. 2014 Apr 22;5:162. doi: 10.3389/fimmu.2014.00162

Table 4.

Diseases of immune dysregulation.

Disease	Genetic defect/presumed pathogenesis	Inheritance	Circulating T cells	Circulating B cells	Functional defect	Associated features	OMIM number
1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes
1.1 FHL syndromes without hypopigmentation
(a) Perforin deficiency (FHL2)	Mutations in PRF1; perforin is a major cytolytic protein	AR	Increased activated T cells	Normal	Decreased to absent NK and CTL activities (cytotoxicity)	Fever, hepatosplenomegaly (HSMG), hemophagocytic lymphohistiocytosis (HLH), cytopenias	603553
(b) UNC13D/Munc13-4 deficiency (FHL3)	Mutations in UNC13D ^a; required to prime vesicles for fusion	AR	Increased activated T cells	Normal	Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation)	Fever, HSMG, HLH, cytopenias	608898
(c) Syntaxin 11 deficiency (FHL4)	Mutations in STX11, required for secretory vesicle fusion with the cell membrane	AR	Increased activated T cells	Normal	Decreased NK activity (cytotoxicity and/or degranulation)	Fever, HSMG, HLH, cytopenias	603552
(d) STXBP2/Munc18-2 deficiency (FHL5)	Mutations in STXBP2, required for secretory vesicle fusion with the cell membrane	AR	Increased activated T cells	Normal	Decreased NK and CTL activities (cytotoxicity and/or degranulation)	Fever, HSMG, HLH, cytopenias	613101
1.2. FHL syndromes with hypopigmentation
(a) Chediak–Higashi syndrome	Mutations in LYST Impaired lysosomal trafficking	AR	Increased activated T cells	Normal	Decreased NK and CTL activities (cytotoxicity and/or degranulation)	Partial albinism Recurrent infections, fever HSMG, HLH Giant lysosomes, neutropenia, cytopenias Bleeding tendency Progressive neurological dysfunction	214500
(b) Griscelli syndrome, type 2	Mutations in RAB27A encoding a GTPase that promotes docking of secretory vesicles to the cell membrane	AR	Normal	Normal	Decreased NK and CTL activities (cytotoxicity and/or degranulation)	Partial albinism, fever, HSMG, HLH, cytopenias	607624
(c) Hermansky–Pudlak syndrome, type 2	Mutations in AP3B1 gene, encoding for the b subunit of the AP-3 complex	AR	Normal	Normal	Decreased NK and CTL activities (cytotoxicity and/or degranulation)	Partial albinism Recurrent infections Pulmonary fibrosis Increased bleeding Neutropenia HLH	608233
2. Lymphoproliferative syndromes
(a) SH2D1A deficiency (XLP1)	Mutations in SH2D1A encoding an adaptor protein regulating intracellular signaling	XL	Normal or increased activated T cells	Reduced memory B cells	Partially defective NK cell and CTL cytotoxic activity	Clinical and immunological features triggered by EBV infection: HLH Lymphoproliferation, aplastic anemia, lymphoma Hypogammaglobulinemia Absent iNKT cells	308240
(b) XIAP deficiency (XLP2)	Mutations in XIAP/BIRC4 encoding an inhibitor of apoptosis	XL	Normal or increased activated T cells; low/normal iNK T cells	Normal or reduced memory B cells	Increased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD)	EBV infection, splenomegaly, lymphoproliferation HLH, colitis, IBD, hepatitis Low iNKT cells	300635
(c) ITK deficiency^a	Mutations in ITK encoding IL-2 inducible T cell kinase required for TCR-mediated activation	AR	Progressive decrease	Normal	Decreased T cell activations	EBV-associated B cell lymphoproliferation, lymphoma Normal or decreased IgG	613011
(d) CD27 deficiency^a	Mutations in CD27, encoding TNF-R member superfamily required for generation and long-term maintenance of T cell immunity	AR	Normal	No memory B cells	Low T and NK cells functions	Clinical and immunological features triggered by EBV infection: HLH Aplastic anemia, lymphoma, hypogammaglobulinemia Low iNKT cells	615122
3. Genetic defects of regulatory T cells
(a) IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked	Mutations in FOXP3, encoding a T cell transcription factor	XL	Normal	Normal	Lack of (and/or impaired function of) CD4⁺ CD25⁺ FOXP3⁺ regulatory T cells (Tregs)	Autoimmune enteropathy Early-onset diabetes Thyroiditis, hemolytic anemia, thrombocytopenia, eczema Elevated IgE, IgA	304790
(b) CD25 deficiency^a	Mutations in IL-2RA, encoding IL-2Rα chain	AR	Normal to decreased	Normal	No CD4+ C25+ cells with impaired function of Tregs cells	Lymphoproliferation, autoimmunity. Impaired T cell proliferation	606367
(c) STAT5b deficiency^a	Mutations in STAT5B, signal transducer, and transcription factor, essential for normal signaling from IL-2 and 15, key growth factors for T and NK cells	AR	Modestly decreased	Normal	Impaired development and function of γδT cells, Tregs, and NK cells Low T cell proliferation	Growth-hormone insensitive dwarfism	245590
						Dysmorphic features
						Eczema
						Lymphocytic interstitial pneumonitis, autoimmunity
4. Autoimmunity without lymphoproliferation
(a) APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy	Mutations in AIRE, encoding a transcription regulator needed to establish thymic self-tolerance	AR	Normal	Normal	AIRE-1 serves as checkpoint in the thymus for negative selection of autoreactive T cells and for generation of Tregs	Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction, and other endocrine abnormalities	240300
						Chronic mucocutaneous candidiasis
						Dental enamel hypoplasia
						Alopecia areata
						Enteropathy, pernicious anemia
(b) ITCH deficiency^a	Mutations in ITCH, an E3 ubiquitin ligase catalyzes the transfer of ubiquitin to a signaling protein in the cell including phospholipase Cγ1 (PLCγ1)	AR	Not assessed	Not assessed	Itch deficiency may cause immune dysregulation by affecting both anergy induction in autoreactive effector T cells and generation of Tregs	Early-onset chronic lung disease (interstitial pneumonitis)	613385
						Autoimmune disorder (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis)
						Failure to thrive, developmental delay, dysmorphic facial features
5. Autoimmune lymphoproliferative syndrome (ALPS)
(a) ALPS–FAS	Germinal mutations in TNFRSF6, encoding CD95/Fas cell surface apoptosis receptor^b	AD	Increased CD4⁻CD8⁻ TCRα/β double negative (DN) T cells	Normal, low memory B cells	Apoptosis defect FAS mediated	Splenomegaly, adenopathies, autoimmune cytopenias	601859
		AR^c				Increased lymphoma risk
						IgG and A normal or increased
						Elevated FasL and IL-10, vitamin B12
(b) ALPS– FASLG	Mutations in TNFSF6, Fas ligand for CD95 apoptosis	AR	Increased DN T cells	Normal	Apoptosis defect FAS mediated	Splenomegaly, adenopathies, autoimmune cytopenias, SLE	134638
						Soluble FasL is not elevated
(c) ALPS–caspase 10^a	Mutations in CASP10, intracellular apoptosis pathway	AD	Increased DN T cells	Normal	Defective lymphocyte apoptosis	Adenopathies, splenomegaly, autoimmunity	603909
(d) ALPS–caspase 8^a	Mutations in CASP8, intracellular apoptosis, and activation pathways	AR	Slightly increased DN T cells	Normal	Defective lymphocyte apoptosis and activation	Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia	607271
(e) FADD deficiency^a	Mutations in FADD encoding an adaptor molecule interacting with FAS, and promoting apoptosis	AR	Increased DN T cells	Normal	Defective lymphocyte apoptosis	Functional hyposplenism, bacterial and viral infections	613759
						Recurrent episodes of encephalopathy and liver dysfunction
(f) CARD11 gain-of-function (GOF) mutations^a	GOF mutations in CARD11, encoding a protein required for antigen receptor–induced NF-κB activation in B and T lymphocytes	AD	Normal	Increased M⁺D⁺CD19⁺ CD20⁺ B cells	Constitutive activation of NF-κB in B & T	Lymphoproliferation	606445
						Bacterial and viral infections
						EBV chronic infection
						Autoimmune cytopenia
						Hypogammaglobulinemia
(g) PRKCδ deficiency^a	Mutations in PRKCD, encoding a member of the protein kinase C family critical for regulation of cell survival, proliferation, and apoptosis	AR	Normal	Low memory B cells and elevation of CD5 B cells	Apoptotic defect in B cells	Recurrent infections; EBV chronic infection	615559
						Lymphoproliferation
						SLE-like autoimmunity (nephrotic and antiphospholipid syndromes)
						HypoIgG
6. Immune dysregulation with colitis
(a) IL-10 deficiency^a	Mutations in IL-10, encoding IL-10	AR	Normal	Normal	No functional IL-10 secretion	Inflammatory bowel disease (IBD) folliculitis	Not assigned
						Recurrent respiratory diseases
						Arthritis
(b) IL-10Rα deficiency	Mutations in IL-10RA, encoding IL-10R1	AR	Normal	Normal	Leukocytes, no response to IL-10	IBD, folliculitis	613148
						Recurrent respiratory diseases
						Arthritis, lymphoma
(c) IL-10Rβ deficiency	Mutations in IL-10RB, encoding IL-10R2	AR	Normal	Normal	Leukocytes, no response to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29	IBD, folliculitis	612567
						Recurrent respiratory diseases
						Arthritis, lymphoma
7. Type 1 interferonopathies
(a) TREX1 deficiency, Aicardi–Goutieres syndrome 1 (AGS1)	Mutations in TREX1, encoding nuclease involves in clearing cellular nucleic debris	AR	Not assessed	Not assessed	Intracellular accumulation of abnormal single-stranded (ss) DNA species leading to increased CSF alpha-IFN production	Progressive encephalopathy intracranial calcifications	606609
		AD^e				Cerebral atrophy, leukodystrophy
						HSMG, thrombocytopenia
						Elevated hepatic transaminases
						Chronic cerebrospinal fluid (CSF) lymphocytosis
(b) RNASEH2B deficiency, AGS2	Mutations in RNASEH2B, encoding nuclease subunit involves in clearing cellular nucleic debris	AR	Not assessed	Not assessed	Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production	Progressive encephalopathy intracranial calcifications	610326
						Cerebral atrophy, leukodystrophy
						HSMG, thrombocytopenia
						Elevated hepatic transaminases
						Chronic CSF lymphocytosis
(c) RNASEH2C deficiency, AGS3	Mutations in RNASEH2C, encoding nuclease subunit involves in clearing cellular nucleic debris	AR	Not assessed	Not assessed	Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production	Progressive encephalopathy intracranial calcifications	610330
						Cerebral atrophy, leukodystrophy
						HSMG, thrombocytopenia
						Elevated hepatic transaminases
						Chronic CSF lymphocytosis
(d) RNASEH2A deficiency, AGS4^a	Mutations in RNASEH2A, encoding nuclease subunit involves in clearing cellular nucleic debris	AR	Not assessed	Not assessed	Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production	Progressive encephalopathy intracranial calcifications	606034
						Cerebral atrophy, leukodystrophy
						HSMG, thrombocytopenia
						Elevated hepatic transaminases
						Chronic CSF lymphocytosis
(e) SAMHD1 deficiency, AGS5	Mutations in SAMHD1, encoding negative regulator of the immunostimulatory DNA response	AR	Not assessed	Not assessed	Induction of the cell intrinsic antiviral response, apoptosis, and mitochondrial DNA destruction leading to increased CSF alpha-IFN production	Progressive encephalopathy intracranial calcifications	612952
						Cerebral atrophy, leukodystrophy
						HSMG, thrombocytopenia, anemia elevated lactates
						Chronic CSF lymphocytosis
						Skin vasculitis, mouth ulcers, arthropathy
(f) ADAR1 deficiency, AGS6	Mutations in ADAR1, encoding an RNA-specific adenosine deaminase	AR	Not assessed	Not assessed	Catalyzes the deamination of adenosine to inosine in dsRNA substrates markedly elevated CSF IFN-alpha	Progressive encephalopathy intracranial calcification Severe developmental delay, leukodystrophy	615010
(g) Spondyloenchondro-dysplasia with immune dysregulation (SPENCD)	Mutations in ACP5, encoding tartrate-resistant acid phosphatase (TRAP)	AR	Not assessed	Not assessed	Upregulation of IFN-alpha and type I IFN-stimulated genes	Recurrent bacterial and viral infections, intracranial calcification	607944
						SLE-like autoimmunity (Sjögren’s syndrome, hypothyroidism, inflammatory myositis, Raynaud’s disease and vitiligo), hemolytic anemia, thrombocytopenia, skeletal dysplasia, short stature

XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; FHL, familial hemophagocytic lymphohistiocytosis; HLH, hemophagocytic lymphohistiocytosis; HSMG, hepatosplenomegaly; DN, double negative; SLE, systemic lupus erythematous; IBD, inflammatory bowel disease; CSF, chronic cerebrospinal fluid.

^aTen or fewer unrelated cases reported in the literature.

^bSomatic mutations of TNFRSF6 cause a similar phenotype (ALPS–sFAS), see Table 9. Germinal mutation and somatic mutation of TNFRSF6 can be associated in some ALPS–FAS patients.

^cAR ALPS–FAS patients have a most severe clinical phenotype.

^dSomatic mutations in KRAS or NRAS can give this clinical phenotype associated autoimmune leukoproliferative disease (RALD) and are now included in Table 9 entitled phenocopies of PID.

^eDe novo dominant TREX1 mutations have been reported.

Fourteen new disorders have been added to Table 4. Two new entries have been added in the table, including immune dysregulation with colitis and Type 1 interferonopathies. EBV-driven lymphoproliferation is also observed in MAGT1 deficiency (Table 1).