Table 2.
Key human inborn errors of immunity that predispose to fungal infection
| Gene [protein name] (chromosome arm) | Predominant cellular expression | OMIM no. (clinical syndrome) | Mode of inheritance | Fungal infection susceptibility | Other clinical phenotypes | Antifungal immunological defects |
|---|---|---|---|---|---|---|
| CARD9 (9q) | Myeloid phagocytes and to a lesser extent epithelial cells | 212050 | AR (LOF) | CMC, CNS candidiasis, phaeohyphomycosis, aspergillosis, skin mucormycosis, onychomycosis, deep dermatophytosis | None | Decreased number of blood TH17 cells, impaired cytokine responses by PBMCs and microglia, impaired neutrophil recruitment to the CNS and killing of unopsonized Candida yeasts |
| STAT1 (2q) | Broadly expressed | 614162 | AD (GOF) | Invasive candidiasis, CMC, aspergillosis, mucormycosis, PJP, cryptococcosis, histoplasmosis, coccidioidomycosis | Bacterial, NTM and viral infections, autoimmunity, aneurysms, carcinomas | Decreased number of blood TH17 cells and decreased IL-17 production by PBMCs associated with increased cellular responses to IFNα/β, IFNγ and IL-27 |
| STAT3 (17q) | Broadly expressed | 147060 (AD HIES, Job syndrome) | AD (DN) | CMC, dermatophytosis, aspergillosis, cryptococcosis, histoplasmosis, gastrointestinal tract coccidioidomycosis, skin fusariosis, PJP | Skin staphylococcal infections, bacterial pneumonias, eczema, pneumatoceles, aneurysms, skeletal abnormalities, increased IgE | Decreased number of blood TH17 cells |
| IL12RB1 (19p) | Lymphoid and myeloid cells | 614891 (MSMD) | AR (LOF) | CMC, cryptococcosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis | Salmonella and NTM infections | Impaired TH17 cell differentiation, impaired IL-12-dependent and IL-23-dependent IFNγ production |
| IL17RA (22q) | Myeloid cells and epithelial cells | 613953 | AR (LOF) | CMC | Skin staphylococcal infections, bacterial pneumonias, eczema | Abolished IL-17 cellular responses |
| IL17RC (3p) | Epithelial cells | 616445 | None | |||
| AIRE (21q) | mTECs and eTACs | 240300 (APECED) | AR (LOF) or AD (DN) | CMC | Multiorgan autoimmunity, ectodermal dystrophy, severe COVID-19 | Neutralizing serum autoantibodies to IL-17A, IL-17F and IL-22, epithelial barrier disruption caused by IFNγ produced by mucosal T cells |
| CYBB [gp91phox] (Xp) | Myeloid phagocytes | 306400 (X-linked CGD) | X-linked (LOF) | Aspergillosis, invasive candidiasis | Invasive infections with Nocardia, Staphylococcus, Serratia and Burkholderia, IBD | Impaired generation of superoxide |
| NCF2 [p67phox] (1q) | 233710 (AR CGD) | AR (LOF) | ||||
| CYBA [p22phox] (16q) | 233690 (AR CGD) | |||||
| NCF1 [p47phox] (7q) | 233700 (AR CGD) | |||||
| IFNGR1 (6q) | Broadly expressed | 209950 (AR MSMD) | AR (LOF) | Histoplasmosis, coccidioidomycosis | Salmonella and NTM infections | Impaired IFNγ cellular responses |
| 615978 (AD MSMD) | AD (DN) | |||||
| GATA2 (3q) | Neutrophils, and to a lesser extent mononuclear phagocytes and T cells | 614172 (MonoMAC syndrome, Emberger syndrome) | AD (HI) | Aspergillosis, cryptococcosis, histoplasmosis, coccidioidomycosis, blastomycosis, PJP | Viral and NTM infections, PAP, MDS, leukaemia, lymphedema | Decreased monocyte and DC counts, neutrophil granule abnormalities |
An expanded version of Table 2 is presented in Supplementary Table 2. AD, autosomal dominant; APECED, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; AR, autosomal recessive; CGD, chronic granulomatous disease; CMC, chronic mucocutaneous candidiasis; CNS, central nervous system; DC, dendritic cell; DN, dominant negative; eTAC, extrathymic AIRE-expressing cell; GOF, gain of function; HI, haploinsufficiency; HIES, hyper-IgE syndrome; IBD, inflammatory bowel disease; IFN, interferon; LOF, loss of function; MDS, myelodysplastic syndrome; MSMD, Mendelian susceptibility to mycobacterial disease; mTEC, medullary thymic epithelial cell; NTM, non-tuberculous mycobacteria; OMIM, Online Mendelian Inheritance in Man; PAP, pulmonary alveolar proteinosis; PBMC, peripheral blood mononuclear cell; PJP, Pneumocystis jirovecii pneumonia; TH17, T helper 17.