Figure 3.

Proposed pathways the immunoproteasome involved in the pathogenesis of IgAN. (1) Mucosal infection primes naive B cells to class switch to become IgA⁺ plasmablasts (PB) and antibody-secreting cells (ASC) through T-cell-dependent (TCD) and T-cell-independent (TCI) processes. Antigen presentation by immunoproteasome promotes immune response, T cell differentiation and cytokines production. (2) A proportion of antigen-committed IgA PB and ASC with altered homing receptors and therefore they mistakenly “home” to the bone marrow. Immunoproteasome-related cytokines can contribute to the environmental niche in bone marrow. (3) These translocated cells take up residence in the bone marrow, where they secrete IgA into the systemic circulation. Factors such as genetic background and immunoproteasome-related cytokines can alter IgA1 O-glycosylation and lead to Gd-IgA1 production. (4) Plasma cells secrete IgG and IgA autoantibodies directed against the Gd-IgA1 hinge region O-glycans. In the phase of intense secretion of antibodies, immunoproteasome can balance the unfavorable proteasomal load/capacity ratio and decrease plasma cells apoptosis. (5) Formation of immune complexes from autoantigen (Gd-IgA1) and O-glycan-specific antibodies. (6) Deposition of pathogenic immune complexes in the mesangium, activation of mesangial cells, and induction of glomerular injury. PB: plasmablasts; ASC: antibody-secreting cells; TCD: T-cell-dependent; TCI: T-cell-independent; Gd-IgA1: galactose-deficient IgA1; Anti-Gd-IgA1-autoAb: Anti-Gd-IgA1-autoantibody.