Autoimmunity and immune dysregulation in inborn error of immunity/primary immunodeficiency disorders

IEI/PID/syndrome (in approximate order of prevalence)	Estimated prevalence	IUIS IEI classification^[1]	Hallmarks (of the IEI)	Immunodeficiency features	Possible manifestations of autoimmunity and/or immune dysregulation	Suspected predominant mechanism(s) of autoimmunity or immune dysregulation^[2-5]
Selective IgA deficiency	1 to 3:1000	Predominantly antibody deficiencies	Allergies; may precede CVID or have positive family history	Asymptomatic or recurrent sinopulmonary bacterial infections	Endocrinopathies Cytopenia	Lacking clearance of antigens from mucosal surfaces Autoreactive B cells due to impaired negative selection and regulation Reduced T regulatory function Reduced debris clearance
22q11 deletion syndrome (DiGeorge)	2 to 5:10,000	CID with syndromic features	Cardiac Abnormal facies Thymic hypoplasia Cleft palate Hypoparathyroidism Cognitive and speech problems	Variable, opportunistic infections	Cytopenia Endocrinopathies Arthritis	Impaired T regulatory cell function and diversity Oligoclonal TCR repertoire Residual autoreactive T cells
Wiskott-Aldrich syndrome (WAS)	1:20,000	CID with syndromic features	Microthrombocytopenia Eczema	Severe, viral, and bacterial opportunistic infections	Skin (eczema, atopic dermatitis) Cytopenia Vasculitis Kidney disease (nephritis, IgA nephropathy, glomerulonephritis) Arthritis IBD	Defective T regulatory cell function Impaired lymphocyte migration and activation Loss of inhibitory signaling
CVID and CVID-like diseases including NFKB1 and NFKB2 deficiencies	1 to 10:100,000	Predominantly antibody deficiencies	Hypogammaglobulinemia	Recurrent infections	Cytopenia Endocrinopathies IBD Granuloma formation Arthritis Parenchymal lung disease Lymphoproliferation Lymphoma Alopecia	BCR editing checkpoint, B cell maturation, and other signaling defects leading to residual autoreactive B cell clones Loss of inhibitory signaling Reduced T regulatory cell function Impaired T helper cell activity
Combined immunodeficiencies (CID)*	Unknown, estimated 1 to 5:100,000	CID	Depending on subtype/genetic cause	Combined, variable severity	Cytopenia Endocrinopathies IBD Skin (eczema, rash, other) Lymphoproliferation Parenchymal lung disease Lymphoma	Impaired T and T regulatory cell function and diversity Oligoclonal TCR repertoire Residual autoreactive T cells Hypersensitivity to persisting viral antigens
Autoimmune lymphoproliferative syndrome (ALPS)	Unknown, estimated >1 to 5:100,000	Diseases of immune dysregulation	Increased TCR alpha/beta-positive CD4-CD8- DNT cells	Rare	Cytopenia Endocrinopathies Kidney disease (glomerulonephritis) Lymphoproliferation Lymphoma	Apoptosis defect Immature and senescent T cell phenotype resulting in autoreactive T and B cells Impaired debris clearance
Familial hemophagocytic lymphohistiocytosis (FHL), hemophagocytic lymphohistiocytosis (HLH)	Unknown, estimated 1:50,000	Diseases of immune dysregulation	Hemophagocytosis Fever Hyperferritinemia Syndromes with or without hypopigmentation	EBV or other herpes viruses may be trigger	Cytopenia Lymphoproliferation Hemophagocytosis Neurologic symptoms (CNS infiltration)	Uncontrolled cytokine and interferon-mediated macrophage activation due to impaired cellular cytotoxicity of T and NK cells Apoptosis defects
X-linked agammaglobulinemia (XLA)	1:200,000	Predominantly antibody deficiencies	Agammaglobulinemia	Bacterial, enteroviral	Cytopenia Endocrinopathies Skin (eczema, rash, vitiligo, alopecia, oral ulcerations, mucocutaneous candidiasis) IBD	Unknown
Chronic granulomatous disease (CGD)	1 to 5:500,000	Congenital defects of phagocyte number, function, or both	May mimic Crohn disease or lymphoproliferative disorders HLH	Bacterial (Staphylococci), fungal	Granuloma formation IBD Lymphoproliferation	Ineffective and deregulated phagocyte activation, chemoattraction Impaired T regulatory function Defective clearance of apoptotic cells, hypersensitivity to bacterial antigens (neutrophil, NK mediated)
Hyperimmunoglobulin M syndromes (HIGM)	1 to 2:500,000	CID or predominantly antibody deficiencies	Cryptosporidium infection Pneumocystis pneumonia Sclerosing cholangitis	Bacterial and opportunistic infections	Cytopenia IBD Primary biliary cirrhosis Sclerosing cholangitis	Disturbed T-B cell interaction Residual autoreactive B cells T cell-mediated hypersensitivity to parasitic antigens (Cryptosporidium, Pneumocystis)
Complement deficiencies^¶	1 to 5:500,000	Complement deficiencies		Some have increased risk of neisserial infections	SLE Vasculitis	Ineffective clearance of immune complexes, apoptotic cells, and debris
APECED	1 to 10:1,000,000	Diseases of immune dysregulation	Ectodermal dystrophy 21-hydroxylase autoantibodies	Candidiasis	Endocrinopathies Skin (eczema, rash, vitiligo, alopecia, oral ulcerations, mucocutaneous candidiasis)	Central tolerance defect Anticytokine, enzyme-, and tissue-directed autoantibodies
XLP1 (SH2D1A deficiency)	1 to 5:1,000,000	Diseases of immune dysregulation	Lymphoproliferation Hypo- or agammaglobulinemia HLH Lymphoma	EBV may be trigger	Lymphoproliferation Hemophagocytosis Lymphoma Cytopenia	Disturbed T-B cell cross-talk Impaired T and NK cytotoxicity
CTLA4 haploinsufficiency (ALPSV)	Unknown, estimated <1:1,000,000	Diseases of immune dysregulation	Progressive loss of B cells Hypogammaglobulinemia	Upper and lower respiratory infections	IBD Granuloma formation Pneumonitis Cytopenia SLE Endocrinopathies Arthritis Neurologic disease (encephalitis, cerebellitis, CNS lymphoma) Lymphoproliferation Organ infiltration Malignancy	T regulatory cell defect Impaired T cell help for B cells
Activated PI3K-d syndrome	Unknown, estimated <1:1,000,000	Predominantly antibody deficiency	T and B lymphoid nodules Bronchiectasis CVID-like	Respiratory tract infections, chronic EBV and CMV infection	Pneumonitis Cytopenia Lymphoproliferation	Immature and terminal effector T cell phenotype Transitional B cells increased Lymphocyte sensitivity to activation-induced death
LRBA deficiency	Unknown, estimated <1:1,000,000	Diseases of immune dysregulation	Enteropathy ALPS/CVID-overlap syndrome	Bacterial and opportunistic infections	IBD Cytopenia Arthritis Myasthenia gravis Neurologic disease (encephalitis, cerebellitis, CNS lymphoma) Lymphoproliferation	CTLA4-dependent T regulatory cell defect Impaired autophagy Autoreactive B cells
IPEX and IPEX-like syndromes	Unknown, estimated <1:1,000,000	Diseases of immune dysregulation	Early-onset enteropathy Type 1 diabetes mellitus	Combined, variable severity	IBD Endocrinopathies Cytopenia Skin (eczema, rash, vitiligo) Autoimmune hepatitis	T regulatory cell deficiency or loss of function
XLP2 (XIAP deficiency)	Unknown, estimated <1:1,000,000	Diseases of immune dysregulation	Lymphoproliferation IBD HLH	EBV may be trigger	IBD Autoimmune hepatitis Lymphoproliferation Cytopenia	T cell apoptosis and activation-induced cell death
CD27 deficiency	Unknown, estimated <1:1,000,000	Diseases of immune dysregulation	Hypogammaglobulinemia Lymphoma	EBV may be a trigger	Lymphoproliferation Hemophagocytosis Lymphoma Cytopenia	Impaired antigen-activated T and B cell expansion and memory development Impaired NK function
ITK deficiency	Unknown	Diseases of immune dysregulation	Hodgkin (and rarer non-Hodgkin) lymphoma	EBV may be trigger	Lymphoproliferation Lymphoma Cytopenia	Skewed CD4 T cell differentiation
Type 1 interferonopathies	Unknown	Autoinflammatory disorders	Progressive encephalopathy		SLE Cytopenia Vasculopathy	Impaired cellular nucleic debris clearance
Early-onset inflammatory bowel disease syndromes	Unknown	Diseases of immune dysregulation		Respiratory infections	IBD Arthritis Lymphoma	Lacking responses to immune regulatory interleukins
CMC/STAT1 gain of function	Unknown	Defects in innate immunity	CMC	Fungal, bacterial, mycobacterial, herpesvirus infections	Endocrinopathies Pneumonitis Cytopenia	Impaired development of IL-17-producing T cells
STAT3 gain of function	Unknown	Diseases of immune dysregulation	Early onset IPEX-like		IBD Endocrinopathies Cytopenia Pneumonitis Autoimmune hepatitis Lymphoproliferation	Increased T cell differentiation towards IL-17 production Perturbed T regulatory cell function
SOCS1 haploinsufficiency	Unknown	Diseases of immune dysregulation	Early-onset severe multiorgan autoimmunity and autoinflammation	Recurrent bacterial infections	Cytopenia Lymphopenia Neutropenia SLE Thyroiditis Eczema Psoriasis Arthritis Hepatitis Nephritis	Reduced T and switched memory B cells Increased interferon I/II signature and STAT1 activation
IKAROS gain of function	Unknown	Diseases of immune dysregulation	Multiorgan autoimmunity		Endocrinopathies Colitis Allergy Cytopenia Lymphoproliferation IgG4-positive plasma cell expansion	Regulatory T cell defect due to IKAROS-mediated gene activation/regulation

IEI: inborn error of immunity; PID: primary immunodeficiency; IUIS: International Union of Immunological Societies; IgA: immunoglobulin A; CVID: common variable immunodeficiency; CID: combined immunodeficiency; TCR: T cell receptor; IBD: inflammatory bowel disease; NFKB: nuclear factor kappa B; SLE: systemic lupus erythematosus; BCR: B cell receptor; DNT: double-negative T; EBV: Epstein-Barr virus; CNS: central nervous system; NK: natural killer; HLH: hemophagocytic lymphohistiocytosis; APECED: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; XLP: X-linked lymphoproliferative disorder; SH2D1A: SH2 domain protein-1A; CTLA4: cytotoxic T lymphocyte-associated protein 4; ALPSV: autoimmune lymphoproliferative syndrome type 5; PI3K-d: phosphoinositide-3 kinases delta; CMV: cytomegalovirus; LRBA: lipopolysaccharide-responsive beige-like anchor; IPEX: immune dysregulation, polyendocrinopathy, and enteropathy, X-linked; XIAP: X-linked inhibitor of apoptosis protein; ITK: interleukin 2-inducible T cell kinase; CMC: chronic mucocutaneous candidiasis; STAT: signal transducer and activator of transcription; IL: interleukin; SOCS1: suppressor of cytokine signaling 1; IgG4: immunoglobulin G4.

* Including Omenn syndrome, leaky or hypomorphic severe combined immunodeficiency (SCID), and defects in various T cell surface receptors, lymphocyte structural, or T-B cell activation or signaling, which are usually less severe than SCID. Some of these disorders are also listed separately in this table because they belong to multiple categories of PID.

¶ Excluding hereditary angioedema.

References:

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.
Arkwright PD, Abinun M, Cant AJ. Autoimmunity in human primary immunodeficiency diseases. Blood 2002; 99:2694.
Todoric K, Koontz JM, Mattox D, Tarrant TK. Autoimmunity in immunodeficiency. Curr Allergy Asthma Rep 2013; 13:361.
Grimbacher B, Warnatz K, Yong PF, et al. The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects. J Allergy Clin Immunol 2016; 137:3.
Fischer A, Provot J, Jais JP, et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol 2017; 140:1388.

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Autoimmunity and immune dysregulation in inborn error of immunity/primary immunodeficiency disorders