What is the etiology of IgA (Immunoglobulin A) nephropathy?

Etiology of IgA Nephropathy

IgA nephropathy is an autoimmune disease caused by the formation and glomerular deposition of immune complexes containing galactose-deficient IgA1 (gd-IgA1) and corresponding IgG or IgA autoantibodies. 1, 2

Pathogenic Mechanism: The Multi-Hit Hypothesis

The etiology follows a sequential four-hit process that explains disease development from immune dysregulation to kidney injury 3, 4, 2:

Hit 1: Production of Aberrant IgA1

• Patients produce elevated levels of IgA1 with undergalactosylated O-glycans in the hinge region (galactose-deficient IgA1), which represents the primary immunochemical abnormality 4, 2
• This aberrant glycosylation alone does not cause disease but serves as the autoantigen 4
• The precise origin of gd-IgA1 production involves genetic, epigenetic, and immunological factors that remain incompletely understood 3

Hit 2: Autoantibody Formation

• Glycan-specific IgG and IgA autoantibodies develop that recognize the undergalactosylated IgA1 as foreign 4, 2
• These autoantibodies often have cross-reactivity with antigens from mucosal microorganisms and may arise from recurrent mucosal infections, particularly tonsillitis 4
• B cells responding to mucosal infections are implicated in producing the nephritogenic IgA1 4

Hit 3: Immune Complex Formation and Deposition

• Circulating IgA1-IgG immune complexes form and deposit in the glomerular mesangium via an unidentified receptor 4, 2
• Decreased hepatic clearance of these complexes contributes to their accumulation and subsequent glomerular deposition 4
• Glomerular immunodeposits in IgAN are enriched for both gd-IgA1 and the corresponding IgG autoantibodies 2

Hit 4: Glomerular Injury

• Deposited immune complexes activate mesangial cells, triggering local production of cytokines, growth factors, and complement activation 4
• This leads to mesangial proliferation, inflammation, and subsequent podocyte and tubulointerstitial injury through mesangio-podocytic-tubular crosstalk 4

Contributing Factors

Genetic Predisposition

• Important genetic factors promote overproduction of aberrant IgA1, though specific genes remain under investigation 4, 5

Environmental Triggers

• Recurrent mucosal infections, especially upper respiratory tract infections and tonsillitis, may trigger autoantibody production and disease flares 4
• Environmental factors interact with genetic susceptibility to drive disease development 5

Immune System Abnormalities

• Both innate and adaptive immune mechanisms are dysregulated, involving abnormal B-cell and T-cell responses 5
• Mucosal immune system dysfunction contributes to aberrant IgA1 production 5

Diagnostic Confirmation

The definitive diagnostic feature is mesangial dominant or co-dominant IgA deposits on kidney biopsy 6, with electron microscopy revealing electron-dense deposits in the mesangium, typically with C3 co-deposition and less commonly C1q 6

Clinical Implications

Circulatory levels of gd-IgA1 and IgG autoantibodies predict disease progression, supporting their pathogenic role 2. The kidneys are damaged as innocent bystanders in this systemic autoimmune process where immune complexes deposit in glomeruli 2.