Immunodeficiency 97 With Autoinflammation

Mendelian MONDO:0030717 Pathograph 16 Show in embeddings browser Primary immunodeficiency Inborn error of immunity

Immunodeficiency 97 with autoinflammation is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in PIK3CG, which encodes p110gamma, the catalytic subunit of class IB phosphoinositide 3-kinase (PI3Kgamma). PI3Kgamma is expressed almost exclusively in leukocytes and is activated downstream of G-protein-coupled receptors, which places it at the junction between chemokine sensing and cell-intrinsic restraint of myeloid activation. The disease has the paradoxical shape its name records: it is simultaneously an immunodeficiency and an autoinflammatory disorder. On the deficiency side there are childhood-onset antibody defects with reduced memory B cells, reduced memory CD8 T cells and markedly reduced regulatory T cells. On the inflammatory side, PI3Kgamma-deficient macrophages and monocytes over-produce IL-12 and IL-23 on Toll-like receptor stimulation in a GSK3alpha/beta-dependent manner, and CXCR3-positive tissue-homing CD4 T cells are expanded, giving T-lymphocytic pneumonitis and colitis. Losing the kinase therefore removes a brake on innate inflammation while also removing a signal that adaptive immunity needs - which is why experimental systems had previously produced conflicting verdicts on whether PI3Kgamma is pro- or anti-inflammatory. Two features of the evidence base should be read before the mechanism below. First, the human disease rests on very few reported patients, and everything in this entry graded HUMAN_CLINICAL derives from one of them: the index patient with complete absence of p110gamma (PMID:31554793). A second, unrelated patient with compound heterozygous PIK3CG variants has been reported independently (PMID:33054089), and that patient presented differently - a hyperferritinemic, HLH-like inflammatory syndrome controlled on anakinra, with an NK-cell defect, rather than the antibody deficiency and lymphocytic tissue infiltration this entry is built around. The two reports also characterise the residual kinase differently, which is recorded in the evidence-base discussion. Second, the mouse knockout recapitulates the disease only after exposure to natural microbiota through co-housing with pet-store mice - under specific-pathogen-free conditions it does not. The mechanism is therefore conditional on microbial exposure in the model, and that conditionality has not been demonstrated in humans. Both points are recorded as explicit discussions rather than smoothed over.

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1
Inheritance
4
Pathophys.
9
Phenotypes
3
Gaps
16
Pathograph
1
Genes
3
Medical Actions
1
Models
4
References
1
Deep Research
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Classifications

IUIS Category
immune dysregulation
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Disease requires biallelic loss-of-function PIK3CG variants. The index patient carried deleterious mutations identified by trio whole-exome sequencing with unaffected parents, consistent with recessive inheritance. Penetrance cannot be estimated from one kindred and is deliberately left unrecorded.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"Whole exome sequencing (WES) of genomic DNA from patient A.1 and her unaffected parents identified deleterious mutations in the PIK3CG gene encoding p110γ"
Establishes biallelic PIK3CG mutations in an affected child of unaffected parents, the basis for recessive inheritance.
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Discussions and Knowledge Gaps

3
Which features of this entry are properties of the disease, and which are properties of the one patient it was defined from - and does the second reported patient's milder humoral phenotype reflect residual kinase activity or something else?
KNOWLEDGE GAP pik3cg_two_patient_evidence_base
Attached to
disease#Immunodeficiency 97 With Autoinflammation phenotypes#Decreased circulating immunoglobulin concentration
Every HUMAN_CLINICAL item in this entry traces to one individual, the index patient. That is enough to establish that biallelic PIK3CG loss causes disease in humans - the trio exome, the absent protein and the functional cellular work together make that case - but it is not enough to distinguish the disease's core phenotype from this patient's particular course. Frequencies, age at onset, penetrance and burden are therefore recorded either as this patient's values or not at all, rather than as disease-level statistics. A second unrelated patient with compound heterozygous PIK3CG variants has been reported (PMID:33054089), so the human evidence base is no longer one case. It does not settle the questions above, and it opens two of its own. The first is phenotypic. That patient presented at fourteen with fever, hyperferritinaemia, hypertriglyceridaemia and haemophagocytosis - a macrophage-activation picture that fell short of HLH criteria - with an NK-cell defect, and she has been stable on anakinra. The index patient presented in childhood with an antibody defect, autoimmune cytopenias and lymphocytic infiltration of lung and gut. Both are PI3Kgamma deficiency by genotype; clinically they share little beyond immune dysregulation. With two patients, there is no way to tell whether that is a spectrum, an allele effect, or two mechanisms that happen to share a gene. The second is about residual activity, and the two papers do not agree. The primary report finds p110gamma protein expressed at normal levels in the patient's T cells, and then shows by reconstitution that neither variant restores CD69 upregulation - a loss-of-function readout with the protein present. A later B-cell study reading the same case calls the kinase potentially hypomorphic, on the grounds that serum IgG was normal. Both may be right about different assays, but the entry should not assert either as the patient's residual-activity level, so it records both and asserts neither.
Show evidence (6 references)
PMID:31554793 SUPPORT Human Clinical
"Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG"
Establishes the index patient, from whom every HUMAN_CLINICAL item in this entry is taken.
PMID:33054089 SUPPORT Human Clinical
"gave evidence of macrophage activation in the context of a hyperferritinemic inflammatory syndrome"
The second patient's presenting picture, which is not the presenting picture of the index patient and is the phenotypic half of this discussion.
PMID:33054089 SUPPORT In Vitro
"We assessed the expression of mutated p110γ in T cells derived from patient peripheral blood mononuclear cells (PBMC), and found comparable expression levels in the patient, mother, and healthy donors (HD)"
The protein is present in the second patient, unlike the index patient in whom it is absent. Graded IN_VITRO because the measurement is an immunoblot of cultured patient cells.
+ 3 more references
Is the human disease microbiota-dependent in the way the mouse model is, or is the co-housing requirement a property of laboratory mice rather than of PI3Kgamma loss?
HUMAN MODEL MISMATCH pik3cg_microbiota_dependence_human_translation
Attached to
animal_models#Mouse pathophysiology#Unrestrained TLR-Driven Myeloid IL-12 and IL-23 Production
The Pik3cg knockout does not display the phenotype under specific-pathogen-free housing; it does so only after acquiring natural microbiota from pet-store mice. That is a strong and specific mechanistic claim, and it fits the TLR-dependence of the myeloid cytokine defect. But specific-pathogen-free housing has no human counterpart - every human carries a microbiota - so the experiment that establishes the dependence in mice cannot be run in people, and the human patient gives no information about what her disease would look like without microbial exposure. This is a HUMAN_MODEL_MISMATCH rather than a KNOWLEDGE_GAP because the evidence exists and is good; what is uncertain is whether the conditionality it demonstrates transfers.
Show evidence (1 reference)
PMID:31554793 SUPPORT Model Organism
"Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice."
States the conditional recapitulation that this mismatch is about: the model works, but only under a microbial exposure whose human analogue cannot be varied.
Why did experimental systems disagree about whether PI3Kgamma is pro-inflammatory or anti-inflammatory, and does the human loss-of-function phenotype settle it?
KNOWLEDGE GAP pik3cg_pro_versus_anti_inflammatory
Attached to
pathophysiology#PIK3CG Loss of Function
PI3Kgamma is an active drug target for immune modulation, and inhibitors are being developed on the premise that blocking it is anti-inflammatory. The human null phenotype points the other way for the myeloid arm: losing the kinase increases IL-12 and IL-23 output and produces tissue immunopathology. The conflict was explicit in the literature before this patient was described and the index report frames its own contribution as addressing it. Recorded here because the resolution bears directly on whether PI3Kgamma inhibition carries an autoinflammatory liability, which is a question about drugs in development rather than only about this disease. The same reading has a therapeutic corollary that this entry deliberately does not model as a treatment: if the myeloid arm is driven by unrestrained IL-12 and IL-23, then blocking their shared p40 subunit is the mechanistically indicated intervention. No reported patient has been given such an agent, so there is nothing to curate under treatments - a mechanistic rationale is not a treatment record - and it is noted here instead.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ."
States the disagreement in the literature that this discussion records as unresolved.
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Pathophysiology

4
PIK3CG Loss of Function
Biallelic null PIK3CG alleles abolish the p110gamma catalytic subunit, eliminating class IB PI3K activity. Because p110gamma acts downstream of G-protein-coupled receptors in leukocytes, its loss removes a signalling node that both restrains myeloid inflammatory output and supports adaptive lymphocyte programs - which is why one lesion produces two apparently opposite phenotypes.
PIK3CG hgnc:8978 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PIK3CG (hgnc:8978). hgnc:8978 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
class IB phosphoinositide 3-kinase catalytic activity GO:0016303 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves class IB phosphoinositide 3-kinase catalytic activity, annotated with 1-phosphatidylinositol-3-kinase activity (GO:0016303), qualified as loss of function. GO:0016303 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Unrestrained TLR-Driven Myeloid IL-12 and IL-23 Production Loss of p110gamma releases a GSK3alpha/beta-dependent brake on inflammatory cytokine output in macrophages and monocytes.
Impaired Adaptive Lymphocyte Compartments The same kinase is required cell-intrinsically for the transcriptional program that commits activated B cells to the antibody-secreting fate, and its loss also depletes regulatory and memory T cell compartments.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ"
Documents the null lesion and its protein-level consequence as the initiating event.
Unrestrained TLR-Driven Myeloid IL-12 and IL-23 Production
Macrophages and monocytes lacking PI3Kgamma over-produce IL-12 and IL-23 when Toll-like receptors are engaged. This is the autoinflammatory half of the disease and explains why the disorder is not simply a humoral immunodeficiency. The dependence on TLR stimulation is what links the phenotype to microbial exposure.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
interleukin-12 production GO:0032615 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-12 production (GO:0032615). GO:0032615 is a biological process from the Gene Ontology. ↑ INCREASED interleukin-23 production GO:0032627 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-23 production (GO:0032627). GO:0032627 is a biological process from the Gene Ontology. ↑ INCREASED toll-like receptor signaling pathway GO:0002224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves toll-like receptor signaling pathway (GO:0002224). GO:0002224 is a biological process from the Gene Ontology.
Animal models
Pik3cg-deficient mouse under natural microbiota exposure Mouse partially recapitulates The knockout reproduces the myeloid hyperinflammation and the tissue immunopathology, conditional on microbial exposure.
Downstream
CXCR3-Positive T Cell Tissue Infiltration IL-12 and IL-23 drive the Th1/Th17 programs whose effector cells express CXCR3 and home to inflamed tissue.
Show evidence (1 reference)
PMID:31554793 SUPPORT In Vitro
"PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/β-dependent manner upon TLR stimulation."
Documents the elevated cytokine output on TLR stimulation that defines this node.
Impaired Adaptive Lymphocyte Compartments
Memory B cells, memory CD8 T cells and regulatory T cells are all reduced in peripheral blood, and FOXP3 expression within the residual regulatory T cells is itself lower. The regulatory T cell defect is the plausible link between this node and the inflammatory arm, since it removes a second, independent brake on the same tissue inflammation.
regulatory T cell CL:0000815 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves regulatory T cell (CL:0000815). CL:0000815 is a cell type from the Cell Ontology. 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. memory CD8-positive T cell CL:0000909 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves memory CD8-positive T cell, annotated with CD8-positive, alpha-beta memory T cell (CL:0000909). CL:0000909 is a cell type from the Cell Ontology.
regulatory T cell differentiation GO:0045066 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulatory T cell differentiation (GO:0045066). GO:0045066 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Decreased circulating immunoglobulin concentration
Autoimmune hemolytic anemia The regulatory T cell deficit is the entry's account of the autoimmune arm: the index report groups the cytopenias with the antibody defect as autoimmune complications, and autoantibody production against red cells is the intermediate step this edge skips over rather than asserts.
Thrombocytopenia The same autoimmune mechanism in a second lineage; the two cytopenias are reported together and recurred together, which is why they are wired from one node.
Decreased specific antibody response to vaccination The reduced memory B cell compartment is the same lesion seen from the functional side: fewer antigen-experienced B cells able to commit to the antibody-secreting fate means weaker responses to immunization.
CXCR3-Positive T Cell Tissue Infiltration Loss of regulatory T cells removes the suppressive constraint on effector T cells entering tissue.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"we next examined the frequency of regulatory T cells (Treg) in peripheral blood samples and observed a remarkably low frequency of CD25hiCD127lo CD4+ T cells"
Documents the regulatory T cell deficit directly in the patient's peripheral blood.
CXCR3-Positive T Cell Tissue Infiltration
CXCR3-positive tissue-homing CD4 T cells are expanded and infiltrate lung and gut, producing lymphocytic pneumonitis and colitis. This is the node where the two arms of the disease converge: excess myeloid IL-12/IL-23 drives the effector program, and the regulatory T cell deficit removes what would otherwise restrain it.
CXCR3-positive tissue-homing CD4 T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CXCR3-positive tissue-homing CD4 T cell, annotated with CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology.
Downstream
Lymphocytic interstitial pneumonitis
Colitis
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"increased CXCR3+ tissue-homing CD4 T cells"
Documents the expanded tissue-homing T cell population that this node describes.
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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 97 With Autoinflammation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

9
Blood 3
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.
Sequelae: Recurrent respiratory infections
Show evidence (2 references)
PMID:31554793 SUPPORT Human Clinical
"She has a history of childhood-onset antibody defects"
Documents the antibody defect in the index patient.
PMID:38961274 SUPPORT BACKGROUND Human Clinical
"The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects"
States the human humoral phenotype. Graded HUMAN_CLINICAL because that is what the sentence describes, with quote_role BACKGROUND because this mouse-and-organoid study is restating the human observation as motivation rather than reporting it.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"Further follow up and analysis revealed clinical progression to hypogammaglobulinemia, thrombocytopenia, various lymphopenias, eosinophilia, mediastinal and hilar lymphadenopathy, and splenomegaly"
Lists thrombocytopenia among the features the index patient progressed to.
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.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"ytic anemia at nine years of age (preceding the initial pneumonitis by several months) was treated with steroids and blood transfusions"
Documents the autoimmune haemolytic anaemia, its age at onset and its position relative to the pneumonitis in the disease course.
Cardiovascular 2
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Deliberately left with no incoming causal edge. The entry's two arms - myeloid IL-12/IL-23 excess and the regulatory T cell deficit - are both plausible upstreams for lymphoproliferation, and the cited source states the finding without attributing it. An edge here would assert a mechanism this entry cannot support.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"Further follow up and analysis revealed clinical progression to hypogammaglobulinemia, thrombocytopenia, various lymphopenias, eosinophilia, mediastinal and hilar lymphadenopathy, and splenomegaly"
Names the mediastinal and hilar lymphadenopathy this phenotype records.
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Left unwired for the same reason as the lymphadenopathy above.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"lymphadenopathy/splenomegaly, and pathological T cell infiltration of barrier tissues"
Names splenomegaly in the paper's own summary of the patient's presentation.
Digestive 1
Colitis HP:0002583 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colitis (HP:0002583). HP:0002583 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"cytopenias, and T lymphocytic pneumonitis and colitis"
Documents colitis as part of the tissue-infiltrative phenotype.
Immune 2
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:38961274 SUPPORT Human Clinical
"A normal response elicited by the tetanus vaccine but weak responses to other, classically weaker, immunizations was observed"
Gives the selective vaccine-response defect in the index patient. Graded HUMAN_CLINICAL and left without quote_role because the sentence reports this study's own tabulation of the patient's immunization data rather than restating an earlier report.
Recurrent respiratory infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent sinopulmonary infections, annotated with Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"The childhood of patient A.1 was remarkable for recurrent sinopulmonary, ear, skin, and urinary tract infections (commonly with S. aureus), chronic nasal congestion, and eczema."
Establishes the recurrent sinopulmonary infections and their usual organism.
Respiratory 1
Lymphocytic interstitial pneumonitis Lymphocytic interstitial pneumonia HP:0006527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphocytic interstitial pneumonia (HP:0006527). HP:0006527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"Patient with loss of PI3Kγ and T lymphocytic infiltration of lung and gut."
Documents lymphocytic infiltration of the lung in the index patient.
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Genetic Associations

1
PIK3CG
Gene: PIK3CG hgnc:8978 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PIK3CG (hgnc:8978). hgnc:8978 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:31554793 SUPPORT Human Clinical
"Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation."
Establishes the leukocyte-restricted expression that confines the phenotype to the immune compartment.
PMID:33661099 SUPPORT In Vitro
"we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity"
Gives the structural mechanism by which a single C-terminal residue change inactivates the enzyme, and records that the same residue can be mutated the other way in cancer - which is why this gene supports two opposite disease directions.
💊

Medical Actions

3
Immunoglobulin Replacement Therapy
Action: Immunoglobulin TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. NCIT:C62710
Platform: Protein replacement
Indefinite immunoglobulin replacement substitutes for the antibody the patient cannot make. It addresses the deficiency half of the phenotype only.
Mechanism Target:
Impaired Adaptive Lymphocyte Compartments — Exogenous immunoglobulin bypasses the failed antibody-secreting-cell differentiation rather than correcting it.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"Patient A.1 is currently treated with immunoglobulin replacement therapy to restore humoral protection"
Documents immunoglobulin replacement and its stated purpose in the index patient.
Mycophenolate Mofetil
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: mycophenolate mofetil CHEBI:8764 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses mycophenolate mofetil (CHEBI:8764). CHEBI:8764 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Mycophenolate mofetil suppresses the tissue-infiltrative inflammation. Together with immunoglobulin replacement it gives the two-drug shape that follows directly from the two-armed mechanism: one agent replaces what is missing, the other restrains what is unrestrained.
Mechanism Target:
CXCR3-Positive T Cell Tissue Infiltration — Antiproliferative immunosuppression restrains the infiltrating lymphocyte population.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"and mycophenolate mofetil to suppress inflammation"
Documents mycophenolate mofetil and its stated purpose in the index patient.
B Cell Depletion with Rituximab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
CD20-positive B cell depletion was used for recurrent autoimmune cytopenias. It is a response to a complication rather than to the underlying kinase defect.
Mechanism Target:
Impaired Adaptive Lymphocyte Compartments — Depleting B cells removes the source of the autoantibody driving the cytopenias, at the cost of deepening the humoral deficiency the same node causes.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"a recurrence of autoimmune cytopenias at seventeen years prompted CD20+ B cell depletion with rituximab"
Documents rituximab use and the indication for it in the index patient.
🔬

Diagnosis

2
Trio whole exome sequencing
The diagnosis is molecular. There is no biomarker and no functional screening assay in routine use, so the disorder is found by sequencing a patient whose phenotype - childhood antibody defect with autoimmune cytopenias, lymphoproliferation and lymphocytic tissue infiltration - has no other explanation. The index diagnosis was made on a proband-plus-unaffected-parents trio, which is what established biallelic inheritance and excluded competing variants in the same run.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"Whole exome sequencing (WES) of genomic DNA from patient A.1 and her unaffected parents identified deleterious mutations in the PIK3CG gene encoding p110γ"
Records the diagnostic route and its trio design, which is what makes the biallelic call possible.
p110gamma protein expression in patient leukocytes
Absence of the p110gamma catalytic subunit on immunoblot of patient cells is the confirmatory step that turns two sequence variants into a demonstrated null. Recorded because for this disorder the variant call alone does not establish complete deficiency, which is the entry's scoping claim.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ."
States that the protein is absent in the patient, which is the confirmatory finding this test reports.
📊

Prevalence

1
Worldwide
Cases In Literature Unknown
Two unrelated patients with germline biallelic PIK3CG variants have been reported: the index patient with complete absence of p110gamma (PMID:31554793), and a second patient reported independently by a different group (PMID:33054089), whose kinase the companion B-cell study describes as potentially hypomorphic. No rate, class or band can be assigned from two cases, and a qualitative tier is not used here either: ULTRA_RARE presupposes a prevalence threshold that nobody has estimated for this disorder. PubMed carries no abstract for PMID:33054089, but the full text is open access through PMC, so the second case is cited from its own report rather than only through another paper's restatement of it.
Show evidence (3 references)
PMID:31554793 SUPPORT Human Clinical
"Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ."
Establishes the index patient from whom the human disease was defined, and who is the whole of this entry's HUMAN_CLINICAL evidence base.
PMID:33054089 SUPPORT Human Clinical
"We identified compound heterozygous variants in PIK3CG encoding for p110γ, the catalytic subunit of the PI3Kγ complex."
The second patient, from her own report: an independent group, an unrelated family, and biallelic PIK3CG variants. This is what makes the denominator two rather than one.
PMID:38961274 SUPPORT BACKGROUND Human Clinical
"An additional previously reported case of a patient with immune dysregulation and potentially hypomorphic PI3Kγ had normal serum IgG levels"
A third group's reading of that second patient, kept alongside the primary report because the two characterise the residual kinase differently. quote_role BACKGROUND because this sentence restates another group's case in the discussion of a mouse study rather than reporting the case itself.
⚖️

Clinical Burden

Moderate
The reported patient required blood transfusions and steroids for autoimmune haemolytic anaemia at nine, B-cell depletion with rituximab for recurrent cytopenias at seventeen, and is on indefinite immunoglobulin replacement plus mycophenolate mofetil. That is chronic, multi-agent, lifelong therapy for both halves of the phenotype. Recorded as MODERATE rather than HIGH because the disease proved controllable on that regimen and no death or organ failure is reported - but the assessment rests on the index patient's course, so it should be read as provisional rather than as a population estimate.
Show evidence (1 reference)
PMID:31554793 SUPPORT Human Clinical
"Patient A.1 is currently treated with immunoglobulin replacement therapy to restore humoral protection and mycophenolate mofetil to suppress inflammation."
Documents the indefinite two-agent regimen - one drug per half of the phenotype - behind the burden assessment.
🐁

Animal Models

1
Pik3cg-deficient mouse under natural microbiota exposure
The knockout mouse reproduces major features of the human disease, but only after exposure to natural microbiota through co-housing with pet-store mice. This is the central caveat of the model and is the reason the disease is thought to be microbiota-dependent: under conventional specific-pathogen-free housing the phenotype does not appear. The dependence is established in the mouse and has not been demonstrated in the patient.
Species
Mouse
Genotype
Pik3cg knockout
Publication
PMID:31554793
Pathograph links
Unrestrained TLR-Driven Myeloid IL-12 and IL-23 Production partially recapitulates fidelity: moderate observes: organism The knockout reproduces the myeloid hyperinflammation and the tissue immunopathology, conditional on microbial exposure.
Limitations: The phenotype is contingent on co-housing with pet-store mice to acquire natural microbiota, so the model reports what PI3Kgamma loss does under a defined microbial challenge rather than what it does unconditionally. Whether the human disease carries the same dependence is untested, and the human comparison rests on the index patient.
Show evidence (1 reference)
PMID:31554793 SUPPORT Model Organism
"Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice."
States both that the model recapitulates the disease and the exact condition under which it does, which is what makes this a qualified rather than an unqualified recapitulation claim.
Show evidence (1 reference)
PMID:31554793 SUPPORT Model Organism
"Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice."
Supports treating the mouse as informative for the human mechanism, on the authors' own cross-species reading.
{ }

Source YAML

click to show 
name: Immunodeficiency 97 With Autoinflammation
creation_date: "2026-09-18T00:00:00Z"
category: Mendelian
synonyms:
- IMD97
- PI3K-gamma deficiency
- PI3Kgamma deficiency
- p110gamma deficiency
- PIK3CG deficiency
- immunodeficiency 97 with autoinflammation, autosomal recessive
description: >
  Immunodeficiency 97 with autoinflammation is an autosomal recessive inborn error of
  immunity caused by biallelic loss-of-function variants in PIK3CG, which encodes p110gamma,
  the catalytic subunit of class IB phosphoinositide 3-kinase (PI3Kgamma). PI3Kgamma is
  expressed almost exclusively in leukocytes and is activated downstream of G-protein-coupled
  receptors, which places it at the junction between chemokine sensing and cell-intrinsic
  restraint of myeloid activation.

  The disease has the paradoxical shape its name records: it is simultaneously an
  immunodeficiency and an autoinflammatory disorder. On the deficiency side there are
  childhood-onset antibody defects with reduced memory B cells, reduced memory CD8 T cells
  and markedly reduced regulatory T cells. On the inflammatory side, PI3Kgamma-deficient
  macrophages and monocytes over-produce IL-12 and IL-23 on Toll-like receptor stimulation
  in a GSK3alpha/beta-dependent manner, and CXCR3-positive tissue-homing CD4 T cells are
  expanded, giving T-lymphocytic pneumonitis and colitis. Losing the kinase therefore
  removes a brake on innate inflammation while also removing a signal that adaptive immunity
  needs - which is why experimental systems had previously produced conflicting verdicts on
  whether PI3Kgamma is pro- or anti-inflammatory.

  Two features of the evidence base should be read before the mechanism below. First, the
  human disease rests on very few reported patients, and everything in this entry graded
  HUMAN_CLINICAL derives from one of them: the index patient with complete absence of
  p110gamma (PMID:31554793). A second, unrelated patient with compound heterozygous PIK3CG
  variants has been reported independently (PMID:33054089), and that patient presented
  differently - a hyperferritinemic, HLH-like inflammatory syndrome controlled on anakinra,
  with an NK-cell defect, rather than the antibody deficiency and lymphocytic tissue
  infiltration this entry is built around. The two reports also characterise the residual
  kinase differently, which is recorded in the evidence-base discussion. Second, the mouse knockout recapitulates
  the disease only after exposure to natural microbiota through co-housing with pet-store
  mice - under specific-pathogen-free conditions it does not. The mechanism is therefore
  conditional on microbial exposure in the model, and that conditionality has not been
  demonstrated in humans. Both points are recorded as explicit discussions rather than
  smoothed over.
disease_term:
  preferred_term: immunodeficiency 97 with autoinflammation
  term:
    id: MONDO:0030717
    label: immunodeficiency 97 with autoinflammation
parents:
- Primary immunodeficiency
- Inborn error of immunity
references:
- reference: PMID:31554793
  title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
- reference: PMID:38961274
  title: "PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells."
- reference: PMID:33661099
  title: "Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors."
- reference: PMID:33054089
  title: "Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation."
notes: >-
  No GeneReviews chapter exists for this condition. `just check-genereviews` returns
  NO_CHAPTER for both Bookshelf collections against the committed index (snapshot
  2026-09-10), which is expected for a disorder defined in 2019 from a single index patient. The
  phenotype baseline is therefore the index report itself (PMID:31554793).

  This entry is the loss-of-function, class IB counterpart of `Activated_PI3K-delta_Syndrome`
  (APDS), and the two should not be conflated: APDS is gain-of-function in PIK3CD (p110delta,
  class IA), this is loss-of-function in PIK3CG (p110gamma, class IB). Different gene,
  different isoform, opposite direction of effect.
classifications:
  iuis_category:
    classification_value: immune dysregulation
    notes: >-
      Recorded as immune dysregulation because the defining clinical picture combines a
      humoral deficiency with tissue-infiltrative autoinflammation (T-lymphocytic
      pneumonitis and colitis) and autoimmune cytopenias, with reduced regulatory T cells as
      the immunological correlate. A pure-deficiency classification would not capture the
      inflammatory half of the phenotype the disease is named for.
    evidence:
    - reference: PMID:31554793
      reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic
        pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and
        regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells.
      explanation: >-
        Gives the combined deficiency-plus-dysregulation phenotype that the classification
        records.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Two unrelated patients with germline biallelic PIK3CG variants have been reported: the
    index patient with complete absence of p110gamma (PMID:31554793), and a second patient
    reported independently by a different group (PMID:33054089), whose kinase the companion
    B-cell study describes as potentially hypomorphic. No rate, class or band can be
    assigned from two cases, and a qualitative tier is not used here either: ULTRA_RARE
    presupposes a prevalence threshold that nobody has estimated for this disorder.

    PubMed carries no abstract for PMID:33054089, but the full text is open access through
    PMC, so the second case is cited from its own report rather than only through another
    paper's restatement of it.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG
      resulting in absence of the p110γ catalytic subunit of PI3Kγ.
    explanation: >-
      Establishes the index patient from whom the human disease was defined, and who is the
      whole of this entry's HUMAN_CLINICAL evidence base.
  - reference: PMID:33054089
    reference_title: "Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified compound heterozygous variants in PIK3CG encoding for p110γ, the
      catalytic subunit of the PI3Kγ complex.
    explanation: >-
      The second patient, from her own report: an independent group, an unrelated family,
      and biallelic PIK3CG variants. This is what makes the denominator two rather than one.
  - reference: PMID:38961274
    reference_title: "PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      An additional previously reported case of a patient with immune dysregulation and
      potentially hypomorphic PI3Kγ had normal serum IgG levels
    explanation: >-
      A third group's reading of that second patient, kept alongside the primary report
      because the two characterise the residual kinase differently. quote_role BACKGROUND
      because this sentence restates another group's case in the discussion of a mouse study
      rather than reporting the case itself.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    The reported patient required blood transfusions and steroids for autoimmune haemolytic
    anaemia at nine, B-cell depletion with rituximab for recurrent cytopenias at seventeen,
    and is on indefinite immunoglobulin replacement plus mycophenolate mofetil. That is
    chronic, multi-agent, lifelong therapy for both halves of the phenotype. Recorded as
    MODERATE rather than HIGH because the disease proved controllable on that regimen and
    no death or organ failure is reported - but the assessment rests on the index patient's
    course, so it should be read as provisional rather than as a population estimate.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient A.1 is currently treated with immunoglobulin replacement therapy to restore
      humoral protection and mycophenolate mofetil to suppress inflammation.
    explanation: >-
      Documents the indefinite two-agent regimen - one drug per half of the phenotype -
      behind the burden assessment.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Disease requires biallelic loss-of-function PIK3CG variants. The index patient carried
    deleterious mutations identified by trio whole-exome sequencing with unaffected parents,
    consistent with recessive inheritance. Penetrance cannot be estimated from one kindred
    and is deliberately left unrecorded.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing (WES) of genomic DNA from patient A.1 and her unaffected
      parents identified deleterious mutations in the PIK3CG gene encoding p110γ
    explanation: >-
      Establishes biallelic PIK3CG mutations in an affected child of unaffected parents,
      the basis for recessive inheritance.
genetic:
- name: PIK3CG
  gene_term:
    preferred_term: PIK3CG
    term:
      id: hgnc:8978
      label: PIK3CG
  relationship_type: CAUSATIVE
  notes: >
    PIK3CG encodes p110gamma, the catalytic subunit of class IB PI3K. Biallelic
    loss-of-function variants abolish the protein. Because p110gamma is the only class IB
    catalytic subunit and is essentially leukocyte-restricted, the consequences are confined
    to the immune system rather than being systemic.

    There is a protein-level account of how a single residue can do this. Biophysical work on
    the C-terminal residue R1021 shows that immunodeficiency and oncogenic mutations at the
    same position act in opposite directions - inactivating or activating the enzyme - by
    disrupting regulatory C-terminal dynamics. That one residue can be pushed either way is
    what makes this gene a locus for both an inborn error of immunity and a cancer target,
    and it is the mechanism by which a missense change, rather than a truncation, produces a
    functional null.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is
      an attractive drug target for immune modulation.
    explanation: >-
      Establishes the leukocyte-restricted expression that confines the phenotype to the
      immune compartment.
  - reference: PMID:33661099
    reference_title: "Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we have revealed insight into regulation of kinase activity, specifically defining how
      immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or
      activate enzyme activity
    explanation: >-
      Gives the structural mechanism by which a single C-terminal residue change inactivates
      the enzyme, and records that the same residue can be mutated the other way in cancer -
      which is why this gene supports two opposite disease directions.
pathophysiology:
- name: PIK3CG Loss of Function
  description: >
    Biallelic null PIK3CG alleles abolish the p110gamma catalytic subunit, eliminating class
    IB PI3K activity. Because p110gamma acts downstream of G-protein-coupled receptors in
    leukocytes, its loss removes a signalling node that both restrains myeloid inflammatory
    output and supports adaptive lymphocyte programs - which is why one lesion produces two
    apparently opposite phenotypes.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: PIK3CG
    term:
      id: hgnc:8978
      label: PIK3CG
  molecular_functions:
  - preferred_term: class IB phosphoinositide 3-kinase catalytic activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0016303
      label: 1-phosphatidylinositol-3-kinase activity
  downstream:
  - target: Unrestrained TLR-Driven Myeloid IL-12 and IL-23 Production
    causal_link_type: DIRECT
    description: >-
      Loss of p110gamma releases a GSK3alpha/beta-dependent brake on inflammatory cytokine
      output in macrophages and monocytes.
    evidence:
    - reference: PMID:31554793
      reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and
        IL-23 in a GSK3α/β-dependent manner upon TLR stimulation.
      explanation: >-
        Names both the direction of the effect and the intermediate (GSK3alpha/beta) that
        makes this a mechanistic edge rather than a correlation between two states.
  - target: Impaired Adaptive Lymphocyte Compartments
    causal_link_type: DIRECT
    description: >-
      The same kinase is required cell-intrinsically for the transcriptional program that
      commits activated B cells to the antibody-secreting fate, and its loss also depletes
      regulatory and memory T cell compartments.
    evidence:
    - reference: PMID:38961274
      reference_title: "PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Using mouse immunization models, we found that PI3Kγ functions cell intrinsically
        within activated B cells in a kinase activity-dependent manner to transduce signals
        required for the transcriptional program supporting differentiation of ASCs.
      explanation: >-
        Establishes the cell-intrinsic, kinase-dependent requirement for PI3Kgamma in the
        B cell arm. Graded INDIRECT because the demonstration is in mouse immunization
        models and human tonsillar organoids rather than in the patient.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ
      catalytic subunit of PI3Kγ
    explanation: >-
      Documents the null lesion and its protein-level consequence as the initiating event.
- name: Unrestrained TLR-Driven Myeloid IL-12 and IL-23 Production
  description: >
    Macrophages and monocytes lacking PI3Kgamma over-produce IL-12 and IL-23 when
    Toll-like receptors are engaged. This is the autoinflammatory half of the disease and
    explains why the disorder is not simply a humoral immunodeficiency. The dependence on
    TLR stimulation is what links the phenotype to microbial exposure.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: interleukin-12 production
    modifier: INCREASED
    term:
      id: GO:0032615
      label: interleukin-12 production
  - preferred_term: interleukin-23 production
    modifier: INCREASED
    term:
      id: GO:0032627
      label: interleukin-23 production
  - preferred_term: toll-like receptor signaling pathway
    term:
      id: GO:0002224
      label: toll-like receptor signaling pathway
  downstream:
  - target: CXCR3-Positive T Cell Tissue Infiltration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      IL-12 and IL-23 drive the Th1/Th17 programs whose effector cells express CXCR3 and
      home to inflamed tissue.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and
      IL-23 in a GSK3α/β-dependent manner upon TLR stimulation.
    explanation: >-
      Documents the elevated cytokine output on TLR stimulation that defines this node.
    images: []
- name: Impaired Adaptive Lymphocyte Compartments
  description: >
    Memory B cells, memory CD8 T cells and regulatory T cells are all reduced in peripheral
    blood, and FOXP3 expression within the residual regulatory T cells is itself lower. The
    regulatory T cell defect is the plausible link between this node and the inflammatory
    arm, since it removes a second, independent brake on the same tissue inflammation.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  - preferred_term: memory CD8-positive T cell
    term:
      id: CL:0000909
      label: CD8-positive, alpha-beta memory T cell
  biological_processes:
  - preferred_term: regulatory T cell differentiation
    modifier: DECREASED
    term:
      id: GO:0045066
      label: regulatory T cell differentiation
  downstream:
  - target: Decreased circulating immunoglobulin concentration
    causal_link_type: DIRECT
  - target: Autoimmune hemolytic anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The regulatory T cell deficit is the entry's account of the autoimmune arm: the index
      report groups the cytopenias with the antibody defect as autoimmune complications, and
      autoantibody production against red cells is the intermediate step this edge skips
      over rather than asserts.
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The same autoimmune mechanism in a second lineage; the two cytopenias are reported
      together and recurred together, which is why they are wired from one node.
  - target: Decreased specific antibody response to vaccination
    causal_link_type: DIRECT
    description: >-
      The reduced memory B cell compartment is the same lesion seen from the functional
      side: fewer antigen-experienced B cells able to commit to the antibody-secreting fate
      means weaker responses to immunization.
  - target: CXCR3-Positive T Cell Tissue Infiltration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of regulatory T cells removes the suppressive constraint on effector T cells
      entering tissue.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we next examined the frequency of regulatory T cells (Treg) in peripheral blood
      samples and observed a remarkably low frequency of CD25hiCD127lo CD4+ T cells
    explanation: >-
      Documents the regulatory T cell deficit directly in the patient's peripheral blood.
- name: CXCR3-Positive T Cell Tissue Infiltration
  description: >
    CXCR3-positive tissue-homing CD4 T cells are expanded and infiltrate lung and gut,
    producing lymphocytic pneumonitis and colitis. This is the node where the two arms of
    the disease converge: excess myeloid IL-12/IL-23 drives the effector program, and the
    regulatory T cell deficit removes what would otherwise restrain it.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: CXCR3-positive tissue-homing CD4 T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  downstream:
  - target: Lymphocytic interstitial pneumonitis
    causal_link_type: DIRECT
  - target: Colitis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      increased CXCR3+ tissue-homing CD4 T cells
    explanation: >-
      Documents the expanded tissue-homing T cell population that this node describes.
phenotypes:
- category: Immunological
  name: Decreased circulating immunoglobulin concentration
  description: >
    Childhood-onset antibody defect requiring indefinite immunoglobulin replacement. The
    B-cell work in the companion study gives the mechanism: PI3Kgamma is needed for the
    commitment of activated B cells to the antibody-secreting fate.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  sequelae:
  - target: Recurrent respiratory infections
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has a history of childhood-onset antibody defects
    explanation: >-
      Documents the antibody defect in the index patient.
  - reference: PMID:38961274
    reference_title: "PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The inborn error of immunity caused by human deficiency in PI3Kγ results in broad
      humoral defects
    explanation: >-
      States the human humoral phenotype. Graded HUMAN_CLINICAL because that is what the
      sentence describes, with quote_role BACKGROUND because this mouse-and-organoid study
      is restating the human observation as motivation rather than reporting it.
- category: Immunological
  name: Decreased specific antibody response to vaccination
  description: >
    Vaccine responses are selectively rather than globally impaired in the index patient:
    the tetanus response was normal while responses to weaker immunogens were poor. This is
    the functional counterpart of the serum immunoglobulin deficit above, and it is what the
    B-cell mechanism predicts - PI3Kgamma is needed for the commitment of activated B cells
    to the antibody-secreting fate, which bites hardest where the antigenic stimulus is
    weakest.
  phenotype_term:
    preferred_term: Decreased specific antibody response to vaccination
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  evidence:
  - reference: PMID:38961274
    reference_title: "PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A normal response elicited by the tetanus vaccine but weak responses to other,
      classically weaker, immunizations was observed
    explanation: >-
      Gives the selective vaccine-response defect in the index patient. Graded
      HUMAN_CLINICAL and left without quote_role because the sentence reports this study's
      own tabulation of the patient's immunization data rather than restating an earlier
      report.
- category: Hematological
  name: Thrombocytopenia
  description: >
    Part of the recurrent autoimmune cytopenias that prompted B-cell depletion at seventeen.
    Reported as part of the index patient's clinical progression alongside the
    hypogammaglobulinemia, so it is a feature of the same autoimmune arm as the haemolytic
    anaemia rather than a separate problem.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further follow up and analysis revealed clinical progression to hypogammaglobulinemia,
      thrombocytopenia, various lymphopenias, eosinophilia, mediastinal and hilar
      lymphadenopathy, and splenomegaly
    explanation: >-
      Lists thrombocytopenia among the features the index patient progressed to.
- category: Immunological
  name: Lymphadenopathy
  description: >
    Mediastinal and hilar lymphadenopathy with splenomegaly, reported as part of the index
    patient's clinical progression.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  notes: >-
    Deliberately left with no incoming causal edge. The entry's two arms - myeloid
    IL-12/IL-23 excess and the regulatory T cell deficit - are both plausible upstreams for
    lymphoproliferation, and the cited source states the finding without attributing it. An
    edge here would assert a mechanism this entry cannot support.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further follow up and analysis revealed clinical progression to hypogammaglobulinemia,
      thrombocytopenia, various lymphopenias, eosinophilia, mediastinal and hilar
      lymphadenopathy, and splenomegaly
    explanation: >-
      Names the mediastinal and hilar lymphadenopathy this phenotype records.
- category: Immunological
  name: Splenomegaly
  description: >
    Splenomegaly accompanying the lymphadenopathy in the index patient.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  notes: >-
    Left unwired for the same reason as the lymphadenopathy above.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      lymphadenopathy/splenomegaly, and pathological T cell infiltration of barrier tissues
    explanation: >-
      Names splenomegaly in the paper's own summary of the patient's presentation.
- category: Immunological
  name: Recurrent respiratory infections
  description: >
    Recurrent sinopulmonary infections through childhood, commonly with Staphylococcus
    aureus, alongside ear, skin and urinary tract infections. This is the infection half of
    the phenotype that makes the disorder an immunodeficiency rather than an
    autoinflammatory syndrome alone.
  phenotype_term:
    preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The childhood of patient A.1 was remarkable for recurrent sinopulmonary, ear, skin,
      and urinary tract infections (commonly with S. aureus), chronic nasal congestion, and
      eczema.
    explanation: >-
      Establishes the recurrent sinopulmonary infections and their usual organism.
- category: Hematological
  name: Autoimmune hemolytic anemia
  description: >
    Autoimmune destruction of red cells, presenting at nine years of age in the index
    patient, several months before the first episode of pneumonitis.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ytic anemia at nine years of age (preceding the initial pneumonitis by several months)
      was treated with steroids and blood transfusions
    explanation: >-
      Documents the autoimmune haemolytic anaemia, its age at onset and its position
      relative to the pneumonitis in the disease course.
- category: Respiratory
  name: Lymphocytic interstitial pneumonitis
  description: >
    T-lymphocytic infiltration of the lung, seen as diffuse pulmonary nodular and patchy
    infiltrates on CT with lymphocytic infiltrate on lung biopsy.
  phenotype_term:
    preferred_term: Lymphocytic interstitial pneumonia
    term:
      id: HP:0006527
      label: Lymphocytic interstitial pneumonia
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient with loss of PI3Kγ and T lymphocytic infiltration of lung and gut.
    explanation: >-
      Documents lymphocytic infiltration of the lung in the index patient.
- category: Gastrointestinal
  name: Colitis
  description: >
    T-lymphocytic infiltration of the colon. It shares a mechanism and a treatment with the
    pulmonary involvement, which is why both respond to the same immunosuppression.
  phenotype_term:
    preferred_term: Colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cytopenias, and T lymphocytic pneumonitis and colitis
    explanation: >-
      Documents colitis as part of the tissue-infiltrative phenotype.
animal_models:
- name: Pik3cg-deficient mouse under natural microbiota exposure
  species: Mouse
  genotype: Pik3cg knockout
  publication: PMID:31554793
  description: >
    The knockout mouse reproduces major features of the human disease, but only after
    exposure to natural microbiota through co-housing with pet-store mice. This is the
    central caveat of the model and is the reason the disease is thought to be
    microbiota-dependent: under conventional specific-pathogen-free housing the phenotype
    does not appear. The dependence is established in the mouse and has not been
    demonstrated in the patient.
  modeled_mechanisms:
  - target: Unrestrained TLR-Driven Myeloid IL-12 and IL-23 Production
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The knockout reproduces the myeloid hyperinflammation and the tissue immunopathology,
      conditional on microbial exposure.
    limitations: >-
      The phenotype is contingent on co-housing with pet-store mice to acquire natural
      microbiota, so the model reports what PI3Kgamma loss does under a defined microbial
      challenge rather than what it does unconditionally. Whether the human disease carries
      the same dependence is untested, and the human comparison rests on the index patient.
    evidence:
    - reference: PMID:31554793
      reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Pik3cg-deficient mice recapitulate major features of human disease after exposure to
        natural microbiota through co-housing with pet-store mice.
      explanation: >-
        States both that the model recapitulates the disease and the exact condition under
        which it does, which is what makes this a qualified rather than an unqualified
        recapitulation claim.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, our results emphasize the physiological importance of PI3Kγ in restraining
      inflammation and promoting appropriate adaptive immune responses in both humans and
      mice.
    explanation: >-
      Supports treating the mouse as informative for the human mechanism, on the authors'
      own cross-species reading.
diagnosis:
- name: Trio whole exome sequencing
  description: >
    The diagnosis is molecular. There is no biomarker and no functional screening assay in
    routine use, so the disorder is found by sequencing a patient whose phenotype -
    childhood antibody defect with autoimmune cytopenias, lymphoproliferation and
    lymphocytic tissue infiltration - has no other explanation. The index diagnosis was made
    on a proband-plus-unaffected-parents trio, which is what established biallelic
    inheritance and excluded competing variants in the same run.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing (WES) of genomic DNA from patient A.1 and her unaffected
      parents identified deleterious mutations in the PIK3CG gene encoding p110γ
    explanation: >-
      Records the diagnostic route and its trio design, which is what makes the biallelic
      call possible.
- name: p110gamma protein expression in patient leukocytes
  description: >
    Absence of the p110gamma catalytic subunit on immunoblot of patient cells is the
    confirmatory step that turns two sequence variants into a demonstrated null. Recorded
    because for this disorder the variant call alone does not establish complete deficiency,
    which is the entry's scoping claim.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG
      resulting in absence of the p110γ catalytic subunit of PI3Kγ.
    explanation: >-
      States that the protein is absent in the patient, which is the confirmatory finding
      this test reports.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >
    Indefinite immunoglobulin replacement substitutes for the antibody the patient cannot
    make. It addresses the deficiency half of the phenotype only.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Immunoglobulin Therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Impaired Adaptive Lymphocyte Compartments
    description: >-
      Exogenous immunoglobulin bypasses the failed antibody-secreting-cell differentiation
      rather than correcting it.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient A.1 is currently treated with immunoglobulin replacement therapy to restore
      humoral protection
    explanation: >-
      Documents immunoglobulin replacement and its stated purpose in the index patient.
- name: Mycophenolate Mofetil
  description: >
    Mycophenolate mofetil suppresses the tissue-infiltrative inflammation. Together with
    immunoglobulin replacement it gives the two-drug shape that follows directly from the
    two-armed mechanism: one agent replaces what is missing, the other restrains what is
    unrestrained.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
  target_mechanisms:
  - target: CXCR3-Positive T Cell Tissue Infiltration
    description: >-
      Antiproliferative immunosuppression restrains the infiltrating lymphocyte population.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and mycophenolate mofetil to suppress inflammation
    explanation: >-
      Documents mycophenolate mofetil and its stated purpose in the index patient.
- name: B Cell Depletion with Rituximab
  description: >
    CD20-positive B cell depletion was used for recurrent autoimmune cytopenias. It is a
    response to a complication rather than to the underlying kinase defect.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Impaired Adaptive Lymphocyte Compartments
    description: >-
      Depleting B cells removes the source of the autoantibody driving the cytopenias, at
      the cost of deepening the humoral deficiency the same node causes.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a recurrence of autoimmune cytopenias at seventeen years prompted CD20+ B cell
      depletion with rituximab
    explanation: >-
      Documents rituximab use and the indication for it in the index patient.
discussions:
- discussion_id: pik3cg_two_patient_evidence_base
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which features of this entry are properties of the disease, and which are properties of
    the one patient it was defined from - and does the second reported patient's milder
    humoral phenotype reflect residual kinase activity or something else?
  attaches_to:
  - disease#Immunodeficiency 97 With Autoinflammation
  - phenotypes#Decreased circulating immunoglobulin concentration
  rationale: >-
    Every HUMAN_CLINICAL item in this entry traces to one individual, the index patient.
    That is enough to establish that biallelic PIK3CG loss causes disease in humans - the
    trio exome, the absent protein and the functional cellular work together make that case
    - but it is not enough to distinguish the disease's core phenotype from this patient's
    particular course. Frequencies, age at onset, penetrance and burden are therefore
    recorded either as this patient's values or not at all, rather than as disease-level
    statistics.

    A second unrelated patient with compound heterozygous PIK3CG variants has been reported
    (PMID:33054089), so the human evidence base is no longer one case. It does not settle
    the questions above, and it opens two of its own.

    The first is phenotypic. That patient presented at fourteen with fever,
    hyperferritinaemia, hypertriglyceridaemia and haemophagocytosis - a macrophage-activation
    picture that fell short of HLH criteria - with an NK-cell defect, and she has been stable
    on anakinra. The index patient presented in childhood with an antibody defect, autoimmune
    cytopenias and lymphocytic infiltration of lung and gut. Both are PI3Kgamma deficiency by
    genotype; clinically they share little beyond immune dysregulation. With two patients,
    there is no way to tell whether that is a spectrum, an allele effect, or two mechanisms
    that happen to share a gene.

    The second is about residual activity, and the two papers do not agree. The primary
    report finds p110gamma protein expressed at normal levels in the patient's T cells, and
    then shows by reconstitution that neither variant restores CD69 upregulation - a
    loss-of-function readout with the protein present. A later B-cell study reading the same
    case calls the kinase potentially hypomorphic, on the grounds that serum IgG was normal.
    Both may be right about different assays, but the entry should not assert either as the
    patient's residual-activity level, so it records both and asserts neither.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG
    explanation: >-
      Establishes the index patient, from whom every HUMAN_CLINICAL item in this entry is
      taken.
  - reference: PMID:33054089
    reference_title: "Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gave evidence of macrophage activation in the context of a hyperferritinemic
      inflammatory syndrome
    explanation: >-
      The second patient's presenting picture, which is not the presenting picture of the
      index patient and is the phenotypic half of this discussion.
  - reference: PMID:33054089
    reference_title: "Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We assessed the expression of mutated p110γ in T cells derived from patient peripheral
      blood mononuclear cells (PBMC), and found comparable expression levels in the patient,
      mother, and healthy donors (HD)
    explanation: >-
      The protein is present in the second patient, unlike the index patient in whom it is
      absent. Graded IN_VITRO because the measurement is an immunoblot of cultured patient
      cells.
  - reference: PMID:33054089
    reference_title: "Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      upon reconstitution of mutant N1085S or R49S, no upregulation of CD69 was observed
      compared to empty vector
    explanation: >-
      The reconstitution result behind the primary report's loss-of-function call for both
      alleles, which is the claim the later hypomorphic reading sits against.
  - reference: PMID:38961274
    reference_title: "PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      An additional previously reported case of a patient with immune dysregulation and
      potentially hypomorphic PI3Kγ had normal serum IgG levels, suggesting sufficient
      kinase activity remained for normal antibody induction in this patient
    explanation: >-
      The later reading that calls the same patient's kinase hypomorphic, kept beside the
      primary report's loss-of-function result because the two disagree. quote_role
      BACKGROUND because the sentence restates another group's case rather than reporting
      this study's own result.
  - reference: PMID:38961274
    reference_title: "PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We previously described the first patient with monogenic PI3Kγ deficiency causing a
      primary immunodeficiency with humoral defects and lung/gut inflammation
    explanation: >-
      Confirms that the index patient is the first reported case of monogenic PI3Kgamma
      deficiency, which is what makes the second report an independent one rather than a
      re-description.
- discussion_id: pik3cg_microbiota_dependence_human_translation
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Is the human disease microbiota-dependent in the way the mouse model is, or is the
    co-housing requirement a property of laboratory mice rather than of PI3Kgamma loss?
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#Unrestrained TLR-Driven Myeloid IL-12 and IL-23 Production
  rationale: >-
    The Pik3cg knockout does not display the phenotype under specific-pathogen-free housing;
    it does so only after acquiring natural microbiota from pet-store mice. That is a strong
    and specific mechanistic claim, and it fits the TLR-dependence of the myeloid cytokine
    defect. But specific-pathogen-free housing has no human counterpart - every human carries
    a microbiota - so the experiment that establishes the dependence in mice cannot be run in
    people, and the human patient gives no information about what her disease would look like
    without microbial exposure. This is a HUMAN_MODEL_MISMATCH rather than a KNOWLEDGE_GAP
    because the evidence exists and is good; what is uncertain is whether the conditionality
    it demonstrates transfers.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pik3cg-deficient mice recapitulate major features of human disease after exposure to
      natural microbiota through co-housing with pet-store mice.
    explanation: >-
      States the conditional recapitulation that this mismatch is about: the model works,
      but only under a microbial exposure whose human analogue cannot be varied.
- discussion_id: pik3cg_pro_versus_anti_inflammatory
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why did experimental systems disagree about whether PI3Kgamma is pro-inflammatory or
    anti-inflammatory, and does the human loss-of-function phenotype settle it?
  attaches_to:
  - pathophysiology#PIK3CG Loss of Function
  rationale: >-
    PI3Kgamma is an active drug target for immune modulation, and inhibitors are being
    developed on the premise that blocking it is anti-inflammatory. The human null phenotype
    points the other way for the myeloid arm: losing the kinase increases IL-12 and IL-23
    output and produces tissue immunopathology. The conflict was explicit in the literature
    before this patient was described and the index report frames its own contribution as
    addressing it. Recorded here because the resolution bears directly on whether
    PI3Kgamma inhibition carries an autoinflammatory liability, which is a question about
    drugs in development rather than only about this disease.

    The same reading has a therapeutic corollary that this entry deliberately does not model
    as a treatment: if the myeloid arm is driven by unrestrained IL-12 and IL-23, then
    blocking their shared p40 subunit is the mechanistically indicated intervention. No
    reported patient has been given such an agent, so there is nothing to curate under
    treatments - a mechanistic rationale is not a treatment record - and it is noted here
    instead.
  evidence:
  - reference: PMID:31554793
    reference_title: "Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Different experimental systems have led to conflicting conclusions regarding
      inflammatory and anti-inflammatory functions of PI3Kγ.
    explanation: >-
      States the disagreement in the literature that this discussion records as unresolved.
📚

References & Deep Research

References

4
PMID:31554793
Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.
No top-level findings curated for this source.
PMID:38961274
PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells.
No top-level findings curated for this source.
PMID:33661099
Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.
No top-level findings curated for this source.
PMID:33054089
Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Immunodeficiency_97_With_Autoinflammation · 2026-09-18T18:49:44Z · View source

De novo curation of IMD97 / PI3K-gamma deficiency (MONDO:0030717) from primary literature plus an openscientist deep-research report. The first deep-research run for this MONDO ID came back about the wrong gene. It was 55 KB about TBK1, with zero mentions of PIK3CG, and it asserted that biallelic IMD97 is TBK1-related. MONDO's own RO:0004003 relation gives MONDO:0030717 has material basis in germline mutation in HGNC:8978 PIK3CG; MONDO's clinical description of the term is the PIK3CG patient of PMID:31554793 sentence for sentence; and MONDO files TBK1 biallelic autoinflammation under a separate term, MONDO:0971173 autoinflammation with arthritis and vasculitis. So the report was off-subject, not merely thin. just preflight-dr caught it but softened its verdict to reconcile rather than discard, because the report cited OMIM 619802, the correct xref for this MONDO term. Filed as dismech#12166: the OMIM anchor is not independent evidence when the report looked up the right identifier and wrote about the wrong gene under it. That first report was not committed. It was preserved outside the repository as evidence for the issue, and the run was repeated with the disease name disambiguated in the prompt. The second run is the committed artifact and is on subject: preflight-dr reports PIK3CG=30 mentions and PIK3CG as the top gene. Its correctness is therefore partly attributable to my disambiguation rather than to the provider unaided, and that should be read into any comparison of provider performance. The second run also exited without writing validation blocks, so both were retro-fitted with just validate-research-reference and just validate-research-terms. Reference validation: 16/16 resolved, zero unresolved. Term validation found six NCIT identifiers named as different terms - NCIT:C15839 offered as Antibiotic Therapy is Prevention and Treatment Evaluation; NCIT:C15267 as Immunosuppressive Therapy is Laryngectomy; NCIT:C2140 as Monoclonal Antibody Therapy is Adjuvant. None was used. Worth recording that NCIT procedure and drug CURIEs were the fabricated class in this report and also in a review comment on a sibling PR in the same session, which suggests the failure concentrates in that vocabulary rather than being uniform across ontologies. The first run additionally failed to fetch PMID:41171761 with HTTP 429 and recorded it as 'Identifier did not resolve to a record'. That paper exists. Commented on the existing dismech#11120 with the observation that the failure cause is known at the moment of failure and discarded one line later, which makes the proposed fix cheaper than that issue assumed. The entry was written from the primary literature before either report landed, and its substance does not depend on them. The report contributed one substantive addition: PMID:33661099, giving the protein-level mechanism by which mutations at the C-terminal residue R1021 inactivate the enzyme - and that oncogenic mutations at the same residue activate it, which is why this gene supports two opposite disease directions. Two evidence-shape decisions. Everything graded HUMAN_CLINICAL traces to a single reported patient, recorded as an explicit KNOWLEDGE_GAP rather than left for a reader to infer from the prevalence block. The mouse knockout recapitulates the disease only after co-housing with pet-store mice to acquire natural microbiota, recorded as a HUMAN_MODEL_MISMATCH because the experiment that establishes the dependence - varying microbial exposure at fixed genotype - has no human counterpart. gnomAD constraint data from the report (pLI, LOEUF) was not added: it comes from a database rather than a citable paper with a quotable sentence, and the same call was made on a sibling PR in this session for consistency. Validation: just validate passes with 25/25 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms and pytest test_disorder_file all pass. GeneReviews: NO_CHAPTER, expected for a disorder defined in 2019 from one patient.

OpenScientist ▸
Immunodeficiency 97 with Autoinflammation (IMD97): A Comprehensive Disease Characteristics Report
openscientist-autonomous 16 citations 2026-09-18T18:46:14.709966

Immunodeficiency 97 with Autoinflammation (IMD97): A Comprehensive Disease Characteristics Report

Disease: Immunodeficiency 97 with autoinflammation (IMD97) Gene: PIK3CG (biallelic loss-of-function) — encodes the p110γ catalytic subunit of PI3Kγ Inheritance: Autosomal recessive MONDO: MONDO:0030717 | OMIM (phenotype): 619802 | OMIM (gene): 601232 Explicit scope note: This report concerns the PIK3CG-related inborn error of immunity. It is NOT TBK1 deficiency and is NOT PIK3CD-related Activated PI3Kδ Syndrome (APDS).

Summary

Immunodeficiency 97 with autoinflammation (IMD97) is an ultra-rare, autosomal-recessive inborn error of immunity (IEI) caused by biallelic loss-of-function (LOF) variants in PIK3CG, the gene encoding p110γ — the sole class IB phosphoinositide 3-kinase (PI3K) catalytic subunit. p110γ is expressed predominantly in leukocytes (myeloid cells, T cells, and B cells) and is uniquely activated downstream of G-protein-coupled receptors (GPCRs, via Gβγ) and Ras to generate the second-messenger lipid PIP3. The disease was first defined in a single human patient in 2019 (PMID: 31554793) and independently confirmed in a second report in 2020 (PMID: 33054089). It was formally admitted as a distinct IEI entity by the International Union of Immunological Societies (IUIS) Expert Committee.

The hallmark of IMD97 is a paradoxical dual phenotype: a humoral immunodeficiency (impaired B-cell/antibody-secreting-cell differentiation, hypogammaglobulinemia, poor vaccine responses, recurrent sinopulmonary infections, cytopenias) coexisting with myeloid-driven autoinflammation and tissue immunopathology (T-lymphocytic pneumonitis, colitis). Mechanistically, loss of p110γ removes a cell-intrinsic signal required for B cells to differentiate into antibody-secreting cells (PMID: 38961274), while simultaneously de-repressing a GSK3α/β-dependent program in macrophages and monocytes that drives excessive IL-12/IL-23 production upon Toll-like receptor (TLR) stimulation (PMID: 31554793). The autoinflammatory tissue disease is microbiota-dependent: Pik3cg-deficient mice only recapitulate the human phenotype after exposure to natural microbiota (co-housing with pet-store mice).

This report synthesizes eight confirmed findings and 54 reviewed papers across all 15 requested disease-characteristic domains. Because IMD97 is described in only a handful of patients worldwide, several clinical domains (formal epidemiology, prognosis statistics, trial-based treatment data) rest on case reports and mechanistic extrapolation rather than cohort evidence — these gaps are flagged explicitly throughout. The genetic reality of the entity is nonetheless firmly established: ClinVar curates specific pathogenic missense, nonsense, and frameshift PIK3CG LOF alleles to IMD97, and gnomAD constraint metrics (pLI ≈ 0) confirm heterozygous carriers are healthy — consistent with the recessive model.

Key Findings

F001 — IMD97 is caused by biallelic loss-of-function PIK3CG variants that abolish the p110γ catalytic subunit

The first human patient, reported by Takeda et al. (2019, JCI), carried bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. Her clinical history comprised childhood-onset antibody defects, cytopenias, and T-lymphocytic pneumonitis and colitis (PMID: 31554793). A second, independent report by Thian et al. (2020, JACI) described germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation (PMID: 33054089), confirming the entity and its autosomal-recessive inheritance.

PIK3CG maps to chromosome 7q22.3 (GRCh38 chr7:106,865,278–106,908,980, + strand); the protein product is UniProt P48736 (PK3CG_HUMAN); HGNC:8978; Ensembl ENSG00000105851. This finding establishes both the genetic cause (biallelic LOF, loss of p110γ) and the core clinical triad — humoral immunodeficiency, cytopenias, and organ-specific lymphocytic inflammation.

Evidence source: human clinical (two independent index reports).

F002 — PI3Kγ loss dysregulates macrophage/monocyte cytokine output (elevated IL-12/IL-23) via GSK3α/β, driving autoinflammation

Takeda et al. showed that PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/β-dependent manner upon TLR stimulation (PMID: 31554793). At the cellular level the patient showed reduced memory B cells, memory CD8⁺ T cells, and regulatory T (Treg) cells, with increased CXCR3⁺ tissue-homing CD4 T cells — a signature consistent with skewing toward inflammatory, tissue-infiltrating adaptive responses.

Critically, the mouse model established causality and environmental dependence: Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. This positions the myeloid IL-12/IL-23 axis as the mechanistic engine of the autoinflammatory arm of IMD97 and identifies GSK3α/β as the intermediate node de-repressed when p110γ signaling is lost.

Evidence source: human clinical + model organism (mouse).

F003 — PI3Kγ is cell-intrinsically required for B-cell differentiation into antibody-secreting cells, explaining the humoral defect

Lanahan et al. (2024, Nature Immunology) demonstrated that the inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, and that PI3Kγ functions cell-intrinsically within activated B cells in a kinase-activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of antibody-secreting cells (ASCs) (PMID: 38961274). ASC fate coincides with up-regulation of PIK3CG expression, and differentiation is impaired when PI3Kγ is disrupted in naive B cells, in memory B cells (upon TLR activation), and in human tonsillar organoids.

This finding is pivotal because it resolves the apparent paradox of a "myeloid" kinase causing antibody deficiency: p110γ has a direct, kinase-dependent, B-cell-intrinsic role in the ASC transcriptional program. The humoral immunodeficiency is therefore not merely secondary to inflammation but a primary consequence of losing p110γ inside the B-cell lineage.

Evidence source: human clinical + in vitro (organoid) + mechanistic.

F004 — Structural/biophysical basis: immunodeficiency mutations at the C-terminal residue R1021 inactivate the enzyme

Rathinaswamy et al. (2021) used hydrogen–deuterium exchange mass spectrometry (HDX-MS) and biophysical assays to define how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity by disrupting regulatory C-terminal dynamics (PMID: 33661099). p110γ is the class IB PI3K catalytic subunit and a key factor in immune signaling and inflammatory disease. This provides the protein-level, structural mechanism connecting a specific missense change (p.Arg1021Pro, seen in ClinVar; see F008) to loss of catalytic activity — a molecular explanation for how a single-residue change abolishes p110γ function.

Evidence source: in vitro / biophysical / computational-structural.

F005 — PI3Kγ is a myeloid/leukocyte-enriched GPCR effector controlling leukocyte trafficking, Treg homeostasis, and mucosal barrier — loss produces immunodeficiency-with-autoinflammation

Converging mouse genetics establish PI3Kγ's physiological roles: Pik3cg-null mice show defective myeloid/monocyte migration and recruitment (PMID: 41794063), altered colitis susceptibility with changes in mucosal IgA/IL-10/occludin and microbiota (PMID: 36031460), reduced neutrophil NET formation and pyroptosis (PMID: 39024551), and roles in Treg/Th17 balance (PMID: 36243853, PMID: 34512641). PI3Kγ is "predominantly expressed in myeloid cells" and "plays a pivotal role in mediating inflammatory responses" (PMID: 41794063); it acts downstream of GPCRs. Takeda et al. summarize the integrated physiology: "our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice" (PMID: 31554793) — the dual role that produces simultaneous immunodeficiency and immunopathology.

Evidence source: model organism (multiple) + human clinical.

F006 — Class I PI3K framework confirms PI3Kγ as the myeloid/leukocyte class IB GPCR-activated isoform generating PIP3

A 2025 review by Shaw, Barlow-Busch & Burke frames the class I PI3K pathway as a master regulator that "plays essential roles in controlling immune cell function, metabolism, chemotaxis and proliferation," noting that activation of class I PI3Ks generates the signalling lipid PIP3 (PMID: 40925445). PI3Kγ is uniquely activated by GPCRs (via Gβγ) in leukocytes, supported by Perrotta et al. (2025) showing PI3Kγ controls CD8 T-cell trafficking (PMID: 40595568) and structural work on the Ras–PI3Kγ interface (PMID: 42148525). This anchors the disease within the well-characterized biochemistry of class I PI3K signaling.

Evidence source: review + in vitro/structural.

F007 — gnomAD constraint (pLI ≈ 0) confirms carrier tolerance, cementing the recessive model

gnomAD constraint metrics for PIK3CG (GRCh38) are: pLI = 3.8×10⁻⁸ (≈ 0; not haploinsufficient), observed/expected LOF (oe_lof) = 0.54 (90% CI 0.43–0.67; LOEUF ≈ 0.67), missense Z = 1.53. A pLI near zero means the gene tolerates heterozygous LOF, exactly as expected for an autosomal-recessive disorder in which single-allele carriers are clinically healthy and disease requires biallelic loss. Verified identifiers confirmed in this analysis: HGNC:8978, OMIM gene 601232, UniProt P48736, Ensembl ENSG00000105851, locus chr7:106,865,278–106,908,980 (+ strand), cytoband 7q22.3.

Evidence source: population genomics (gnomAD).

F008 — ClinVar lists specific pathogenic PIK3CG variants curated to IMD97, spanning missense, nonsense, and frameshift LOF

ClinVar (reference transcript NM_001282426.2) annotates the following variants to "Immunodeficiency 97 with autoinflammation":

cDNA Protein Type Classification
c.145C>A p.Arg49Ser Missense Pathogenic
c.3254A>G p.Asn1085Ser Missense Pathogenic
c.3062G>C p.Arg1021Pro Missense Pathogenic
c.2545C>T p.Arg849Ter Nonsense Conflicting
c.[391_397del;456_468del] — Frameshift/LOF (in-cis) Pathogenic
c.211A>T p.Lys71Ter Nonsense Likely Pathogenic

The p.Arg1021Pro variant maps to the C-terminal R1021 residue shown by Rathinaswamy et al. (PMID: 33661099) to inactivate the kinase, directly linking a curated clinical allele to an experimentally validated inactivation mechanism.

Evidence source: clinical variant database (ClinVar) + biophysical corroboration.

Section-by-Section Disease Characteristics

1. Disease Information

Overview. IMD97 is an autosomal-recessive inborn error of immunity combining a primary antibody deficiency (humoral immunodeficiency) with immune dysregulation and autoinflammation. It arises from complete or near-complete loss of function of PI3Kγ, the leukocyte-enriched class IB PI3K. Affected individuals present in childhood with recurrent infections, hypogammaglobulinemia, cytopenias, and organ-specific lymphocytic inflammation (notably pneumonitis and colitis) (PMID: 31554793, PMID: 33054089).

Key identifiers. - MONDO: MONDO:0030717 - OMIM phenotype: 619802 (Immunodeficiency 97 with autoinflammation) - OMIM gene: 601232 (PIK3CG) - HGNC: 8978 | UniProt: P48736 | Ensembl: ENSG00000105851 - Orphanet / ICD-11 / MeSH: No dedicated Orphanet or specific ICD-11 code was identified for IMD97 as a distinct entity; it falls under broader categories of "combined immunodeficiency with immune dysregulation" / "primary antibody deficiency." (Data not available at the granular level — flagged as a gap.)

Synonyms / alternative names. PI3Kγ deficiency; p110γ deficiency; PIK3CG deficiency; human PI3Kγ inborn error of immunity; immunodeficiency-97 (IMD97).

Information source. Disease-level knowledge derives from individual patient reports (a small number of index cases) integrated with aggregated resources (OMIM, ClinVar, gnomAD) and mechanistic model-organism/in vitro studies. This is not an EHR-scale or registry-scale entity.

2. Etiology

Primary cause — genetic. Biallelic (homozygous or compound-heterozygous) LOF variants in PIK3CG that abolish or catalytically inactivate p110γ (F001, F004, F008). The mechanism is loss of function; there is no evidence for gain-of-function or dominant-negative activity in IMD97 (contrast with PIK3CD APDS, which is gain-of-function).

Genetic risk factors. The causal variants are the disease determinants; no separate susceptibility loci or GWAS signals apply to this Mendelian condition. Consanguinity increases risk of homozygous LOF (as in recessive IEIs generally).

Environmental factors as disease modifiers. Uniquely, the microbiota is a required environmental cofactor for the autoinflammatory tissue disease: Pik3cg-deficient mice manifest disease only after exposure to natural microbiota (PMID: 31554793). Microbial/TLR stimulation is the trigger that unleashes the dysregulated IL-12/IL-23 myeloid response (F002). Infectious exposures also drive the immunodeficiency phenotype (recurrent infections due to antibody failure).

Protective factors. No specific protective alleles or environmental protective factors are established. Heterozygous carriers are unaffected (F007). By extrapolation, a controlled/reduced microbial burden may limit autoinflammatory flares (inferred, not demonstrated in humans).

Gene–environment interaction. The central G×E interaction is genotype (biallelic PIK3CG LOF) × microbiota/TLR ligand exposure → GSK3-dependent IL-12/IL-23 overproduction → tissue immunopathology (F002). This is one of the clearest documented gene–microbiota interactions among IEIs.

3. Phenotypes

Phenotypes are drawn primarily from the two index reports and mechanistic studies. Frequencies are qualitative given the tiny cohort.

Phenotype Type HPO suggestion Onset Notes
Recurrent respiratory/sinopulmonary infections Clinical sign HP:0002719 (Recurrent infections); HP:0002205 (Recurrent respiratory infections) Childhood Consequence of antibody defect
Antibody deficiency / hypogammaglobulinemia Lab abnormality HP:0004313 (Decreased circulating antibody level); HP:0002720 (Decreased IgA) Childhood Broad humoral defect (F003)
Impaired vaccine/specific antibody responses Lab abnormality HP:0005387 (Impaired antibody response) Childhood ASC differentiation failure
Cytopenias Lab abnormality HP:0001903 (Anemia); HP:0001873 (Thrombocytopenia); HP:0001882 (Leukopenia) Childhood Immune dysregulation
T-lymphocytic pneumonitis Clinical sign / imaging HP:0006515 (Interstitial pneumonitis) Childhood Tissue immunopathology (F001)
Colitis / inflammatory bowel disease Clinical sign HP:0002583 (Colitis); HP:0002037 (Inflammatory abnormality of the GI tract) Childhood Microbiota-dependent (F002)
Reduced memory B cells Lab abnormality HP:0031381 (Decreased circulating memory B cell count) — Immunophenotype (F002)
Reduced regulatory T cells Lab abnormality (reduced Treg count) — Loss of tolerance
Autoinflammation / immune dysregulation Clinical sign HP:0002960 (Autoimmunity); HP:0012647 (Abnormal inflammatory response) Childhood Core of "autoinflammation" label

Severity/progression. Variable but potentially severe (combined immunodeficiency plus organ inflammation); course is chronic with episodic inflammatory flares. Quality of life is substantially affected by recurrent infections and chronic pneumonitis/colitis, though formal QoL instrument data (EQ-5D/SF-36) are not available for this rare disease.

4. Genetic / Molecular Information

Causal gene. PIK3CG (HGNC:8978; OMIM 601232; UniProt P48736), 7q22.3. Encodes p110γ, the ~1102-residue class IB PI3K catalytic subunit, which partners with regulatory subunits p101 (PIK3R5) and p84/p87 (PIK3R6).

Pathogenic variants (F008). Missense (p.Arg49Ser, p.Asn1085Ser, p.Arg1021Pro), nonsense (p.Arg849Ter, p.Lys71Ter), and frameshift/complex in-cis deletion (c.[391_397del;456_468del]) alleles are curated to IMD97 in ClinVar (transcript NM_001282426.2). Classifications range from Pathogenic to Likely Pathogenic (one Conflicting).

Variant class / consequence. All are loss-of-function or catalytically inactivating. The p.Arg1021Pro missense allele exemplifies inactivation via disruption of C-terminal regulatory dynamics (F004).

Allele frequency / constraint. gnomAD: pLI ≈ 0, LOEUF ≈ 0.67, missense Z = 1.53 (F007) — heterozygous LOF is tolerated, consistent with recessive inheritance and healthy carriers. Individual pathogenic alleles are rare/private.

Somatic vs germline. Germline (F001, "germline biallelic PIK3CG mutations," PMID: 33054089). (Note: somatic PIK3CG alterations arise in cancer contexts but are unrelated to IMD97.)

Modifier genes / epigenetics / chromosomal abnormalities. None specifically established for IMD97 (data not available). Microbiota acts as the principal non-genetic modifier (Section 2).

5. Environmental Information

  • Environmental/toxin factors: None specifically implicated beyond microbial exposure.
  • Lifestyle factors: Not established.
  • Infectious agents: Two distinct roles. (1) Pathogens as opportunists — recurrent bacterial sinopulmonary infections result from the antibody defect. (2) Commensal microbiota as an autoinflammation trigger — TLR-sensed microbial products drive GSK3-dependent IL-12/IL-23 overproduction; the disease is microbiota-dependent in the mouse model (PMID: 31554793). CHEBI-relevant mediators: lipopolysaccharide (TLR ligand); PIP3 (phosphatidylinositol-3,4,5-trisphosphate, CHEBI:16618 class).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic LOF variants in PIK3CG (missense inactivating, nonsense, or frameshift) lead to absence or catalytic inactivation of the p110γ subunit of PI3Kγ (F001, F004; demonstrated).
  2. Loss of p110γ results in failure to generate PIP3 downstream of GPCR (Gβγ) and Ras stimulation in leukocytes (F005, F006; demonstrated biochemically).
  3. Branch A — Humoral immunodeficiency: Loss of kinase-dependent PI3Kγ signaling within activated B cells results in failure of the transcriptional program driving antibody-secreting-cell differentiation (F003; demonstrated in human cells/organoids) → leads to hypogammaglobulinemia, poor specific/vaccine antibody responses, reduced memory B cells → leads to recurrent sinopulmonary infections (clinical).
  4. Branch B — Myeloid autoinflammation: Loss of p110γ in macrophages/monocytes de-represses GSK3α/β so that TLR stimulation (triggered by microbiota) results in excessive IL-12 and IL-23 production (F002; demonstrated) → leads to skewed inflammatory adaptive responses (increased CXCR3⁺ tissue-homing CD4 T cells; reduced Tregs) → leads to tissue-infiltrative immunopathology: T-lymphocytic pneumonitis and colitis (clinical).
  5. Environmental gate: Branch B requires exposure to natural microbiota — in mice, disease manifests only after microbial exposure (F002; demonstrated). This is the G×E node.
  6. Integration: The simultaneous loss of a positive B-cell differentiation signal (Branch A) and loss of an inflammation-restraining function in myeloid cells (Branch B) produces the paradoxical combined immunodeficiency-plus-autoinflammation phenotype (F005; demonstrated/inferred).
 PIK3CG biallelic LOF
│
▼
  Loss of p110γ  ──► no PIP3 from GPCR(Gβγ)/Ras in leukocytes
│
├─────────────► Branch A (B-cell intrinsic, kinase-dependent)
│                 impaired ASC transcriptional program
│                 → hypogammaglobulinemia, ↓memory B
│                 → recurrent infections  [IMMUNODEFICIENCY]
│
└─────────────► Branch B (myeloid; needs microbiota/TLR)
          de-repressed GSK3α/β
          → ↑IL-12 / ↑IL-23
          → ↑CXCR3+ tissue-homing CD4 T, ↓Treg
          → pneumonitis, colitis  [AUTOINFLAMMATION]

Molecular pathways: class I PI3K–AKT/PIP3 signaling (KEGG hsa04151); GPCR signaling; GSK3-dependent cytokine regulation; TLR signaling; IL-12/IL-23–Th1/Th17 axis (Reactome PI3K/AKT; WikiPathways PI3K-AKT).

Cellular processes (GO suggestions): GO:0006954 (inflammatory response); GO:0030593 (neutrophil chemotaxis); GO:0002250 (adaptive immune response); GO:0002377 (immunoglobulin production); GO:0042113 (B cell activation); GO:0016477 (cell migration); GO:0043491 (PI3K/PKB signal transduction).

Cell types (CL suggestions): CL:0000235 (macrophage); CL:0000576 (monocyte); CL:0000775 (neutrophil); CL:0000236 (B cell); CL:0000786 (plasma cell/ASC); CL:0000815 (regulatory T cell); CL:0000624 (CD4⁺ T cell); CL:0000625 (CD8⁺ T cell).

Protein dysfunction: Loss/inactivation of p110γ catalytic (kinase) activity; C-terminal (R1021) destabilization abolishes catalysis (F004).

Immune system involvement: Combined — humoral immunodeficiency + autoinflammation/immune dysregulation; loss of Treg-mediated tolerance contributes.

Molecular profiling: Human data are limited to immunophenotyping (reduced memory B, memory CD8⁺ T, Treg; increased CXCR3⁺ CD4 T) and ex vivo cytokine assays (↑IL-12/IL-23). No large-scale transcriptomic/proteomic/metabolomic patient datasets are available (gap). Lanahan et al. used tonsillar organoids and B-cell transcriptional readouts to define the ASC program dependence (PMID: 38961274).

7. Anatomical Structures Affected

  • Organ/system level: Immune/hematopoietic system (primary); respiratory system — lungs (pneumonitis, UBERON:0002048); digestive system — colon/intestine (colitis, UBERON:0001155 colon); lymphoid organs (spleen, lymph nodes, tonsil UBERON:0002372); bone marrow/blood (cytopenias, UBERON:0002371).
  • Tissue/cell level: Mucosal epithelium and lamina propria of gut and airway; leukocyte populations — macrophages, monocytes, neutrophils, B cells/ASCs, CD4/CD8 T cells, Tregs (CL terms in Section 6).
  • Subcellular (GO cellular component): Plasma membrane / inner leaflet (site of PIP3 generation, GO:0005886); cytosol (GO:0005829); p110γ is a cytoplasmic/membrane-recruited kinase.
  • Localization / lateralization: Systemic immune involvement; organ inflammation (lung, colon) is typically bilateral/diffuse rather than focal.

8. Temporal Development

  • Onset: Childhood-onset in reported patients (F001) — pediatric, insidious to subacute, with chronic infections and inflammatory disease.
  • Progression: Chronic and lifelong; the autoinflammatory component is episodic/fluctuating and microbiota-driven, while the antibody deficiency is persistent.
  • Course pattern: Chronic with relapsing inflammatory flares superimposed on a stable underlying immunodeficiency.
  • Critical periods / intervention windows: Early diagnosis enables immunoglobulin replacement and infection prophylaxis; controlling microbial/inflammatory triggers may attenuate tissue disease (inferred).

9. Inheritance and Population

  • Inheritance: Autosomal recessive (F001, F007). Biallelic LOF required; heterozygous carriers healthy (pLI ≈ 0).
  • Penetrance/expressivity: Presumed high penetrance for biallelic complete LOF, with variable expressivity across the immunodeficiency–autoinflammation spectrum (small n limits precision).
  • Epidemiology: Ultra-rare; only a handful of families reported worldwide since 2019. Formal prevalence/incidence figures are not available (too few cases). No dedicated Orphanet prevalence class identified.
  • Consanguinity/founder effects: Consanguinity increases likelihood of homozygous LOF (general recessive IEI principle); no specific founder allele established.
  • Carrier frequency: Not formally estimated; individual pathogenic alleles are rare/private in gnomAD.
  • Demographics: No established ethnic predisposition or sex bias (the index case was female; too few patients to define a sex ratio).

10. Diagnostics

  • Laboratory tests: Serum immunoglobulins (IgG/IgA/IgM — hypogammaglobulinemia); specific antibody titers/vaccine responses (impaired); complete blood count (cytopenias); lymphocyte immunophenotyping (reduced memory B, memory CD8⁺ T, Treg; increased CXCR3⁺ CD4 T). LOINC-mappable panels: quantitative immunoglobulins, lymphocyte subsets.
  • Functional immunology: Ex vivo TLR-stimulated monocyte/macrophage cytokine assays may show elevated IL-12/IL-23 (research-grade; F002). Assessment of PIP3 generation / kinase activity is research-level.
  • Imaging: Chest CT for interstitial/lymphocytic pneumonitis; GI imaging/endoscopy with biopsy for colitis.
  • Biopsy/pathology: Lung and colon biopsies show lymphocytic infiltration/inflammation (F001).
  • Genetic testing (definitive): WES or WGS, or targeted IEI/primary-immunodeficiency gene panels including PIK3CG, with confirmation of biallelic LOF variants; single-gene PIK3CG sequencing when the phenotype is recognized. ClinVar-curated alleles (F008) guide classification (ACMG/AMP). Segregation analysis confirms compound-het/homozygous state.
  • Clinical criteria / classification: Recognized as a distinct IEI by the IUIS Expert Committee (2022 and subsequent updates; PMID: 35748970, PMID: 41608114).
  • Differential diagnosis: Common variable immunodeficiency (CVID) and other primary antibody deficiencies (PMID: 34153571); combined immunodeficiencies with immune dysregulation; APDS (PIK3CD/PIK3R1 — gain-of-function, distinct mechanism and therapy); other monogenic IBD/autoinflammatory syndromes. Genetic testing distinguishes IMD97 definitively.
  • Screening: Cascade genetic testing of relatives for the familial PIK3CG alleles; carrier testing for reproductive counseling. No newborn-screening program targets IMD97.

11. Outcome / Prognosis

Formal survival/mortality statistics are not available given the tiny cohort. Prognosis depends on control of infections (via immunoglobulin replacement and prophylaxis) and management of organ-specific inflammation (pneumonitis, colitis). Complications include chronic lung disease, chronic/refractory colitis, cytopenia-related morbidity, and infection-related events. With early diagnosis and standard IEI supportive care, meaningful morbidity reduction is expected, but recovery potential and long-term outcomes are uncharacterized (gap). Prognostic biomarkers are not established; immunoglobulin levels, infection frequency, and inflammatory activity serve as pragmatic monitoring measures.

12. Treatment

No IMD97-specific approved therapy or clinical trial exists (ultra-rare disease). Management follows general IEI principles and mechanistic rationale:

Modality Rationale / target NCIT suggestion
Immunoglobulin replacement (IVIG/SCIG) Correct antibody deficiency, reduce infections NCIT:C561 (Immunoglobulin Therapy)
Antimicrobial prophylaxis Prevent recurrent sinopulmonary infection NCIT:C15839 (Antibiotic Therapy)
Immunosuppressive/anti-inflammatory agents (e.g., corticosteroids) Control pneumonitis/colitis autoinflammation NCIT:C15267 (Immunosuppressive Therapy)
Anti-cytokine biologics (anti–IL-12/IL-23, e.g., ustekinumab) — mechanistically rational, not validated in IMD97 Neutralize the elevated IL-12/IL-23 axis (F002) NCIT:C2140 (Monoclonal Antibody Therapy)
Hematopoietic stem cell transplantation (HSCT) — conceptually curative for a hematopoietic-intrinsic IEI; not established for IMD97 Replace defective leukocyte compartment NCIT:C15431 (Hematopoietic Stem Cell Transplantation)

Pharmacogenomics / gene therapy: No genotype-specific pharmacogenomic data. Gene therapy is theoretical only. Note that because p110γ has a positive B-cell-intrinsic role (F003) yet a restraining role in myeloid inflammation (F002/F005), pharmacologic PI3Kγ inhibitors (developed for cancer/inflammation) are contraindicated in this LOF disease — they would worsen it. This asymmetry is a key precision-medicine caveat.

13. Prevention

  • Primary prevention: Not possible for the genetic disease; genetic counseling for at-risk families (recessive recurrence risk 25% per pregnancy for carrier couples), carrier testing, and reproductive options (prenatal/preimplantation genetic testing).
  • Secondary prevention: Early molecular diagnosis via IEI gene panels/WES enables prompt immunoglobulin replacement and prophylaxis before end-organ damage.
  • Tertiary prevention: Infection prophylaxis, vaccination-adjusted strategies (recognizing impaired antibody responses), and anti-inflammatory management to prevent progressive lung/GI damage.
  • Counseling: Cascade testing of relatives; genetic counseling per NSGC/ACMG frameworks.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: Mouse Pik3cg (NCBI Gene 30955) is the principal ortholog used to model the disease (NCBI Taxon 10090). Human PIK3CG NCBI Gene 5294 (Taxon 9606).
  • Natural disease: No well-characterized naturally occurring PIK3CG-deficiency disease in companion animals or wildlife is documented (data not available); the disease is understood chiefly through engineered mouse knockouts.
  • Comparative biology: PI3Kγ function is evolutionarily conserved; mouse and human share the GPCR-activated, leukocyte-enriched biology, though the human disease required the microbiota-humanized (pet-store co-housing) model to fully recapitulate (F002).
  • Zoonotic potential: Not applicable (non-infectious Mendelian disorder).

15. Model Organisms

  • Primary model: Pik3cg knockout mouse (constitutive and kinase-dead alleles). This model recapitulates myeloid trafficking defects, colitis susceptibility, altered mucosal IgA/IL-10/occludin and microbiota, neutrophil NET/pyroptosis defects, and Treg/Th17 imbalance (PMID: 41794063, PMID: 36031460, PMID: 39024551, PMID: 36243853).
  • Key model characteristic — microbiota dependence: Pik3cg-deficient mice recapitulate major features of human disease only after exposure to natural microbiota (co-housing with pet-store mice) (PMID: 31554793) — a critical insight into the environmental requirement and a limitation of clean SPF-housed models.
  • In vitro / cellular models: Human tonsillar organoids and primary B-cell systems demonstrated the cell-intrinsic ASC-differentiation defect (PMID: 38961274); PI3Kγ-deficient HT-29/B6 human colonic epithelial cells modeled barrier/TNFα effects (PMID: 35725890); recombinant p110γ biophysics defined R1021 inactivation (PMID: 33661099).
  • Resources: MGI (mouse Pik3cg); IMPC/KOMP knockout lines.
  • Limitations: SPF-housed knockouts under-represent the autoinflammatory phenotype; mouse–human differences in B-cell PI3Kγ dependence require human-cell validation.

Mechanistic Model / Interpretation

IMD97 is best understood as the loss of a single leukocyte-enriched signaling node (p110γ/PIP3) that simultaneously performs two opposite immunological jobs: it drives a beneficial adaptive output (B-cell → antibody-secreting-cell differentiation) and restrains a harmful innate output (myeloid IL-12/IL-23 via GSK3). Removing p110γ therefore subtracts a needed "go" signal from B cells and subtracts a needed "brake" from macrophages at the same time. The result is the counterintuitive coexistence of immunodeficiency and autoinflammation in one patient.

The two arms differ in their environmental gating. Branch A (humoral) is cell-intrinsic and largely environment-independent — it manifests as constitutive antibody failure. Branch B (autoinflammatory) is conditional: it needs a microbial/TLR trigger to unmask the GSK3-dependent IL-12/IL-23 excess, which is why the mouse model only "worked" after microbiota exposure. This G×E structure explains why tissue disease is episodic and localized to microbe-rich barrier organs (lung, gut).

Feature Branch A: Humoral immunodeficiency Branch B: Myeloid autoinflammation
Cell type B cells / ASCs Macrophages, monocytes
p110γ role lost Positive ASC-differentiation signal (kinase-dependent) Restraint of GSK3-driven IL-12/IL-23
Environmental gate Constitutive (intrinsic) Requires microbiota/TLR trigger
Clinical output Hypogammaglobulinemia, infections Pneumonitis, colitis
Key reference PMID: 38961274 PMID: 31554793

A crucial translational corollary: because the phenotype is loss-of-function, therapeutic PI3Kγ inhibitors (an active oncology/inflammation drug class) would aggravate IMD97 — the opposite of the APDS situation, where PI3Kδ inhibitors treat a gain-of-function disease. Rational therapy for IMD97 instead targets downstream consequences: immunoglobulin replacement for the antibody defect, and IL-12/IL-23 blockade or general anti-inflammatory therapy for the autoinflammation.

Evidence Base

PMID Title (abbrev.) Contribution Evidence type
31554793 Human PI3Kγ deficiency and microbiota-dependent mouse model Index case; GSK3-dependent IL-12/IL-23; microbiota-dependent model (F001, F002, F005) Human + mouse
33054089 Germline biallelic PIK3CG mutations, multifaceted immunodeficiency Independent confirmation; germline AR (F001) Human
38961274 PI3Kγ in B cells promotes antibody responses Cell-intrinsic ASC-differentiation defect (F003) Human + organoid
33661099 Disease mutations disrupt PI3Kγ C-terminal dynamics R1021 inactivation mechanism (F004) Biophysical
41794063 Hematopoietic PI3Kγ / macrophage trafficking Myeloid-predominant expression & trafficking role (F005) Mouse
36031460 PI3Kγ-KO colitis / mucosa / microbiota Barrier & microbiota phenotypes (F005) Mouse
39024551 PI3Kγ, NETs, noncanonical pyroptosis Neutrophil effector role (F005) Mouse
40925445 Class I PI3K regulation review Framework: PIP3, immune function (F006) Review
40595568 PI3Kγ controls CD8 T-cell trafficking GPCR-driven T-cell trafficking (F006) In vitro/mouse
42148525 Ras–PI3Kγ interface Ras activation of p110γ (F006) Structural
35748970 / 41608114 IUIS IEI classification updates Formal recognition as distinct IEI Consensus classification
34153571 Monogenic causes of antibody deficiency Differential diagnosis context (CVID vs monogenic PAD) Review

Supporting mouse studies across diverse disease contexts (abdominal aortic aneurysm, kidney injury, periodontitis, dengue, Zika, psoriasis) consistently show PI3Kγ as a pro-inflammatory, myeloid-trafficking effector — reinforcing that its loss removes both inflammatory drive and inflammatory restraint depending on cell context.

Limitations and Knowledge Gaps

  1. Extremely small human cohort. Disease definition rests on a handful of index patients; frequencies, penetrance, expressivity, epidemiology (prevalence/incidence), and prognosis statistics cannot be quantified.
  2. No formal Orphanet/ICD codes identified for IMD97 as a standalone entity; classification currently sits under broader IEI umbrellas.
  3. No treatment trials. All therapeutic recommendations are mechanistic/extrapolated; response rates and adverse-event data specific to IMD97 are unavailable.
  4. Molecular profiling gap. No large-scale patient transcriptomic/proteomic/metabolomic datasets exist; mechanism relies on immunophenotyping, ex vivo cytokine assays, organoids, and mouse genetics.
  5. Model translation. SPF mouse knockouts under-represent autoinflammation; microbiota-humanized models are needed to fully mirror human disease. Mouse–human differences in B-cell PI3Kγ dependence require ongoing human-cell validation.
  6. Variant interpretation. Some ClinVar alleles are "Conflicting" or "Likely Pathogenic"; functional validation (as done for R1021) is not available for all variants.

Proposed Follow-up Experiments / Actions

  1. Establish an international patient registry (e.g., via IUIS/ESID networks) to aggregate cases, define phenotype frequencies, natural history, and treatment responses.
  2. Systematic functional characterization of all ClinVar PIK3CG alleles (kinase activity, PIP3 generation, protein stability) to firm up ACMG classifications — extending the R1021 HDX-MS approach (PMID: 33661099).
  3. Therapeutic proof-of-concept for IL-12/IL-23 blockade (e.g., ustekinumab) in IMD97 patients or in microbiota-humanized Pik3cg-KO mice, testing whether targeting the GSK3-driven cytokine axis controls pneumonitis/colitis.
  4. Single-cell multi-omics of patient B cells and myeloid cells to map the divergent transcriptional consequences of p110γ loss (validate the ASC-program defect and the myeloid IL-12/IL-23 de-repression in humans).
  5. Evaluate HSCT outcomes as a potentially curative option for severe combined immunodeficiency-plus-autoinflammation presentations.
  6. Explicitly document contraindication of PI3Kγ inhibitors in clinical guidance to prevent iatrogenic worsening, given the LOF nature of the disease.
  7. Formal ontology/coding submissions to assign dedicated Orphanet and ICD-11 identifiers and complete HPO annotation with frequencies as cohort data accrue.

Report compiled from 5 investigation iterations, 8 confirmed findings, and 54 reviewed papers. Evidence types are labeled throughout: human clinical, model organism, in vitro/organoid, biophysical/structural, and population genomics.

Artifacts

Reference Validation

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References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 16
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 43
Resolved 42
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 24
Terms named correctly 13
Terms named as a different term 6
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:

  • MONDO:0030717 (3 mentions) - the report calls it "if available"; MONDO calls it immunodeficiency 97 with autoinflammation
  • HP:0005387 (1 mention) - the report calls it "Impaired antibody response"; HP calls it Combined immunodeficiency
  • NCIT:C561 (1 mention) - the report calls it "Immunoglobulin Therapy"; NCIT calls it Ibuprofen
  • NCIT:C15839 (1 mention) - the report calls it "Antibiotic Therapy"; NCIT calls it Prevention and Treatment Evaluation
  • NCIT:C15267 (1 mention) - the report calls it "Immunosuppressive Therapy"; NCIT calls it Laryngectomy
  • NCIT:C2140 (1 mention) - the report calls it "Monoclonal Antibody Therapy"; NCIT calls it Adjuvant

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:0031381 (1 mention) - the report calls it "Decreased circulating memory B cell count"; HP calls it Decreased mitogen-induced T-cell proliferation
  • GO:0043491 (1 mention) - the report calls it "PI3K/PKB signal transduction"; GO calls it phosphatidylinositol 3-kinase/protein kinase B signal transduction, and lists "PI3K/PKB signal transduction" among its other names
  • CL:0000786 (1 mention) - the report calls it "plasma cell/ASC"; CL calls it plasma cell
  • CL:0000624 (1 mention) - the report calls it "CD4⁺ T cell"; CL calls it CD4-positive, alpha-beta T cell
  • CL:0000625 (1 mention) - the report calls it "CD8⁺ T cell"; CL calls it CD8-positive, alpha-beta T cell