Table 4.
Diseases of immune dysregulation
| Disease | Genetic defect/Presumed pathogenesis Gene OMIM |
Inheritance | Circulating T Cells | Circulating B cells | Functional defect | Associated Features | Phenotype OMIM number |
|---|---|---|---|---|---|---|---|
| 1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes | |||||||
| 1.1. FHL syndromes without hypopigmentation | |||||||
| Perforin deficiency (FHL2) | Mutations in PRF1; perforin is a major cytolytic protein 170280 |
AR | Increased activated T cells | Normal | Decreased to absent NK and CTL activities cytotoxicity | Fever, Hepato-Splenomegaly (HSMG), Hemophagocytic lymphohistiocytosis (HLH), Cytopenias | 603553 |
| (UNC13D / Munc13-4 deficiency (FHL3) | Mutations in UNC13D; required to prime vesicles for fusion 608897 |
AR | Increased activated T cells | Normal | Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation) |
Fever, HSMG, HLH, Cytopenias, | 608898 |
| Syntaxin 11 deficiency, (FHL4) | Mutations in STX11, required for secretory vesicle fusion with the cell membrane 605014 |
AR | Increased activated T cells | Normal | Decreased NK activity (cytotoxicity and/or degranulation) | Fever, HSMG, HLH, Cytopenias, | 603552 |
| STXBP2 / Munc18-2 deficiency (FHL5) | Mutations in STXBP2, required for secretory vesicle fusion with the cell membrane 601717 |
AR or AD | Increased activated T cells | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Fever, HSMG, HLH, Cytopenias, | 613101 |
| SH2D1A deficiency (XLP1) | Mutations in SH2D1A encoding an adaptor protein regulating intracellular signaling 300490 |
XL | Normal or increased activated T cells | Reduced Memory B cells | partially defective NK cell and CTL cytotoxic activity | Clinical and immunologic features triggered by EBV infection: HLH, lymphoproliferation, Aplastic anaemia, lymphoma. Hypogammaglobulinemia, absent iNKT cells |
308240 |
| XIAP deficiency (XLP2) | Mutations in XIAP/ BIRC4 encoding an inhibitor of apoptosis 300079 |
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 |
| 1.2. FHL syndromes with hypopigmentation | |||||||
| Chediak-Higashi syndrome | Mutations in LYST, impaired lysosomal trafficking 606897 |
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 |
| Griscelli syndrome, type2 | Mutations in RAB27A encoding a GTPase that promotes docking of secretory vesicles to the cell membrane 603868 |
AR | Normal | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Partial albinism, fever, HSMG, HLH, cytopenias | 607624 |
| Hermansky-Pudlak syndrome, type 2 | Mutations in AP3B1 gene, encoding for the β subunit of the AP-3 complex 603401 |
AR | Normal | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Partial albinism, recurrent infections, pulmonary fibrosis Increased bleeding, neutropenia, HLH |
608233 |
| Hermansky-Pudlak syndrome, type 9 | Mutations in PLDN, encoding Pallidin, a component of the biogenesis of lysosome-related organelles complex-1 (BLOC-1) 604310 |
AR | (Not assessed; leukopenia) | (Not assessed, leukopenia) | Decreased NK cell cytolytic activity | Oculocutaneous albinism, recurrent cutaneous infections, leukopenia, thrombocytopenia | 614171 |
| 2. T regulatory cells genetic defects | |||||||
| IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked | Mutations in FOXP3, encoding a T cell transcription factor 300292 |
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 |
| CD25 deficiency | Mutations in IL2RA, encoding IL-2Rα chain, 147730 | AR | Normal to decreased | Normal | No CD4 + C25+ cells with impaired function of Tregs cells | Lymphoproliferation, autoimmunity. Impaired T cell proliferation | 606367 |
| CTLA4 deficiency (ALPSV) | Mutations in CTLA4, encoding Cytotoxic T Lymphocyte antigen 4, a protein that negatively regulate T cell receptor signaling and T cell activation. 123890 |
AD | Decreased | Decreased | Impaired function of Treg cells. | Autoimmune cytopenias, enteropathy, interstitial lung disease, extra-lymphoid lymphocytic infiltration recurrent infections, | 616100 |
| STAT3 GOF mutations | Mutations in STAT3, encoding Signal Transducer and activator 3 102582 |
AD | Decreased | Decreased | Enhanced STAT3 signaling, leading to increased Th17 cell differentiation, lymphoproliferation and autoimmunity. Decreased Treg cell numbers and impaired phenotype | Lymphoproliferation, Solid organ autoimmunity, recurrent infections. | 615952 |
| 3. Autoimmunity with or without lymphoproliferation | |||||||
| APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy | Mutations in AIRE, encoding a transcription regulator needed to establish thymic self-tolerance 607358 |
AR | Normal | Normal | AIRE-1 serves as check-point 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, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata Enteropathy, Pernicious anemia, |
240300 |
| ITCH deficiency | Mutations in ITCH, an E3 ubiquitin ligase catalyzes the transfer of ubiquitin to a signaling proteins in the cell including phospholipase Cγ1 (PLCγ1) 606409 |
AR | Not assessed | Not assessed | Itch deficiency may cause immune dysregulation by affecting both anergy induction in auto-reactive effector T cells and generation of Tregs | Early-onset chronic lung disease (interstitial pneumonitis) Autoimmune disorder (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis) Failure to thrive, developmental delay, dysmorphic facial features |
613385 |
| Tripeptidyl-Peptidase II Deficiency | Mutations in TPP2, encoding tripeptidyl-peptidase II, serine exopeptidase involved in extralysosomal peptide degradation 190470 |
AR | Decreased | Decreased | TPP2 deficiency results in premature immunosenescence and immune dysregulation | Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections, | Not yet assigned |
| 3. Autoimmune lymphoproliferative syndrome (ALPS) | |||||||
| ALPS-FAS | Germinal mutations in TNFRSF6, encoding CD95/Fas cell surface apoptosis receptor** 134637 |
AD AR*** |
Increased CD4−CD8−TCRαβ double negative (DN) T cells | Normal, low memory B cells | Apoptosis defect FAS mediated | Splenomegaly, adenopathies, Autoimmune cytopenias, increased lymphoma risk. IgG and A normal or increased Elevated FasL and IL-10, vitamin B12 |
601859 |
| ALPS-FASLG | Mutations in TNFSF6, Fas ligand for CD95 apoptosis 134638 |
AR | Increased DN T cells | Normal | Apoptosis defect FAS mediated | Splenomegaly, adenopathies, autoimmune cytopenias, SLE; Soluble FasL is not elevated |
601859 |
| ALPS-Caspase10 | Mutations in CASP10, intracellular apoptosis pathway 601762 |
AD | Increased DN T cells | Normal | Defective lymphocyte apoptosis | Adenopathies, splenomegaly, autoimmunity. | 603909 |
| ALPS-Caspase 8 | Mutations in CASP8, intracellular apoptosis and activation pathways 601763 |
AR | Slightly increased DN T cells | Normal | Defective lymphocyte apoptosis and activation | Adenopathies, splenomegaly, Bacterial and viral infections, Hypogammaglobulinemia |
607271 |
| FADD deficiency | Mutations in FADD encoding an adaptor molecule interacting with FAS, and promoting apoptosis 602457 |
AR | Increased DN T cells | Normal | Defective lymphocyte apoptosis | Functional hyposplenism, Bacterial and viral infections, Recurrent episodes of encephalopathy and liver dysfunction. |
613759 |
| PRKC delta deficiency | Mutations in PRKCD, encoding a member of the protein kinase C family critical for regulation of cell survival, proliferation and apoptosis 176977 |
AR | Normal | Low memory B cells and Elevation of CD5 B cells |
Apoptotic defect in B cells | Recurrent infections; EBV chronic infection Lymphoproliferation SLE-like autoimmunity (Nephrotic and antiphospholipid syndromes) HypoIgG |
615559 |
| 4. Immune dysregulation with colitis | |||||||
| IL-10 deficiency | Mutations in IL10, encoding IL-10 124092 |
AR | Normal | Normal | No functional IL-10 secretion | Inflammatory bowel disease (IBD) Folliculitis, Recurrent respiratory diseases, Arthritis, |
not assigned |
| IL-10Rα deficiency | Mutations in IL10RA, encoding IL-10R1 146933 |
AR | Normal | Normal | Leukocytes no response to IL-10 |
IBD, Folliculitis, Recurrent respiratory diseases, Arthritis, Lymphoma |
613148 |
| IL-10Rβ deficiency | Mutations in IL10RB, encoding IL-10R2 123889 |
AR | Normal | Normal | Leukocytes no response to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29 |
IBD, Folliculitis, Recurrent respiratory diseases, Arthritis, Lymphoma |
612567 |
| NFAT5 haploinsufficiency | Hemizygous deletion of NFAT5
604708 |
AD | Normal | Normal | Decreased memory B cells and plasmablasts | IBD, recurrent sinopulmonary infections | Not yet assigned |
| 5. Type 1 Interferonopathies | |||||||
| TREX1 deficiency, Aicardi-Goutieres syndrome 1 (AGS1) | Mutations in TREX1, encoding nuclease involves in clearing cellular nucleic debris 606609 |
AR AD***** |
Not assessed | Not assessed | Intracellular accumulation of abnormal single-stranded (ss) DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy Intracranial calcifications, Cerebral atrophy, leukodystrophy, HSMG, Thrombocytopenia, Elevated hepatic transaminases Chronic cerebrospinal fluid (CSF) lymphocytosis |
225750 |
| RNASEH2B deficiency, AGS2 | Mutations in RNASEH2B, encoding nuclease subunit involves in clearing cellular nucleic debris 610326 |
AR | Not assessed | Not assessed | Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy Intracranial calcifications, Cerebral atrophy, leukodystrophy, HSMG, thrombocytopenia, Elevated hepatic transaminases Chronic CSF lymphocytosis |
610181 |
| RNASEH2C deficiency, AGS3 | Mutations in RNASEH2C, encoding nuclease subunit involves in clearing cellular nucleic debris 610330 |
AR | Not assessed | Not assessed | Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy Intracranial calcifications, Cerebral atrophy, leukodystrophy, HSMG, thrombocytopenia, Elevated hepatic transaminases Chronic CSF lymphocytosis |
610329 |
| RNASEH2A deficienc y, AGS4 | Mutations in RNASEH2A, encoding nuclease subunit involves in clearing cellular nucleic debris 606034 |
AR | Not assessed | Not assessed | Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy Intracranial calcifications, Cerebral atrophy, leukodystrophy, HSMG, thrombocytopenia, Elevated hepatic transaminases Chronic CSF lymphocytosis |
610333 |
| SAMHD1 deficiency, AGS5 | Mutations in SAMHD1, encoding negative regulator of the immunostimulatory DNA response 606754 |
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, Cerebral atrophy, leukodystrophy, HSMG, thrombocytopenia, anemia elevated lactates Chronic CSF lymphocytosis, Skin vascularitis, mouth ulcers, arthropathy |
612952 |
| ADAR1 deficiency, AGS6 | Mutations in ADAR1, encoding a RNA-specific adenosine deaminase 146920 |
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 |
| Aicardi-Goutieres syndrome 7 (AGS7) |
IFIH1
606951 |
AD | Not assessed | Not assessed | IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule | Progressive encephalopathy intracranial calcification, Severe developmental delay, leukodystrophy |
615846 |
| Spondyloenchondro-dysplasia with immune dysregulation (SPENCD) | Mutations in ACP5, encoding tartrate-resitant acid phosphatase (TRAP) 171640 |
AR | Not assessed | Not assessed | Upregulation of IFN-alpha and type I IFN-stimulated genes | Recurrent bacterial and viral infections, Intracranial calcification, SLE-like autoimmunity (Sjögren’s syndrome, hypothyroidism, inflammatory myositis, Raynaud’s disease and vitiligo), hemolytic anemia, thrombocytopenia, skeletal dysplasia, short stature |
607944 |
| STING--associated vasculopathy, infantile-onset |
TMEM173 encoding for STIMULATOR OF INTERFERON GENES 612374 |
AR | Not assessed | Not assessed | STING activates both the NF-kappa-B and IRF3 transcription pathways to induce expression of IFN-alpha and IFN-beta and exert a potent antiviral effect | Severe infantile-onset autoinfammatory vasculopathy, | 615934 |
| ADA2 deficiency | Mutations in CECR1; encoding ADA2 607575 |
AR | Not assessed | Not assessed | ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors | Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever | 615688 |
Total no. of genes in Table 4: 37
New genes added: PLDN, CTLA4, TPP2, NFAT5, IFIH1, TMEM173, CECR1, STAT 3 (GOF)
XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, FHL familial hemophagocytic lymphohistiocytosis, HLH Hemophagocytic lymphohistiocytosis, HSMG hepato-splenomegaly, DN double-negative, SLE systemic lupus erythematous, IBD inflammatory bowel disease, CSF chronic cerebrospinal fluid
** Somatic mutations of TNFRSF6 cause a similar phenotype (ALPS-sFAS) see Table 9. Germinal mutation and somatic mutations of TNFRSF6 can be associated in some ALPS-FAS patients
*** AR ALPS-FAS patients have a most severe clinical phenotype
**** Somatic mutations in KRAS or NRAS can give this clinical phenotype associated auto-immune leukoproliferative disease (RALD) and are now include in Table 9 entitled Phenocopies of PID
***** de novo dominant TREX1 mutations have been reported