IUIS classification of phenocopies of inborn errors of immunity (category X inborn errors of immunity)

Disease	Genetic defect/presumed pathogenesis	Circulating T cells	Circulating B cells	Serum immunoglobulin	Associated features/similar inborn error of immunity
Associated with somatic mutations
Autoimmune lymphoproliferative syndrome (ALPS-SFAS)	Somatic mutation in TNF receptor superfamily member 6 (TNFRSF6)	Increased CD4^–CD8^– DN alpha-beta T cells	Normal but increased numbers of CD5⁺ B cells	Normal or increased	Splenomegaly, lymphadenopathy, autoimmune cytopenias, defective lymphocyte apoptosis; similar to ALPS-FAS (ALPS type Im)
RAS-associated autoimmune leukoproliferative disease (RALD)	Somatic mutation in KRAS proto-oncogene, GTPase (KRAS; GOF)	Normal	B cell lymphocytes	Normal or increased	Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis; ALPS-like
RAS-associated autoimmune leukoproliferative disease (RALD)	Somatic mutation in NRAS proto-oncogene, GTPase (NRAS; GOF)	Increased CD4^–CD8^– DN alpha-beta T cells	Lymphocytosis	Normal or increased	Splenomegaly, lymphadenopathy, autoantibodies; ALPS-like
Cryopyrinopathy (Muckle-Wells/CINCA/NOMID-like syndrome)	Somatic mutation in NLR family pyrin domain containing 3 (NLRP2)	Normal	Normal	Normal	Urticaria-like rash, arthropathy, neurologic signs
Hypereosinophilic syndrome due to somatic mutations in STAT5b	Somatic mutation in signal transducer and activation of transcription 5B (STAT5B; GOF)	Normal	Normal	Normal	Eosinophilia, atopic dermatitis, urticarial rash, diarrhea
VEXAS (vacuoles, E1 enzyme, XL, autoinflammatory, somatic) syndrome	Somatic mutation in ubiquitin-like modifier-activating enzyme 1 (UBA1; XL)		Reduced		Late-onset, treatment-refractory syndrome (fevers, cytopenias, dysplastic bone marrow, interstitial nephritis, chondritis, vasculitis)
TLR8 GOF	Somatic mutation in toll-like receptor 8 (TLR8)	Mildly increased CD4⁺ and CD8⁺ T cells, effector/memory subsets; decreased NK cells	Normal B cells/subsets; decreased pDCs	Normal/low IgG; increased IgM/IgA	Severe cytopenias, hepatosplenomegaly, lymphadenopathy, recurrent infections, hypocellular bone marrow, elevated proinflammatory serum cytokines
Associated with autoantibodies
Chronic mucocutaneous candidiasis	Autoantibodies to IL-19 and/or IL-22	Normal	Normal	Normal	Endocrinopathy, chronic mucocutaneous candidiasis
Adult-onset immunodeficiency with susceptibility to mycobacteria	Autoantibodies to IFN-gamma	Decreased naïve T cells	Normal	Normal	Mycobacterial, fungal, Salmonella, VZV infections; similar to MSMD or CID
Recurrent skin infection	Autoantibodies to IL-6	Normal	Normal	Normal	Staphylococcal infections; similar to STAT3 deficiency
Pulmonary alveolar proteinosis	Autoantibodies to GM-CSF	Normal	Normal	Normal	Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis; similar to CSF2RA deficiency
Acquired angioedema	Autoantibodies to C1 inhibitor	Normal	Normal	Normal	Angioedema; similar to C1 inhibitor deficiency (hereditary angioedema)
Atypical hemolytic uremic syndrome	Autoantibodies to complement factor H	Normal	Normal	Normal	Atypical hemolytic uremic syndrome caused by spontaneous activation of the alternative complement pathway
Thymoma with hypogammaglobulinemia (Good syndrome)	Autoantibodies to various cytokines	Increased CD8⁺ T cells	No B cells	Decreased	Invasive bacterial, viral, or opportunistic infections; autoimmunity; PRCA; lichen planus; cytopenia; colitis; chronic diarrhea
Severe COVID-19	Autoantibodies to type 1 IFNs (IFN-alpha, IFN-omega)				Severe, life-threatening infection with SARS-CoV-2

Total number of conditions in table: 15 (7 due to somatic mutations; 8 due to autoantibodies).

IUIS: International Union of Immunological Societies; FAS: Fas cell surface death receptor; TNF: tumor necrosis factor; CD: cluster of differentiation; DN: double negative; GOF: gain of function; CINCA: chronic infantile neurologic cutaneous and articular; NOMID: neonatal-onset multisystem inflammatory disorder; XL: X linked; NK: natural killer; pDC: plasmacytoid dendritic cell; IgG: immunoglobulin G; IgM: immunoglobulin M; IgA: immunoglobulin A; IL: interleukin; IFN: interferon; VZV: varicella zoster virus; MSMD: Mendelian susceptibility to mycobacterial disease; CID: combined immunodeficiency; STAT: signal transducer and activator of transcription; GM-CSF: granulocyte macrophage colony-stimulating factor; CSF2RA: colony-stimulating factor 2 receptor subunit alpha; PRCA: pure red cell aplasia; COVID-19: coronavirus disease 2019; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

From: Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022; 42:1473. Copyright © 2022 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0.

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IUIS classification of phenocopies of inborn errors of immunity (category X inborn errors of immunity)