Table 1.
Clinical and immunological characteristics of genetic defects associated with development of mucosal and systemic fungal disease
| Gene (chromosome) | Clinical syndrome | Mode of inheritance | Mucosal versus systemic fungal disease | Fungal pathogens | Nonfungal infection susceptibility | Noninfectious manifestations | Immunological defects accounting for fungal susceptibility |
|---|---|---|---|---|---|---|---|
| A. Disorders of phagocyte oxidative machinery | |||||||
| CYBB (Xp) CYBA (16q) NCF-1 (7q) NCF-2 (1q) NCF-4 (22q) |
CGD | X linked AR AR AR AR |
Systemic | Aspergillosis (including A. nidulans) Other molds (Paecilomyces, Neosartorya) Systemic candidiasis |
Staphylococcus Serratia Nocardia Burkholderia |
Inflammatory bowel disease | Lack of superoxide generation |
| MPO (17q) | MPO deficiency | AR | Systemic | Systemic candidiasis | None | None | Lack of hypochlorous acid production |
| B. Disorders of cytokine signaling | |||||||
| IFNGR1 (6q) | MSMD | AD | Systemic | Coccidioidomycosis Histoplasmosis | NTM Salmonella | None | Impaired IFN-γ cellular responses |
| IL12RB1 (19p) | MSMD | AD or AR | Both | Coccidioidomycosis Paracoccidioidomycosis Histoplasmosis Cryptococcosis CMC |
NTM Salmonella |
None | Impaired IL-12/ IL-23-dependent IFN-γ production Impaired IL-12Rβ1-dependent Th17 differentiation |
| IL-17RA (22q) | AR | Mucosal | CMC |
Staphylococcus URIs |
Atopic dermatitis | Lack of IL-17 cellular responses | |
| IL-17F (6p) | AD | Mucosal | CMC |
Staphylococcus URIs |
Asthma | Impaired IL-17F receptor binding and bioactivity | |
| ACT1 (6q) | AR | Mucosal | CMC | Staphylococcus | Atopic dermatitis | Impaired ACT1 interactions with IL-17 receptors Impaired IL-17 cellular responses |
|
| IL2RG (Xq) | SCID | X linked | Both | PCP CMC |
URIs Bacteria Viruses |
Failure to thrive Diarrhea Graft versus host disease |
Severe lymphocytopenia |
| IL7RA (5p) CD45 (11q) ADA (20q) AK2 (1p) RAG1 (11p) RAG2 (11p) JAK3 (19p) ARTEMIS (10p) |
SCID | AR | Both | PCP CMC |
URIs Bacteria Viruses |
Failure to thrive Diarrhea Graft versus host disease |
Severe lymphocytopenia |
| C. Disorders of transcription factors | |||||||
| STAT3 (17q) | HIES (Job’s syndrome) |
AD | Both | CMC Nail dermatophytosis Aspergillosis Scedosporiosis PCP Cryptococcosis Histoplasmosis Coccidioidomycosis |
Bacteria (skin, lungs) | Eczema Pneumatoceles Characteristic facial features Scoliosis Coronary artery aneurysms Tooth development abnormalities Bone fractures |
Impaired Th17 differentiation Decreased proportion of IL-17/IL-22+-producing T cells Decreased IL-17 production by mononuclear cells Impaired production of antimicrobial peptides by keratinocytes Impaired candidacidal activity of saliva Decreased levels of IL-17-induced candidacidal antimicrobial peptides in saliva |
| STAT1 (2q) | AD | Both | Coccidioidomycosis Histoplasmosis Fusariosis (skin) CMC |
CMV Bacteria |
Inflammatory bowel disease Hypothyroidism Squamous cell carcinoma |
Decreased IL-17 production by mononuclear cells Enhanced cellular responses to IFN-α/β, IFN-γ, and IL-27, which inhibit Th17 differentiation Defective IL-12R/IL-23R signaling |
|
| GATA2 (3q) | MonoMAC syndrome | AD | Systemic | Aspergillosis Histoplasmosis Cryptococcosis |
NTM Warts |
MDS/AML Lymphedema PAP |
Monocytopenia Decreased circulating and tissue-resident dendritic cells Neutrophil abnormalities |
| AIRE (21q) | APECED | AR | Mucosal | CMC | None | Autoimmune endocrinopathies Autoimmune hepatitis Malabsorption Dental enamel abnormalities Oral/esophageal carcinoma Vitiligo |
Neutralizing autoantibodies to IL-17A, IL-17F, and IL-22 Decreased production of IL-17/IL-22 and other proinflammatory cytokines by mononuclear cells Impaired candidacidal activity of saliva Decreased levels of candidacidal antimicrobial peptides in saliva |
| IRF8 (16q) | AR | Mucosal | CMC | NTM | None | Monocytopenia Decreased circulating and tissue-resident dendritic cells Decreased IL-17 production by mononuclear cells Impaired antigen presentation |
|
| D. Disorders of other signaling molecules | |||||||
| CARD9 (9q) | AR | Both |
Candida meningitis Invasive dermatophytosis Subcutaneous phaeohyphomycosis CMC Nail dermatophytosis |
None | None | Impaired IL-17 and proinflammatory cytokine cellular responses Decreased proportion of IL-17/IL-22+-producing T cells Impaired neutrophil Candida killing |
|
| DECTIN-1 (12p) | AR | Mucosal | Vaginal candidiasis Nail dermatophytosis |
None | None | Decreased IL-17 production by mononuclear cells | |
| DOCK8 (9p) | HIES | AR | Mucosal | CMC Nail dermatophytosis |
Viruses (skin) | Eczema Vasculitis Hematological malignancy Squamous cell carcinoma |
Decreased IL-17 production by mononuclear cells Impaired Th17 differentiation |
| TYK2 (19p) | HIES MSMD |
AR | Mucosal | CMC | Bacteria NTM Viruses |
Atopic dermatitis | Unknown |
| NEMO/IKBKG (Xq) | EDA-ID HIGM |
X-linked | Both | PCP CMC |
NTM Bacteria Viruses |
Anhidrotic ectodermal dysplasia | Severe lymphocytopenia |
| IKBA (14q) | EDA-ID HIGM |
AD | Both | PCP CMC |
NTM Bacteria |
Anhidrotic ectodermal dysplasia Colitis |
Severe lymphocytopenia Decreased proportion of IL-17+-producing T cells |
| CD40L (Xq) | HIGM | X-linked | Systemic | PCP | NTM Bacteria Cryptosporidia |
Inflammatory bowel disease | Impaired T-cell responses |
| STK4 (20q) | AR | Mucosal | CMC | Bacteria HSV Viruses (skin) |
EBV-driven lymphoproliferation Structural heart abnormalities |
Impaired T-cell survival and proliferation | |
AD, autosomal dominant; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome; AR, autosomal recessive; CGD, chronic granulomatous disease; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; EBV, Epstein–Barr virus; EDA-ID, anhidrotic ectodermal dysplasia with immune deficiency; HIES, hyper-IgE syndrome; HIGM, hyper-IgM syndrome; HSV, herpes simplex virus; MDS/AML, myelodysplastic syndrome/acute myelogenous leukemia; MPO, myeloperoxidase; MSMD, Mendelian susceptibility to mycobacterial disease; NTM, nontuberculous mycobacteria; PAP, pulmonary alveolar proteinosis; PCP, Pneumocystis pneumonia; SCID, severe combined immunodeficiency; URIs, upper respiratory infections.