Table 2 Primary immunodeficiency disorders resulting in immune dysregulation primarily associated with regulatory T-cell dysfunction

From: Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunity

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 naĂŻve 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 naĂŻve 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

  1. 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
  2. aPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit
  3. bLoss-of-function PIK3CD variants
  4. cGain-of-function STAT3 variants
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