Interrupted Immunological Cascades in Selective IgA Deficiency
Primary B Cell Differentiation Defect
The fundamental cascade interrupted in SIgAD is the terminal differentiation of B lymphocytes into IgA-producing plasma cells, representing a failure in the class-switch recombination pathway specifically to IgA. 1, 2
B Cell Maturation Arrest
Switched memory B cell formation is profoundly disrupted, with significantly decreased proportions of both T-cell-dependent (CD27+) and T-cell-independent (CD27-) IgA memory B cells in all SIgAD patients 3, 4
The defect occurs at the terminal differentiation stage, not at earlier B cell activation steps, as in vitro B-cell activation after stimulation remains normal 4
Patients demonstrate decreased marginal zone-like B cells and switched memory B cells, with this reduction being more prominent in severe phenotypes 5
There is a compensatory increase in naïve and transitional B cells, reflecting the accumulation of B cells that cannot complete IgA class switching 5
CD21low B cells are significantly elevated, particularly in severe SIgAD, suggesting ongoing immune dysregulation 5
Intact vs. Impaired Antibody Responses
Specific antibody responses to pneumococcal polysaccharides are impaired in many SIgAD patients, though this doesn't always correlate with infection history 3
The ability to form other antibody classes (IgG, IgM, IgE) and various auto-antibodies remains intact, including the capacity to produce anti-IgA antibodies 2
Secondary T Cell Dysfunction
CD4+ T Helper Cell Abnormalities
Th1 and Th17 cell populations are significantly decreased in adult SIgAD patients, representing a critical defect in cell-mediated immunity that normally supports IgA responses 4
Regulatory T cells (Tregs) are significantly reduced, contributing to the high prevalence of autoimmune manifestations 5
Naïve and central memory CD4+ T cells are decreased, while terminally differentiated effector memory T cells (TEMRA) are elevated 5
CD4+ T cell proliferation is strongly impaired in patients with severe phenotypes, indicating functional defects beyond just numerical changes 5
CD8+ T Cell Alterations
Central and effector memory CD8+ T cell subsets are significantly reduced, while CD8+ TEMRA cells are paradoxically elevated 5
Despite these changes, overall T-cell populations and basic function remain normal in most SIgAD patients 3
Cytokine Dysregulation Cascade
TGF-β1, BAFF, and APRIL levels are significantly elevated in adult SIgAD patients, suggesting disturbed regulation of IgA responses in vivo 4
This cytokine imbalance likely reflects B-cell extrinsic immune defects rather than intrinsic B cell dysfunction 4
The elevated BAFF and APRIL may represent a compensatory mechanism attempting to drive IgA production that ultimately fails due to the terminal differentiation block 4
Clinical Cascade Consequences
Mucosal Immunity Breakdown
Loss of secretory IgA at mucosal surfaces removes the first line of defense against respiratory and gastrointestinal pathogens 1, 6
This predisposes to recurrent sinopulmonary infections, particularly when combined with impaired pneumococcal antibody responses 3
Immune Dysregulation Cascade
Failure of oral tolerance mechanisms due to absent mucosal IgA contributes to the significantly increased prevalence of autoimmune diseases including SLE, thyroid disease, type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis 6
Allergic inflammation occurs frequently, as IgE-mediated responses remain intact while regulatory IgA is absent 7, 8
Important Caveats
The defect is NOT in early B cell development or general antibody production—IgG and IgM responses can be normal or even elevated 3, 1
Some patients may progress to CVID, suggesting SIgAD can represent an evolving immunodeficiency with additional cascades becoming interrupted over time 3
Drug-induced cases exist where the cascade interruption is reversible upon cessation of medications like antiepileptics, sulfasalazine, or NSAIDs 3, 8