Understanding the pathogenesis of IgA nephropathy reveals therapeutic targets. Understanding the pathogenesis of IgA nephropathy reveals therapeutic targets. (A) Mucosal IgA production by plasma cells occurs by T cell–dependent and –independent processes. T cell cytokines such as APRIL promote B cell class switch to IgA1-producing plasma cells. Inhibitors of these cytokines are potential therapeutic targets. B cell and plasma cell inhibitors (e.g., rituximab, bortezomib) may result in decreased IgA production. (B) The IgA1 produced in patients with IgA nephropathy is underglycosylated (Gd-IgA1). Susceptible individuals will also produce anti–Gd-IgA1 autoantibodies (auto-Ab), reviewed in (9). Antiproliferative drugs may affect production of anti-glycan autoantibodies. The Gd-IgA1–auto-Ab immune complexes activate the alternative pathway of complement. Complement inhibitors may prevent formation of immune complexes. (C) The immune complexes are nephritogenic, contributing to local inflammation, cellular proliferation, and ultimately fibrosis. Broad-based targeting of processes implicated in glomerular and tubulo-interstitial injury (e.g., inflammation, fibrosis) target these final common pathways of kidney damage. Anti-Gd-IgA1-auto Ab, autoantibody directed at galactose-deficient IgA1. Jennifer C. Rodrigues et al. CJASN 2017;12:677-686 ©2017 by American Society of Nephrology