Table 6.
Defects in Intrinsic and Innate Immunity
| Disease | Genetic defect/Presumed pathogenesis OMIM gene |
Inheritance | Affected Cell | Functional Defect | Associated Features | Phenotype OMIM Number |
|---|---|---|---|---|---|---|
| 1. Medelian Susceptibility to mycobacterial disease (MSMD) | ||||||
| IL-12 and IL-23 receptor β1 chain deficiency | Mutation in IL12RB1: IL-12 and IL-23 receptor β1 chain 601604 |
AR | L + NK | IFN-γ secretion | Susceptibility to Mycobacteria and Salmonella | 614891 |
| IL-12p40 deficiency | Mutation in IL12B : subunit p40 of IL12/IL23 161561 |
AR | M | IFN-γ secretion | Susceptibility to Mycobacteria and Salmonella | 614890 |
| IFN-γ receptor 1 deficiency | Mutation in IFNGR1: IFN-γR ligand binding chain 107470 |
AR | M + L | IFN-γ binding and signaling | Susceptibility to Mycobacteria and Salmonella | 209950 |
| IFN-γ receptor 1 deficiency | Mutation in IFNGR1: IFN-γR ligand binding chain 107470 |
AD | M + L | IFN-γ binding and signaling | Susceptibility to Mycobacteria and Salmonella | 615978 |
| IFN-γ receptor 2 deficiency | Mutation in IFNGR2: IFN-γR accessory chain 147569 |
AR | M + L | IFN-γ signaling | Susceptibility to Mycobacteria and Salmonella | 614889 |
| STAT1 deficiency (AD form) | Mutation in STAT1 (lost of function) 600555 |
AD | M + L | IFN-γsignaling | Susceptibility to Mycobacteria, Salmonella | 614892 |
| Macrophage gp91 phox deficiency |
Mutation in CYBB: Electron transport protein (gp 91 phox) 300481 |
XL | Mϕ only | Killing (faulty O2 − production) |
Isolated susceptibility to mycobacteria | 300645 |
| IRF8-deficiency (AD form) | Mutation in IRF8: IL12 production by CD1c+ MDC 601565 |
AD | CD1c + MDC | Differentiation of CD1c + MDC subgroup | Susceptibility to Mycobacteria | 614893 |
| Tyk2 deficiency | Mutation in TYK2
176941 |
AR | Normal, but Multiple cytokine signaling defect |
Normal | Susceptibility to intracellular bacteria (Mycobacteria, Salmonella), fungi and viruses (+/−) Elevated IgE |
611521 |
| ISG15 deficiency | Mutation in ISG15
147571 |
AR | IFNγ defect production | Susceptibility to Mycobacteria (BCG) Brain calcification |
616126 | |
| RORc deficiency | Mutation in RORC
602943 |
AR | L + NK | lack of functional RORγT protein : IFNγ defect production complete absence of IL-17A/F-producing T cells |
mycobacteriosis and candidiasis | Not yet assigned |
| 2. Epidermodysplasia verruciformis | ||||||
| EVER1 deficiency | Mutations of TMC6
605828 |
AR | Keratinocytes and leukocytes | EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes | HPV (group B1) infections and cancer of the skin (typical EV) | 226400 |
| EVER2 deficiency | Mutations of TMC8
605829 |
AR | Keratinocytes and leukocytes | EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes | HPV (group B1) infections and cancer of the skin (typical EV) | 226400 |
| WHIM (Warts, Hypogammaglo-bulinemia, infections, Myelokathexis) syndrome | Gain-of-function mutations of CXCR4, the receptor for CXCL12 162643 |
AD | Granulocytes + Lymphocytes | Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) | warts/Human Papilloma virus (HPV) infection Neutropenia Reduced B cell number Hypogammaglobulinemia |
193670 |
| 4. Predisposition to severe viral infection | ||||||
| STAT1 deficiency | Mutations of STAT1
600555 |
AR | T and NK cells and monocytes | STAT1-dependent IFN-α, and -β response |
Severe viral infections Mycobacterial infection |
613796 |
| STAT2 deficiency | Mutations of STAT2
600556 |
AR | T and NK cells | STAT2-dependent IFN-α, and -β response | Severe viral infections (disseminated vaccine-strain measles) |
Not yet assigned |
| IRF7 deficiency | Mutation in IRF7
605047 |
AR | Leukocytes and plasmacytoid dendritic cells, Non-hematopoietic cells |
IFN-α, and -β production IFN-λ production |
Severe influenza disease | Not yet assigned |
| CD16 deficiency | Mutation in CD16 146740 |
AR | NK cells | Deficient spontaneous NK cell cytotoxicity | Susceptibility to severe viral infections, inc. HSV, EBV, HPV | 615707 |
| 5. Herpes simplex encephalitis (HSE) | ||||||
| TLR3 deficiency | (b) Mutations of TLR3
603029 |
AD AR |
Central nervous system (CNS) resident cells and fibroblasts | TLR3-dependent IFN-α, -β, and -λ induction |
Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here) | 613002 |
| UNC93B1 deficiency | (a) Mutations of UNC93B1
608204 |
AR | CNS resident cells and fibroblasts | UNC-93B-dependent IFN-α, -β, and -λ induction |
Herpes simplex virus 1 encephalitis | 610551 |
| TRAF3 deficiency | (c) Mutations of TRAF3
601896 |
AD | CNS resident cells and fibroblasts | TRAF3-dependent IFN-α, -β, and -λ induction |
Herpes simplex virus 1 encephalitis | 614849 |
| TRIF deficiency | (c) Mutations of TRIF, also called TICAM1
607601 |
AD AR |
CNS resident cells and fibroblasts | TRIF-dependent IFN-α, -β, and -λ induction |
Herpes simplex virus 1 encephalitis | 614850 |
| TBK1 deficiency | (c) Mutations of TBK1
604834 |
AD | CNS resident cells and fibroblasts | TBK1-dependent IFN-α, -β, and -λ induction |
Herpes simplex virus 1 encephalitis | Not yet assigned |
| 6. Predisposition to invasive fungal diseases | ||||||
| CARD9 deficiency | Mutations of CARD9
607212 |
AR | Mononuclear phagocytes | CARD9 signaling pathway | Invasive candidiasis infection Deep dermatophytoses |
212050 |
| 7. Chronic mucocutaneous candidiasis (CMC) | ||||||
| IL-17RA deficiency | (a) Mutations in IL17RA
605461 |
AR | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RA signaling pathway | CMC Folliculitis |
613953 |
| IL-17RC deficiency | Mutations in IL17RC 610925 |
AR | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RC signaling pathway | CMC | Not yet assigned |
| IL-17F deficiency | (b) Mutations in IL17F
606496 |
AD | T cells | IL-17 F-containing dimers | CMC Folliculitis |
613956 |
| STAT1 gain-of-function | (c) gain-of-function mutations in STAT1
600555 |
AD | T cells, B cells, monocytes | Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells | CMC Various fungal, bacterial and viral (HSV) infections Auto-immunity (Thyroiditis, diabetes, cytopenia) Enteropathy |
614162 |
| ACT1 deficiency | (c) Mutations in ACT1, also called TRAF3IP2
(607043) |
AR | T cells, fibroblasts | Fibroblasts fail to respond to IL-17A and IL-17 F, and their T cells to IL-17E | CMC Blepharitis, Folliculitis and macroglossia |
615527 |
| 8. TLR signaling pathway deficiency | ||||||
| IRAK-4 deficiency | Mutations of IRAK4, a component of TLR- and IL-1R-signaling pathway 606883 |
AR | Lymphocytes + Granulocytes + Monocytes | TIR-IRAK signaling pathway | Bacterial infections (pyogens) | 607676 |
| MyD88 deficiency | Mutations of MYD88, a component of the TLR and IL-1R signaling pathway 602170 |
AR | Lymphocytes + Granulocytes + Monocytes | TIR-MyD88 signaling pathway | Bacterial infections (pyogens) | 612260 |
| 9. Isolated congenital asplenia (ICA) | Mutations in RPSA
150370 |
AD | Spleen | RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome | Bacteremia (encapsulated bacteria) No spleen |
271400 |
| 8. Trypanosomiasis | Mutations in APOL- I 603743 | AD | APOL-I | Trypanosomiasis | Not yet assigned | |
Total no. of gene defects in Table 6: 32
New genes added : RORC, IRF7, IL17RC, APOL-1
XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, NF-κB nuclear factor Kappa B, TIR Toll and Interleukin 1 Receptor, IFN interferon, HVP human papilloma virus, TLR Toll-like receptor, IL interleukin