What Causes Selective IgA Deficiency (SIgAD)
Selective IgA deficiency results from inherited genetic defects affecting B lymphocyte differentiation and maturation, though the precise molecular mechanisms remain incompletely defined in most cases. 1
Primary Genetic and Immunologic Mechanisms
The pathogenesis of SIgAD involves multiple interconnected defects:
- Defective B cell terminal differentiation is the central mechanism, specifically impairing the switch to IgA-producing plasma cells 2, 3
- Genetic factors include both MHC (major histocompatibility complex) and non-MHC gene abnormalities, though specific causative genes remain largely unidentified 3
- Familial clustering occurs in 20-25% of cases, with family members having either SIgAD or Common Variable Immunodeficiency (CVID), suggesting shared genetic susceptibility 1
- Chromosomal and monogenic mutations have been associated with some cases, though these represent a minority 2
Immunologic Dysregulation
Beyond genetic factors, several immunologic abnormalities contribute:
- T lymphocyte subset abnormalities and perturbations in T helper cell function affect cytokine signaling necessary for IgA class switching 2, 3
- Cytokine and chemokine pathway defects disrupt the signals required for B cell differentiation into IgA-secreting cells 3
- Switched memory B cell deficiency has been documented, correlating with more severe clinical phenotypes including pneumonia and bronchiectasis 1
- Apoptosis dysregulation and microbiota alterations may contribute to the pathogenic process 3
Secondary/Acquired Causes
A thorough medication history is essential, as SIgAD can be drug-induced and potentially reversible: 1, 4
- Antiepileptic drugs: phenytoin, carbamazepine, valproic acid, zonisamide
- Disease-modifying agents: sulfasalazine, gold, penicillamine, hydroxychloroquine
- NSAIDs (nonsteroidal anti-inflammatory drugs)
Cessation of the offending medication may reverse the IgA deficiency in many cases. 1
Ethnic and Demographic Factors
- Prevalence varies dramatically by ethnicity: 1 in 300-700 among white Americans versus approximately 1 in 18,000 in Asian populations 1
- Male predominance may exist, though data are limited 1
- Age-related presentation: By definition, diagnosis requires age >4 years, as IgA levels may be physiologically low in younger children 1
Important Clinical Caveats
- Most patients (estimated >50%) remain asymptomatic despite the immunologic defect 1
- Evolution to CVID occurs in some patients over time, necessitating long-term monitoring 1
- Polyclonal B cell stimulation from repeated environmental exposures may contribute to the high frequency of autoantibodies (found in up to 40% of patients) even in asymptomatic individuals 5
- The defect is multifactorial: Multiple pathways controlling B cell function, epigenetic regulation of the IGHA gene, and long-term survival of IgA-switched memory B cells may be simultaneously impaired in different patients 3
The heterogeneous nature of SIgAD pathogenesis explains why no single genetic or immunologic defect has been identified as universally causative, and why clinical phenotypes range from completely asymptomatic to severe complications including recurrent infections, autoimmunity, and malignancy. 2, 6