Immunoglobulin A Deficiency

Basics

Description

Selective IgA deficiency is the most common primary antibody deficiency; diagnosed by:

  • Increased susceptibility to infection
  • Autoimmune manifestations
  • Serum IgA <7 mg/dL and a normal serum IgG and IgM in patients >4 years of age
  • Exclusion of secondary causes of hypogammaglobulinemia
  • Exclusion of T-cell defect

Risk Factors

Genetics

  • Exact pattern of inheritance remains unclear; however, the following associations may occur:
    • Mutations in genes affecting cellular and humoral immunity (e.g., JAK3, RAG1)
    • Combined immunodeficiencies with syndromic features (e.g., ataxia telangiectasia, Wiskott-Aldrich syndrome)
    • Antibody deficiencies (e.g., BTK)
    • Phagocytic defects (e.g., RAC2)
    • Immune dysregulation (e.g., IFIH1, X-linked inhibitor of apoptosis [XIAP])
    • Defects in intrinsic and innate immunity
    • Complement deficiencies (e.g., C3)
  • IgA deficiency is associated with
    • Trisomy 21
    • 22q11.2 deletion syndrome
    • 18q syndrome
    • Monosomy 22
    • Monosomy 4p
    • Trisomy 8
    • Trisomy 10p
  • Partial deletions in the long or short arm and ring forms of chromosome 18 and 17p11.2 deletions
  • The presence of HLA-A1, HLA-A2, B8, DR3, DQ2 (8.1), and Dw3
  • Also associated with non–MHC-associated genes involved in autoimmunity including IFIH1 on chromosome 2q24, CLEC16A on chromosome 16

Pathophysiology

  • Unknown, however presumed to be a failure of B lymphocyte differentiation into plasma cells producing IgA
  • Defect may be due to
    • Abnormal T-cell regulation (T-helper cells such as Tregs)
    • Antigen-presenting cells
    • Intrinsic B-cell defects
    • Impairment in cytokine networks including IL-21, IL-4, IL-6, IL-7, or IL-10

Commonly Associated Conditions

Increased association with the following:

  • Atopy
  • Recurrent sinopulmonary infections
  • Gastrointestinal (GI) infections (especially Giardia lamblia)
  • GI disease:
    • Celiac disease most common, incidence 2–3% of patients with IgA deficiency
    • Inflammatory bowel disease (Crohn disease and ulcerative colitis)
  • Nodular lymphoid hyperplasia
  • Malignancy, particularly adenocarcinoma of stomach and lymphoma usually of B-cell origin
  • Autoimmune illnesses
    • Systemic lupus erythematosus
    • Immune endocrinopathies (e.g., Graves disease, type 1 diabetes)
    • Autoimmune hematologic conditions
    • Chronic active hepatitis

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