Table 1:
Overview of recently described inborn errors of innate immunity to infections
| Protein | Gene | OMIM n. gene / disease | Inheritance and penetrance | Cells where expressed (mRNA and/or protein) | Cells where tested | Results | Immunological phenotype | Infectious phenotype | Noninfectious phenotype | Autoinfl ammation | N. of report ed patients | Therapy | Year of genetic report |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Upstream defects of the TLR and/or IL-1R signaling pathway | |||||||||||||
| IRAK1 | IRAK1 | 300283 | XL | Ubiquitous | Fibroblasts PBMCs EBV-B cells | TLR responses: impaired in fibroblasts and EBVB cells, normal in PBMCs. Normal responses to IL-1β in fibroblasts and PBMcs | NA | NA | NA (MECP2 deletion sdr) | No | 1 | NA | 2017 (24) |
| TIRAP | TIRAP | 606252 | AR - IP | Ubiquitous | Fibroblasts PBMCs Granulocytes | Impaired responses to TLR2 and TLR4 stimulation | NA | Severe staphylococcal infection | NA | No | 8 | NA | 2017 (25) |
| Inborn errors of the CBM complex | |||||||||||||
| CARD9 | CARD9 | 607212/ 212050 | AR - CP | Granulocytes | PBMCs Monocytederived dendritic cells Macrophages | Impaired T cell dependent IL-17 production. Defective cytokine and chemokine production upon fungal stimulation. Impaired neutrophil killing, impaired neutrophil recruitment to the site of infection. | Eosinophilia, high IgE | Superficial (e.g. chronic mucocutaneous candidiasis) and invasive (e.g. meningoencephalitis) fungal infections | NA | No | 58 | HSCT GM-CSF G-CSF | 2009 (50) |
| Inborn errors of LUBAC | |||||||||||||
| HOIL-1 | HOIL1 (RBCK1) | 610924 | AR - CP | Ubiquitous | Fibroblasts EBV-B cells PBMCs | Impaired NF-κB responses in fibroblasts and EBVB cells. Enhanced response to IL-1β in monocytes. | Impaired vaccine responses | Invasive bacterial infections. | Chronic autoinflammation, muscular amylopectinosis | Yes | 3 | NA | 2012 (57) |
| HOIP | HOIP (RNF31) | 612487 | AR - CP | Ubiquitous | Fibroblasts EBV-B cells PBMCs | Impaired linear ubiquitination and NF-κB activation in fibroblasts. Impaired CD40 activation in B cells. Enhanced response to IL-1β in monocytes. | Lymphopenia, antibody deficiency and impaired distribution and function of T lymphocytes | Recurrent viral and bacterial infections. | Multiorgan autoinflamma tion, chronic diarrhea, subclinical amylopectino sis, systemic lymphangiectasia, | Yes | 1 | NA | 2015 (58) |
| Defects of phagocytes | |||||||||||||
| VPS45 (SCN5) | VPS45 | 610035/615285 | AR - CP | Broadly expressed | Lymphoblasts Fibroblasts Platelets Neutrophils Bone marrow myeloid cells | Impaired cell migration, increased apoptosis, loss of lysosomes. Loss of α-granules in platelets | SCN, G-CSF treatment resistant. Platelet dysfunction, thrombocytopenia, progressive anemia | Invasive pyogenic bacterial and fungal infections of airways, skin and urinary tract; sepsis | Extramedullar hematopoiesi s, bone marrow fibrosis, nephromegaly, hepatospleno megaly, neurological involvement | No | 13 | HSCT | 2013 (69, 70) |
| JAGN1 (SCN6) | JAGN1 | 616012/ 616022 | AR - CP | Ubiquitous | Neutrophils | Ultrastructural defects, few granules, aberrant glycosylation of GCSF-R, increased apoptosis | SCN, mostly G-CSF treatment resistant | Pyogenic bacterial infections of airways and skin; sepsis | Myeloid maturation arrest, osteopenia, teeth abnormalities, facial dysmorphisms, short stature, pancreatic insufficiency | No | 16 | G-CSF HSCT | 2014 (74) |
| G-CSF receptor (SCN7) | CSF3R | 138971/ 617014 | AR - CP | Granulocyte s, placenta and other tissues | PBMCs | Impaired glycosylation, expression at the cell surface and function | SCN, G-CSF treatment resistant | Pyogenic bacterial infections of airways, skin and urinary tract | NA | No | 5 | GM-CSF | 2014 (76) |
| SMARCD2 (SGD2) | SMARCD2 | 601736/ 617475 | AR - CP | Hematopoietic progenitor cells | Hematopoieti c progenitor cells | Myeloid differentiation defects, defect of granulopoiesis and neutrophil granule scarcity | Neutropenia, neutrophil specific granule deficiency, granulocyte maturation arrest | Severe recurrent bacterial infections, sepsis and parasitic infections | Developmental delay, skeletal anomalies, dysmorphic features, delayed separation of umbilical cord, progressive myelofibrosis and MDS, chronic diarrhea | No | 4 | HSCT | 2017 (79) |
| Aip1 | WDR1 | 604734 | AR - CP | Ubiquitous | Neutrophils | Impaired neutrophil polarization, chemotaxis and survival due to impaired actin rearrangement | Mild neutropenia, herniation of neutrophil nuclear lobes, absence of neutrophil granules | Pyogenic bacterial infections of airways, skin and urinary tract; sepsis; disseminated lethal Varicella Zoster infection | Impaired wound healing, severe stomatitis with oral stenosis | Yes | 6 | HSCT | 2016 (83) |
| Defect in a lymphoid organ: isolated congenital asplenia | |||||||||||||
| Riboso mal protein SA | RPSA | 150370/ 271400 | AD - IP | Ubiquitous | PBMCs | Haploinsufficiency | Asplenia | Invasive bacterial infections | Isolated congenital asplenia | No | >30 | NA, penicilli n prophylaxis | 2013 (89) |
| Inborn errors of interferon-γ and IL-12 immunity | |||||||||||||
| TYK2 | TYK2 | 176941/611521 | AR - CP | Broadly expressed | EBV-B cells SV40-fibroblasts HVS-T cells PBMCs Fibroblasts | Impaired responses to type I IFN, IL-12/IL-23 and IL-10 | NA | Mendelian susceptibility to mycobacterial disease and infections with other intracellular organisms and viruses | Hyper-IgE syndrome reported in only one patient | No | 8 | NA | 2006 (96) 2012 (95) 2015 (94) |
| JAK1 | JAK1 | 147795 | AR - CP | Broadly expressed | PBMCs Fibroblasts | Impaired responses to type I and II IFN, IL-2, IL-4, IL-10, IL-27 | Progressive T lymphopenia, increased IgG and IgA | Mendelian susceptibility to mycobacterial disease, warts, superficial parasitic and fungal infections | Early onset bladder carcinoma | No | 1 | NA | 2016 (97) |
| ISG15 | ISG15 | 147571/ 616126 | AR - CP | Broadly expressed | PBMCs Granulocytes SV-40 fibroblasts EBV-B cells | Enhanced type I IFN response. Impaired IFN-γ production by NK and T cells | NA | Mendelian susceptibility to mycobacterial disease | Intracranial calcifications | Yes | 6 | NA | 2012 (100) |
| USP18 | USP18 | 607057/ 617397 | AR - CP | Broadly expressed | Brain tissue Fibroblasts | Enhanced STAT1 and STAT2 phosphorylation and transcription of ISGs upon type I IFN stimulation | Thrombocytopenia | NA | PseudoTORCH syndrome | Yes | 5 | NA | 2016 (104) |
| IRF8 | IRF8 | 601565/ 614894 | AR - CP | Hematopoietic cells | PBMCs Dermal APCs | Impaired IL-12/IFN-γ response, tissue macrophages and DC deficiency. Impaired NK cytotoxic function and differentiation | Monocyte and DC deficiency. NK cell deficiency with decreased CD56dim NK cells | Severe opportunistic infections, mycobacterial infections, candidiasis. Severe EBV, viral and bacterial infections | Myeloprolifer ation, lymphadenopathy, bronchiectasis | No | 4 | HSCT | 2011 (105, 107) |
| IRF8 | IRF8 | 601565/ 614893 | AD - CP | Hematopoie tic cells | PBMCs EBV-B cells | Reduced IL-12 response | Deficiency of CD11c+CD1c+ DCs | Mendelian susceptibility to mycobacterial disease | NA | No | 2 | NA | 2011 (105) |
| IRF4 | IRF4 | 601900 | AD - IP | Bone marrow, lymphoid tissues and gastrointesti nal mucosa | EBV-B cells PBMCs | Impaired Th cell responses | NA | Whipple’s disease (Tropheryma whipplei infection) | NA | No | 4 | NA | 2018 (109) |
| gp130 | IL6ST | 600694 | AR - CP | Ubiquitous | PBMCs EBV-B cells T lymphoblasts | Suppressed STAT1 and STAT3 activation and signaling upon IL-6 or IL-11 stimulation, impaired upon IL-27 or OSM stimulation. Absent acute phase response after stimulation with IL6. | Increased naïve B cells, reduced nonswitched memory B cells, eosinophilia, high IgE | Recurrent severe bacterial respiratory infections with bronchiectasis, | Skeletal anomalies, craniosynosto sis, absent acute phase response | No | 1 | NA | 2017 (112) |
| Inborn errors of IL-17 immunity | |||||||||||||
| STAT1 | STAT1 | 600555/ 614162 | AD - *CP GOF *almost CP | Broadly expressed | PBMCs EBV-B cells Fibroblasts | Increased responses to type I and II IFNs, IL-6 and IL-21, | Low Th17 proportions +/− low memory B cells | Chronic mucocutaneous candidiasis, bacterial and viral infections, invasive fungal infections, mycobacterial disease | Intracranial aneurysms, autoimmunity, enteropathy, bronchiectasis | Yes | >350 | JAK inhibitor (ruxoliti nib) HSCT | 2011 (119, 196) |
| RORγ/γT | RORC | 602943/ 616622 | AR – CP | RORγ broadly expressed RORγT thymocytes and fetal lymphocytes | PBMCs | Almost absent Th17 cells. Impaired IFN-γ production by γδ T cells and CD4+CCR6+CXCR3+ αβ T cells. | Modest T lymphopenia low ILC3, absence of NKT and MAIT cells | Disseminated mycobacterial infections and CMC | NA | No | 7 | NA | 2015 (197) |
| DNA polymer ase α−1 (PDR) | POLA1 | 312040/ 301220 | XL – CP | Ubiquitous | Fibroblasts | Constitutive activation of type I IFN response and pro-inflammatory genes | NA | Recurrent pulmonary infections with bronchiectasis | Type I interferonopa thy with chronic diarrhea, failure to thrive, IBD, urethral strictures, diffuse reticulate skin hyperpigmentation, hypohidrosis, corneal scarring, characteristic facies | Yes | 21 | NA | 2016 (198) |
| Inborn errors of the TLR3 pathway | |||||||||||||
| IRF3 | IRF3 | 603734 | AD - IP | Broadly expressed – relevant for CNS cells | PBMCs Fibroblasts | Impaired IFN response to AT-rich DNA, dsDNA and HSV-1 infection | NA | Herpes simplex encephalitis | NA | No | 2 | NA | 2015 (144, 145) |
| Inborn errors of intracellular viral sensing | |||||||||||||
| DBR1 | DBR1 | 607024 | AR – CP | Ubiquitous, but strongest in the spinal cord and brainstem | Fibroblasts | Deficient lariat processing and impaired control of viral infections | Congenital neutropenia (not fully penetrant) | Viral brainstem encephalitis | Growth retardation, mental retardation, curly hair | No | 5 | NA | 2018 (146) |
| MDA5 | MDA5 (IFIH1) | 606951 | AR – CP AD – IP LOF | Broadly expressed | Respiratory epithelial cells Fibroblasts | Impaired MDA5 enzymatic and IFNinducing function with dominant negative effect. Impaired response to HRV and RSV infection. | NA | HRV and other respiratory viral infections | NA | No | 10 | NA | 2017 (150-152) |
| RNA polymerase III | POLR3A POLR3C | 614258 617454 | AD – IP Digenic or monogenic | Ubiquitous | PBMCs Monocytesmacrophages Fibroblasts Keratinocytes | Impaired IFN response to AT-rich DNA and VZV infection | NA | Acute severe VZV infection with lung and CNS involvement | NA | No | 4 | NA | 2017 (153) |
| SAMD9 | SAMD9 | 610456/617053 | AD - IP GOF | Broadly expressed | Bone marrow cells Adrenal cortex cells Fibroblasts | Structural and functional alterations of the endosome system, inhibition of cell proliferation | Variable mild lymphopenia | Severe invasive fungal and bacterial infections | MIRAGE syndrome: MDS, infection, growth failure, adrenal hypoplasia, genital anomalies, enteropathy. Developmental delay, thrombocytop enia and anemia | Yes | 19 | HSCT | 2016 (161) |
| SAMD9L | SAMD9L | 611170 | AD - IP GOF | Broadly expressed | EBV-B cells PBMCs Bone marrow cells | Inhibition of cell proliferation | Pancytopenia | Bacterial and viral infections | Ataxia/cerebe llar atrophy, pancytopenia, MDS | No | 25 | HSCT | 2016 (163) |
| Inborn errors of type I and III IFN amplification and responses | |||||||||||||
| IRF7 | IRF7 | 605047/ 616345 | AR – CP | Fibroblasts PBMCs pDCs PECs | Impaired responses to type I and III IFNs | NA | Influenza virus lifethreatening infection | NA | No | 1 | NA, influenz a vaccinat ion | 2015 (199) | |
| STAT2 | STAT2 | 600556/ 616636 | AR – IP | Broadly expressed | Fibroblasts PBMCs | Impaired type I IFN response to viral infections | NA | Severe viral infections (disseminated vaccine-strain measles) | Mitochondrial anomalies. Kawasaki-like syndrome, HLH-like syndrome. | Yes | 9 | NA, avoid MMR live vaccinat ion | 2013 (169) |
| IFNAR2 | IFNAR2 | 602376/ 616669 | AR – IP | Broadly expressed | Fibroblasts | Impaired type I IFN responses to viral infections | NA | Disseminated vaccine-strain measles and mumps | NA | No | 2 | NA, avoid MMR live vaccinat ion | 2015 (170) |
| IRF9 | IRF9 | 147574 | AR – CP | Broadly expressed | EBV-B cells SV40-fibroblasts | Impaired type I IFN response to viral infections | NA | Severe viral infections (Influenza virus life-threatening infection, complications after MMR vaccination, other respiratory viral infections) | NA | No | 1 | NA | 2018 (175) |
| IFNAR1 | IFNAR1 | 107450 | AR Digenic with IFNGR2 mutation | Broadly expressed | Fibroblasts | Impaired type I IFN responses to viral infections | NA | Disseminated CMV, Streptococcus viridans sepsis, mycobacterial disease | HLH | No | 1 | HSCT | 2017 (176) |
| Inborn errors of NK cells / with NK cells affected | |||||||||||||
| MCM4 | MCM4 | 602638/ 609981 | AR - CP | Ubiquitous | Fibroblasts EBV-B cells PBMCs | DNA replication defect | NK cell deficiency (reduction of CD56dim NK cells, reduced proliferation and excess spontaneous apoptosis of NK cells) | Recurrent viral infections, especially herpesviruses; viral pulmonary infections leading to respiratory failure | Adrenal insufficiency, severe intra- and extrauterine growth retardation, microcephaly, DNA repair disorder and susceptibility to cancer | No | 24 | Corticos teroid replace ment therapy | 2012 (185, 186, 200) |
| GINS1 | GINS1 | 610608 | AR – CP | Ubiquitous | PBMCs Fibroblasts | DNA replication defect | NK cell deficiency, neutropenia, autoimmune cytopenia, lymphopenia | Bacterial/viral respiratory and GI infections, herpesviruses infections | Intra- and extrauterine growth retardation, facial dysmorphism, eczema, hypothyroidis m, cancer, enteropathy, glaucoma | No | 5 | G-CSF | 2017 (187) |
| GATA2 | GATA2 | 137295/ 614172 | AD – CP | Hematopoietic progenitors, nonhematopoietic embryonic stem cells, lymphatic cells | PBMCs Bone marrow cells | Absent or severely deficient CD56bright NK cells. Functionally impaired CD56dim NK cells. | Deficiency of monocytes, DCs, NK cells and B lymphocytes | Susceptibility to viral infections, mycobacteria, HPV, histoplasmosis | Alveolar proteinosis, MDS/AML, lymphedema, hear loss, miscarriage | No | >400 | HSCT | 2011 (188–191) |
Legend: AML: acute myeloid leukemia; APC: antigen presenting cell; AR: autosomal recessive; AD: autosomal dominant; CBM: CARD-BCL1054 MALT1 complex; CMV: Cytomegalovirus; CNS: central nervous system; CP: complete penetrance; DC: dendritic cell; EBV-B: EBV-immortalized B cell; G-CSF: granulocyte colony-stimulating factor; GI: gastrointestinal; GM-CSF: granulocyte-macrophage colony-stimulating factor; GOF: gain of function; HLH: hemophagocytic lymphohistiocytosis; HPV: Human papillomavirus; HRV: Human rhinovirus; HSCT: hematopoietic stem cell transplantation; HVS-T: herpesvirus saimiri-immortalized T-cell; IBD: inflammatory bowel disease; IFN: interferon; Ig: immunoglobulin; IL: interleukin; ILC: innate lymphoid cell; IP: incomplete penetrance; ISG: IFN-stimulated gene; LOF: loss of function; LUBAC: Linear ubiquitination chain assembly complex; MAIT: mucosa-associated invariant T cells; MDS: myelodysplastic syndrome; MMR: measles-mumps-rubella; n: 60 number; NA: not applicable; OMIM: Online Mendelian Inheritance in Man; PBMC: peripheral blood mononuclear cell; pDC: plasmacytoid DC; PDR: reticulate pigmentary disorder; PEC: pulmonary epithelial cells ref: reference; RSV: Respiratory syncytial virus; SCN: severe congenital neutropenia; SGD: specific granule deficiency; SV40-fibroblast: simian virus 40-immortalized fibroblast; Th: T helper; TLR: Toll-like receptors; 63 TORCH: toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex; VZV: Varicella zoster virus; XL: X-linked.