Pathophysiology of Selective IgA Deficiency
Selective IgA deficiency results from a defect in the terminal differentiation of B lymphocytes, preventing their maturation into IgA-producing plasma cells, though the precise molecular mechanisms remain incompletely understood in most cases. 1, 2
Primary Immunologic Defect
The fundamental pathophysiologic abnormality involves:
- Arrested B-cell maturation: B lymphocytes fail to complete their differentiation pathway into IgA-secreting plasma cells, despite normal development of other immunoglobulin-producing cells 1, 2
- Defective immunoglobulin class switching: The molecular machinery required for switching to IgA production is impaired, while switching to IgG and IgM remains intact 2, 3
- Isolated deficiency pattern: IgA levels fall below 7 mg/dL (0.07 g/L) while IgG and IgM levels remain normal, distinguishing this from more severe combined immunodeficiencies 4, 5
Genetic and Familial Factors
The genetic basis demonstrates:
- Familial clustering: 20-25% of cases show family members with either selective IgA deficiency or Common Variable Immunodeficiency (CVID), indicating shared genetic susceptibility 1
- Cytogenic abnormalities: Specific chromosomal defects and monogenic mutations have been associated with the condition, though most cases lack identified single-gene defects 2
- Ethnic variation: Dramatic differences in prevalence by ethnicity (1:300-700 in white Americans versus 1:18,000 in Asian populations) suggest population-specific genetic factors 1
Secondary and Acquired Mechanisms
Important non-genetic causes include:
- Drug-induced deficiency: Medications including antiepileptic drugs, disease-modifying antirheumatic agents, and NSAIDs can induce reversible IgA deficiency 1, 6
- Potential reversibility: Cessation of offending medications may restore IgA production in drug-induced cases 1
Compensatory Mechanisms and Clinical Implications
The pathophysiology explains variable clinical presentations:
- Immunologic compensation: Most individuals (>50%) remain asymptomatic despite absent IgA, suggesting other immune mechanisms provide adequate mucosal protection 1, 3
- Additional defects in symptomatic patients: Those with clinical manifestations often have concurrent abnormalities including IgG subclass deficiencies (found in 4% of one cohort) or impaired specific antibody responses 6, 3
- Evolution to more severe phenotypes: Some patients progress from selective IgA deficiency to CVID over time, indicating the underlying B-cell defect may worsen 1, 6
Age-Related Considerations
- Physiologic immaturity: IgA levels are naturally low in young children, requiring age >4 years for definitive diagnosis to distinguish pathologic deficiency from normal developmental delay 1
- Progressive manifestations: Clinical complications increase with age, as the cumulative effects of absent mucosal IgA become more apparent 6
Associated Immunologic Abnormalities
Beyond the primary IgA defect: