Four-Hit Hypothesis

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The Four Hit-Hypothesis for IgAN describes how IgAN develops from an immune process to inflammation. 

Hit 1 - The body produces galactose-deficient IgA1 (Gd-IgA1), mainly in the mucosal immune tissues. This production is usually triggered by genetic, immune, and environmental factors.  

Hit 2- Anti-Gd-IgA1 autoantibodies are formed. The immune system produces these autoantibodies against the abnormal IgA1, leading to the formation of circulating immune complexes.

Hit 3- Circulating Gd-IgA1 Immune Complexes are formed. The immune complexes eventually deposit in the kidneys.

Hit 4 -The deposition of Gd-IgA1 Immune Complexes in the mesangium triggers mesangial cell proliferation, expansion of the extracellular matrix, and complement activation, leading to glomerular inflammation and renal injury.