhood into adulthood (longitudinal pattern documented: PMID:40403933) — a step that is observed clinically but whose cellular kinetics (rate of lymphocyte loss, compartment first affected) remain incompletely characterized.
  7. The combined T-cell functional deficiency + progressive antibody deficiency results in recurrent sinopulmonary infections, susceptibility to opportunistic pathogens (e.g., CMV colitis in adulthood), and structural airway complications such as bronchiectasis (clinical endpoint, directly observed).
  8. In parallel, and to some degree independently, chronic NF-κB-driven inflammatory cytokine/chemokine production leads to the autoinflammatory cutaneous phenotype (recurrent rash, cutaneous abscesses, Sweet-syndrome-like plaques) and, in variant-specific cases, organ-specific autoimmunity (e.g., autoimmune hemolytic anemia in the E518K/T559M case) — this branch of the causal chain diverges from the classic infection-predominant IMD15A course and appears to depend on which residue/domain is mutated (kinase active site vs. NEMO-binding region) (PMID:36378426).
  9. The murine V203I knock-in model recapitulates reduced peripheral CD3+ T-cell percentage and abnormal splenocyte IκBα phosphorylation/degradation kinetics at baseline and after ex vivo activation, cross-validating that the human phenotype derives directly from the mutant kinase's biochemical behavior rather than from a confounding second variant (PMID:30337470) — this is model-organism-demonstrated, supporting but not itself proving each downstream human clinical step.

Molecular pathways: Canonical (classical) NF-κB signaling pathway — TNF-receptor/Toll-like-receptor/antigen-receptor-proximal signals → IKK complex (IKKα/IKKβ/NEMO) → IκBα phosphorylation/degradation → NF-κB (RelA/p50) nuclear translocation → transcription of pro-survival, pro-inflammatory, and lymphocyte-activation genes. (KEGG: NF-kappa B signaling pathway, hsa04064; Reactome: R-HSA-975138 TAK1-dependent IKK and NF-kappa-B activation; R-HSA-5602636 IKBKB deficiency causes SCID — the Reactome annotation for the loss-of-function IMD15B mechanism, useful as a contrasting pathway diagram.)

Cellular processes: Aberrant lymphocyte activation signaling; impaired T-cell receptor– and B-cell receptor–induced activation marker upregulation; defective plasmablast differentiation; likely dysregulated apoptosis/activation-induced cell death balance in lymphocytes (inferred from the paradox of hyperactive signaling causing functional lymphopenia, not yet directly measured for apoptotic rate in human IMD15A).

Protein dysfunction: Gain-of-function conformational/kinetic alteration of IKKβ — retained or enhanced catalytic activity combined with disrupted normal holo-complex assembly (V203I: disrupted tetrameric interaction; predicted loss of an inter-chain hydrogen bond for T559M).

Immune system involvement: Central and defining — this is a primary immune-signaling disorder combining features of combined immunodeficiency (T/B lymphopenia, hypogammaglobulinemia, infection susceptibility) with immune dysregulation/autoinflammation (cytokine/chemokine excess, autoimmune cytopenias in variant-specific presentations).

Suggested GO terms: GO:0007249 (I-kappaB kinase/NF-kappaB signaling), GO:0043123 (positive regulation of I-kappaB kinase/NF-kappaB signaling), GO:0002741 (positive regulation of cytokine secretion involved in immune response), GO:0042104 (positive regulation of activated T cell proliferation — for contrast/negative regulation defects), GO:0002322 (B cell proliferation involved in immune response).

Suggested CL terms: CL:0000084 (T cell), CL:0000798 (gamma-delta T cell), CL:0000236 (B cell), CL:0000980 (plasmablast), CL:0000625 (CD8-positive, alpha-beta T cell), CL:0000624 (CD4-positive, alpha-beta T cell).

Molecular profiling: No transcriptomic, proteomic, or single-cell datasets specific to human IMD15A patients are publicly deposited to date (searched GEO/ArrayExpress equivalents — not identified in available literature). Targeted biomarker panels (serum chemokine/cytokine profiling) have been used in individual case reports (PMID:36378426) rather than unbiased omics.

7. Anatomical Structures Affected

Organ level: - Primary: immune system — thymus (T-cell selection/output), bone marrow/peripheral lymphoid organs (B-cell development and antibody production), spleen (splenomegaly reported), lymph nodes. - Secondary/complication-related: respiratory system (recurrent infection, bronchiectasis), gastrointestinal tract (CMV colitis as an opportunistic complication), skin (autoinflammatory lesions, abscesses), eyes (cataracts reported), teeth (hypodontia), nails (dysplasia). - Body systems involved: immune, respiratory, integumentary, ocular, dental/craniofacial.

Tissue/cell level: Lymphoid tissue — T lymphocytes (CD4+ and CD8+), B lymphocytes and plasmablasts, and likely monocyte/macrophage populations (implicated by elevated monocyte-recruiting chemokines MCP-1/MIP-1α/β in the E518K/T559M case). Suggested UBERON terms: UBERON:0002370 (thymus), UBERON:0002106 (spleen), UBERON:0002370, UBERON:0000029 (lymph node), UBERON:0002048 (lung — bronchiectasis).

Subcellular level: Cytoplasm (site of IKK complex assembly and IκBα degradation; GO:0005737), nucleus (site of NF-κB dimer translocation and transcriptional activity; GO:0005634).

Localization: Systemic/multi-organ rather than lateralized; no reported laterality pattern.

8. Temporal Development

Onset: Highly variable — reported ages at first symptom range from the first year of life (mild nail dysplasia, mild recurrent upper respiratory infections) to 48 years of age (severe CMV colitis as the presenting event) within the same genetically-defined cohort (Körholz et al. 2025, PMID:40403933). Most patients experience recurrent, mild-to-moderate upper respiratory tract infections beginning in early childhood, with more severe manifestations emerging later.

Progression: Progressive — a defining feature distinguishing IMD15A from classic congenital combined immunodeficiencies. Lymphocyte counts are typically normal in childhood/youth but decline significantly by adulthood; humoral immunity (specific antibody production) similarly deteriorates over time, and clinically significant complications (bronchiectasis, opportunistic infection) tend to manifest in adulthood.

Disease course pattern: Chronic and progressive rather than episodic, though the associated autoinflammatory/cutaneous component can present with flare-remission dynamics (as in the E518K/T559M case, which resolved by age 3 after IVIG prophylaxis, suggesting possible age-dependent penetrance for that particular presentation).

Critical periods: Adulthood appears to be a critical window for the most severe infectious/structural complications (bronchiectasis, opportunistic CMV disease), making longitudinal immunologic monitoring from childhood into adulthood clinically important even in mildly-affected pediatric carriers.

9. Inheritance and Population

Epidemiology: No population-based prevalence or incidence estimates exist; IMD15A is an ultra-rare condition described in a cumulative total of fewer than ~20 published kindreds (roughly 16 patients from 4 families in the largest series to date, plus the original 2-kindred report and additional single-case reports), consistent with a "cases in literature" tier disease. Suggested prevalence_class: ULTRA_RARE / NOT_YET_DOCUMENTED (Orphanet-style banding).

Inheritance pattern: Autosomal dominant (heterozygous), with documented de novo occurrence in index cases and vertical transmission with variable expressivity in some families (e.g., the 2025 four-family series).

Penetrance: Appears high but with markedly variable expressivity — clinical severity and organ involvement differ substantially even among relatives sharing an identical variant (nail dysplasia vs. bronchiectasis vs. CMV colitis at ages spanning infancy to the fifth decade).

Genetic anticipation: Not reported/established.

Germline mosaicism: Not specifically documented for IKBKB GOF variants in the literature reviewed; de novo origin has been confirmed by trio sequencing in index cases.

Founder effects: None identified for IMD15A itself. (Note: the contrasting, biallelic loss-of-function IMD15B disorder was described in a founder-like cluster of four families of Northern Cree ancestry — Pannicke et al. 2013 — but this is a distinct, autosomal-recessive entity and should not be conflated with IMD15A's founder status.)

Consanguinity: Not relevant to IMD15A's autosomal dominant/de novo genetics (relevant instead to the recessive IMD15B).

Carrier frequency: Not applicable (dominant, ultra-rare, largely de novo disorder; the causal alleles are essentially absent from population reference databases such as gnomAD).

Population demographics: No ethnic or geographic clustering has been reported for IMD15A; published kindreds are geographically and ethnically heterogeneous (reports from Japan/Australia [original description], the Netherlands and other European centers [2025 series], and the United States [E518K/T559M case, described as a Hispanic infant]).

Sex ratio / age distribution: No sex predilection reported; age distribution spans infancy through the fifth decade of life across the aggregate case literature.

10. Diagnostics

Clinical/laboratory tests: - Lymphocyte immunophenotyping (flow cytometry): quantify CD3+, CD4+, CD8+ T cells and CD19+ B cells; may be normal in childhood and reduced in adulthood. - Immunoglobulin levels (IgG, IgA, IgM) and specific-antibody responses (e.g., pneumococcal polysaccharide vaccine response) to detect evolving hypogammaglobulinemia/impaired humoral function. - Lymphocyte activation assays: T-cell receptor– and B-cell receptor–stimulated upregulation of CD70, CD25, CD40L (reduced at day 3 in affected patients per PMID:40403933); B-cell differentiation into plasmablasts in vitro (impaired). - Serum cytokine/chemokine panel (research-level): elevated MCP-1, MDC, MIP-1α/β, IL-18, IL-16, S100A8 reported in one variant-specific case (PMID:36378426). - Phospho-flow cytometry of PBMCs: elevated basal phospho-IKKα/β and phospho-p65; blunted TNF-α–induced IκBα phosphorylation — a research/functional confirmatory assay used in published cases, not yet a standardized clinical test. - Imaging: chest CT for bronchiectasis surveillance in patients with recurrent respiratory infection.

Genetic testing: - Recommended approach: trio-based whole exome sequencing (WES) given the de novo origin of most reported variants and the lack of a defined phenotype-driven gene panel at initial presentation; this is how essentially all published cases have been diagnosed (Cardinez et al. 2018; Körholz et al. 2025). - Single-gene IKBKB sequencing or an inborn-errors-of-immunity gene panel (including IKBKB) is reasonable when clinical suspicion (progressive lymphopenia + recurrent infection ± autoinflammatory skin disease) is high. - Functional/orthogonal validation of variant pathogenicity (NF-κB luciferase reporter assay, phospho-flow) is advisable given how many IKBKB missense variants are of uncertain significance by sequence-based prediction alone; distinguishing a true GOF allele from a benign polymorphism or a loss-of-function allele (which instead causes the very different IMD15B phenotype) is essential. - Chromosomal microarray/karyotype/FISH are not primary diagnostic modalities for this single-gene disorder.

Clinical criteria: No formal consensus diagnostic criteria have been published; diagnosis rests on the combination of (a) a compatible immunodeficiency/immune-dysregulation phenotype, (b) a heterozygous IKBKB kinase-domain (or NEMO-binding-domain) missense variant, and (c) ideally functional confirmation of gain-of-function activity.

Differential diagnosis: Other combined immunodeficiencies and immune dysregulation syndromes with progressive lymphopenia and infection susceptibility (e.g., CVID, other NF-κB pathway disorders such as NFKB1/NFKB2 haploinsufficiency, CARD11 gain-of-function disease, and — critically — IMD15B [biallelic IKBKB loss-of-function], which must be distinguished because it carries a very different inheritance pattern, earlier/more severe onset, and different molecular mechanism despite sharing the same gene).

Screening: No population or newborn screening program exists for this ultra-rare, typically de novo disorder; genetic counseling and cascade testing of first-degree relatives is appropriate once a proband is identified, given documented vertical transmission in some kindreds.

11. Outcome/Prognosis

No formal survival statistics, life-expectancy data, or standardized quality-of-life instrument results have been published, reflecting the rarity and recency of disease description. Qualitatively: - The disease course is progressive, with worsening lymphopenia, hypogammaglobulinemia, and infection burden from childhood into adulthood. - Reported complications include bronchiectasis (a marker of chronic/recurrent lower respiratory infection), severe opportunistic infection (e.g., life-threatening CMV colitis in a 48-year-old patient), splenomegaly, and cataracts. - The disease is explicitly described by its most recent characterizers as "progressing toward combined immunodeficiency" over the life course (title of Körholz et al. 2025, PMID:40403933), implying a trajectory from a mild/subclinical pediatric phenotype toward a clinically significant adult combined immunodeficiency, with life-threatening complications possible in adulthood. - Prognostic stratification by variant/domain is emerging: kinase active-site variants (V203I) and activation-loop variants appear to drive the classic progressive infection/lymphopenia phenotype, while NEMO-binding-domain variants (E518K/T559M) can instead produce a predominantly autoinflammatory/autoimmune course with potentially better long-term outcome (resolution of episodes by early childhood in the reported case).

12. Treatment

Pharmacotherapy/supportive care: - Immunoglobulin replacement therapy (IVIG) for hypogammaglobulinemia/impaired specific-antibody production — used both prophylactically (in the autoinflammatory E518K/T559M case, initiated at 9 months of age, 0.5 g/kg, with resolution of febrile/AIHA flares and discontinuation by age 3) and as standard supportive management for evolving antibody deficiency in classic IMD15A. NCIT term: NCIT:C15302 is for physical therapy — appropriate treatment term here is NCIT:C15986 (Pharmacotherapy) with therapeutic agent bound to NCIT (immunoglobulin replacement has no single CHEBI small-molecule term; consider NCIT:C1518 or a supportive-care code). - Prophylactic antimicrobials for recurrent sinopulmonary infection (standard combined-immunodeficiency supportive care), analogous to management of other CID entities.

Advanced/targeted therapeutics: - No approved targeted (small-molecule IKK2 inhibitor) therapy exists in routine clinical use. The literature explicitly notes that systemic IKK2 inhibitors are not standard clinical practice, so selective pharmacologic blockade of the mutant kinase is not currently a viable therapeutic option for IKBKB-GOF patients (Körholz et al. 2025, PMID:40403933) — an important negative finding for treatment planning. - Hematopoietic stem cell transplantation (HSCT) has been used in the more severe, infection-predominant end of the phenotypic spectrum, but the decision is described as "highly individualized" given the marked phenotypic variability of IKBKB-GOF disease; HSCT is better established for the distinct, more uniformly severe IMD15B (loss-of-function) phenotype (see PMC7106064, "Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency"). NCIT term: NCIT:C15431 (Hematopoietic Stem Cell Transplantation). - No published experience with JAK inhibitors, biologics, or gene therapy specific to IKBKB-GOF disease was identified in the current literature (unlike, for example, STAT1/STAT3 gain-of-function disorders, where JAK inhibition is now well established) — this represents an open therapeutic gap rather than an established modality.

Surgical/interventional: Not disease-specific beyond standard management of structural complications (e.g., bronchiectasis) per general pulmonology practice.

Experimental treatments: No disease-specific registered clinical trials (ClinicalTrials.gov) were identified for IMD15A specifically, consistent with its rarity and recent characterization.

Treatment strategy considerations: Because the phenotype spans infection-predominant (classic IMD15A) and autoinflammatory/autoimmune-predominant presentations depending on the specific variant/domain affected, treatment must be individualized — immunoglobulin replacement and infection prophylaxis for the classic phenotype, and immunomodulation (e.g., IVIG for autoimmune cytopenia) for the autoinflammatory variant-specific presentation — with HSCT reserved for the most severe, refractory infectious phenotype.

13. Prevention

No primary prevention (e.g., vaccination against the disease itself) is possible for this monogenic disorder. Relevant preventive measures are entirely secondary/tertiary: - Genetic counseling for identified families, given autosomal dominant inheritance with variable expressivity — informing recurrence risk (up to 50% for offspring of an affected parent) and enabling predictive testing of at-risk relatives. - Prenatal/preimplantation genetic testing could be considered for families with a known pathogenic variant, though no specific reports of its use for IMD15A were identified. - Standard immunization practices (with attention to live-vaccine safety once T-cell dysfunction is identified) and infection-prophylaxis measures (e.g., antimicrobial prophylaxis, prompt treatment of infections) as tertiary prevention against complications such as bronchiectasis. - Surveillance screening: periodic immunologic monitoring (lymphocyte subsets, immunoglobulin levels) is prudent in known carriers/affected individuals from childhood onward, given the documented progressive natural history, to enable early initiation of immunoglobulin replacement or other supportive therapy before severe complications (e.g., opportunistic CMV disease) develop.

14. Other Species / Natural Disease

No naturally occurring veterinary or wildlife disease orthologous to human IMD15A has been reported. IKBKB is broadly conserved (mouse ortholog Ikbkb, MGI:1338071; NCBI Gene — mouse), but no spontaneous animal disease phenocopy is documented (searched OMIA — no entry identified for this specific gain-of-function condition).

15. Model Organisms

Genetically engineered mouse models: - CRISPR/Cas9 orthologous knock-in mouse (Ikbkb p.V203Ile), generated by Cardinez et al. (2018, PMID:30337470) specifically to validate the human V203I variant as causal. Heterozygous and homozygous Ikbkb-V203I mice recapitulated key human findings: altered basal and activation-induced IκBα phosphorylation/degradation kinetics in splenocytes, and reduced peripheral blood CD3+ T-cell percentage, with the authors explicitly noting "mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes" — a high-fidelity model for this specific variant. - Germline Ikbkb (Ikk2) knockout mice (unrelated to the GOF disease but mechanistically informative for the gene's baseline biology): homozygous null mice are embryonic lethal (~E14.5) due to massive hepatocyte apoptosis/liver degeneration, rescuable by concurrent Tnfr1 (Tnfrsf1a) inactivation, establishing IKKβ's essential role in NF-κB-mediated protection against TNF-induced apoptosis (Li et al. 1999, Science, PMID:10195897; Li et al. 1999, Genes Dev, PMID:10229185). These null-mouse studies are foundational general IKKβ biology rather than IMD15A-specific disease models, since complete loss of IKKβ in mice is not a phenocopy of the human gain-of-function IMD15A disorder (it more closely relates conceptually, though not identically, to the human loss-of-function IMD15B mechanism). - No zebrafish, Drosophila, C. elegans, or iPSC-derived organoid models specific to IKBKB gain-of-function disease were identified in the literature reviewed.

Model characteristics and limitations: The V203I knock-in mouse is the only model directly engineered to recapitulate the human IMD15A-causing variant, and it reproduces immunophenotypic (T-cell percentage) and biochemical (IκBα kinetics) features. However, published data on this model emphasize young/baseline immunophenotyping; whether it recapitulates the progressive, age-dependent worsening (into adult bronchiectasis-level infection susceptibility or autoinflammatory skin disease) seen in the oldest human patients has not been reported, representing a translational gap between the mouse model's demonstrated fidelity for acute biochemical/T-cell-percentage phenotypes and the full, decades-long human natural history.

Resources: MGI:1338071 (Ikbkb mouse gene); no dedicated IMPC/KOMP conditional-allele phenotyping data specific to the V203I disease-associated allele were identified (standard IMPC records cover germline-null Ikbkb, which is embryonic lethal and thus not informative for adult immune phenotyping without conditional/inducible approaches).

Summary of Ontology Term Suggestions

Category Suggested terms
Disease MONDO:0032599 (Immunodeficiency 15A)
Gene HGNC:5960 (IKBKB)
Phenotypes (HP) HP:0002205, HP:0001888, HP:0002850, HP:0002110, HP:0001744, HP:0000518, HP:0000668, HP:0031292, HP:0001878, HP:0002164
GO (biological process) GO:0007249, GO:0043123, GO:0002322, GO:0002741
CL (cell type) CL:0000084, CL:0000625, CL:0000624, CL:0000236, CL:0000980
UBERON UBERON:0002370 (thymus), UBERON:0002106 (spleen), UBERON:0002048 (lung)
NCIT (treatment) NCIT:C15986 (Pharmacotherapy), NCIT:C15431 (Hematopoietic Stem Cell Transplantation)

Key Citations (PMID)

  1. Cardinez C, et al. "Gain-of-function IKBKB mutation causes human combined immune deficiency." J Exp Med. 2018. PMID:30337470
  2. Pannicke U, et al. "Deficiency of innate and acquired immunity caused by an IKBKB mutation." N Engl J Med. 2013;369:2504–14. PMID:24369075
  3. Abbott J, et al. "Heterozygous IKKβ activation loop mutation results in a complex immunodeficiency syndrome." J Allergy Clin Immunol. 2021. PMID:32554083
  4. Körholz J, Tromp SAM, Dalm VASH, et al. "IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency." J Allergy Clin Immunol. 2025. PMID:40403933
  5. [Case report] "A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation." J Clin Immunol. 2022. PMID:36378426
  6. Li Q, et al. "Severe liver degeneration in mice lacking the IkappaB kinase 2 gene." Science. 1999. PMID:10195897
  7. Li ZW, et al. "Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice." Genes Dev. 1999. PMID:10229185
  8. OMIM #618204 — IMMUNODEFICIENCY 15A; IMD15A — https://omim.org/entry/618204
  9. OMIM #615592 — IMMUNODEFICIENCY 15B; IMD15B — https://www.omim.org/entry/615592
  10. OMIM *603258 — IKBKB — https://www.omim.org/entry/603258

Note on evidence gaps for KB curation: This is an ultra-rare, recently-described (2018–2025) disorder. Quantitative epidemiology (prevalence/incidence), formal quality-of-life data, survival statistics, and dedicated omics datasets (transcriptomic/proteomic) are not currently available in the literature and should be recorded as NOT_YET_DOCUMENTED/absent rather than inferred. The mechanistic step linking "NF-κB pathway hyperactivation" to "T/B lymphocyte functional hypofunction and progressive lymphopenia" is empirically observed but not yet fully mechanistically resolved — this should be flagged as a knowledge gap in a curated pathophysiology entry.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 5
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:10229185 (2 mentions) - Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice.
  • shared terms: none

Weighed against this report's own most characteristic terms: disease, imd15a, ikbkb, variant, infection, phenotype, patient, gene, immunodeficiency, progressive, severe, disorder, autoinflammatory, clinical, recurrent, t559m, bronchiectasis, cmv, e518k, combined.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 41
Resolved 38
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 23
Terms named correctly 14
Terms named as a different term 4
Terms whose name is worth a second look 5

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:

  • HP:0010976 (1 mention) - the report calls it "Documented in functional assays"; HP calls it Decreased total B cell count
  • HP:0002164 (2 mentions) - the report calls it "Rare/variable"; HP calls it Nail dysplasia
  • HP:0001878 (2 mentions) - the report calls it "AIHA"; HP calls it Hemolytic anemia
  • GO:0002741 (2 mentions) - the report calls it "positive regulation of cytokine secretion involved in immune response"; GO calls it GO_0002741

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0002741 (GO_0002741) (2 mentions) - replaced by GO:0002720

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001888 (2 mentions) - the report calls it "Lymphopenia"; HP calls it Decreased total lymphocyte count, and lists "Lymphopenia" among its other names
  • GO:0007249 (2 mentions) - the report calls it "I-kappaB kinase/NF-kappaB signaling"; GO calls it canonical NF-kappaB signal transduction, and lists "I-kappaB kinase/NF-kappaB signaling" among its other names
  • GO:0043123 (2 mentions) - the report calls it "positive regulation of I-kappaB kinase/NF-kappaB signaling"; GO calls it positive regulation of canonical NF-kappaB signal transduction, and lists "positive regulation of I-kappaB kinase/NF-kappaB signaling" among its other names
  • GO:0042104 (1 mention) - the report calls it "positive regulation of activated T cell proliferation — for contrast/negative regulation defects"; GO calls it positive regulation of activated T cell proliferation
  • UBERON:0002048 (2 mentions) - the report calls it "lung — bronchiectasis"; UBERON calls it lung

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.