Table 2.
Primary immunodeficiency disorders resulting in immune dysregulation primarily associated with regulatory T-cell dysfunction
| Mutated gene (protein)/locus | Inheritance | Immunodeficiency/infectious manifestations | Autoimmune/lymphoproliferative manifestations | References |
|---|---|---|---|---|
| BACH2 (BACH2)/6q15 | AD | Variable hypogammaglobulinemia (but also hypergammaglobulinemia), reduced memory and class-switched memory B cells | IBD, lymphadenopathy, interstitial lung disease, autoantibodies | 71 |
| CTLA-4 (CTLA-4)/2q33.2 | AD | Hypogammaglobulinemia (84%), herpes infection (30%), bacterial infections (30%), fungal infection (18%) | Gastrointestinal involvement (59%), cytopenia (59%), endocrinopathy (33%), arthritis (14%), renal (12%) and liver involvement (12%) | 56 |
| DEF6 (DEF6/IBP/SLAT)/6p21.31 | AR | Variable hypogammaglobulinemia, low class-switched memory B cells, recurrent bacterial infections, herpes infection | IBD, AIHA, detection of autoantibodies, such as ANCA, ANA and anti-cardiolipin | 65 |
| DOCK8 (DOCK8)/9p24.3 | AR | Elevated IgE, hypogammaglobulinemia in some patients, failure of long-lived antibody responses to vaccines, T-cell lymphopenia, decreased numbers of naïve T cells, sinopulmonary infections, bronchiectasis, viral infections (CMV, EBV, HSV, HPV), PML, abscesses, fungal infections, including mucocutaneous candidiasis | Autoimmune cytopenia, vasculitis, SLE, hypothyroidism, arthritis, IBD, IPEX-like disease | 87,88 |
| IL2RA (CD25)/10p15.1 | AR | Upper and lower respiratory tract infections, persistent EBV and CMV infections | IPEX-like disease (enteropathy, eczema, endocrinopathy, autoimmune cytopenias, lymphadenopathy, organomegaly) | 67,68 |
| IRF4 (IRF4)/6p25.3 | AR | Agammaglobulinemia, thrush, bronchopneumonia | Autoimmune polyendocrinopathy | 93 |
| LRBA (LRBA)/4q31.3 | AR | Recurrent upper and/or lower respiratory tract infections/hypogammaglobulinemia with reduced class-switched memory B cells in the majority of patients | Autoimmune cytopenia, ILD, autoimmune hepatitis, alopecia, enteropathy, lymphadenopathy, organomegaly | 60 |
| PIK3CD (p110δa)/1p36.22 | ARb | Hypogammaglobulinemia (all reported patients), upper and/or lower respiratory infections (all reported patients) | IBD (50%), arthritis, ITP, psoriasis, autoimmune hepatitis | 94 |
| STAT3 (STAT3)/17q21.2 | ADc | Hypogammaglobulinemia, low class-switched memory B cells and low naïve CD4+ T cells, bronchopulmonary infections (>40%), bronchiectasis (~10%), Candida infections | Lymphoproliferation (>60%), autoimmune cytopenia (>60%), IBD (~50%), ILD (~40%) | 82 |
| STAT5b (STAT5b)/17q21.2 | AR |
Variable degree of immunodeficiency, including recurrent respiratory tract and cutaneous infections Mild lymphopenia (reduced T cells, B cells and/or NK cells) reduced T-cell proliferation to mitogens and antigens |
IPEX-like disease (enteropathy, eczema, endocrinopathy), alopecia, interstitial pneumonitis | 76 |
AD autosomal dominant, AIHA autoimmune hemolytic anemia, ANA antinuclear antibodies, ANCA anti-neutrophil cytoplasmic antibodies, AR autosomal recessive, BCG bacillus Calmette-Guérin, CMV cytomegalovirus, EBV Epstein–Barr virus, HSV herpes simplex virus, HPV human papillomavirus, IBD inflammatory bowel disease, ILD interstitial lung disease, IPEX immunodysregulation, polyendocrinopathy, enteropathy, and X-linked, ITP immune thrombocytopenic purpura, PML progressive multifocal leukoencephalopathy, SLE systemic lupus erythematosus, VZV varicella zoster virus
aPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit
bLoss-of-function PIK3CD variants
cGain-of-function STAT3 variants