B cell targeting in IgA nephropathy

The "multi-hit theory/4-hit theory" pathogenesis hypothesis is widely accepted and IgA nephropathy (IgAN) is understood to be a disease originating from Hit 1, galactose deficient IgA1 (GdIgA1). The chronic repetitive activation of the complement pathway (alternative and lectin pathways) and the subsequent inflammation results in progressive glomerular damage that spills over into increased intraglomerular pressure and other hemodynamic changes, increased urinary protein, glomerulosclerosis, and tubulointerstitial fibrosis. The basic pathophysiology of this disease is the progression of a mixture of such acute and chronic pathologies. Currently, a number of new drugs has emerged as promising agents, such as complement regulators, endothelin receptor antagonists, and SGLT2 inhibitors, which are associated with each pathological step after glomerular deposition of GdIgA1/immune complexes. On the other hand, the molecular mechanisms of GdIgA1 production are gradually being elucidated, and the development of several novel therapeutic agents targeting the responsible B cells and their international clinical trials are progressing. These agents that inhibit or control the production of the Hit1, GdIgA1, are highly expected as essential therapies for this disease. The large body of clinical and basic research findings to date strongly suggest that nephritogenic GdIgA1 is a polymeric IgA1 of mucosal origin. In addition, the B cells involved in its nephritogenic GdIgA1 production are mainly differentiated mature B cells such as plasma cells, which may migrate to the bone marrow as well as the mucosa. The innate immune system in the mucosa, especially Toll-like receptors (TLRs), is thought to be involved in their production. Among TLRs, TLT9 and TLR7, which recognize bacterial and viral unmethylated DNA and RNA, have been reported to be involved. The mucosal activation of these TLRs is associated with the production of APRIL (A Proliferation Inducing Ligand) and BAFF (B cell activating factor), which are TNF superfamily cytokines involved in B cell maturation, survival, and IgA class switching, and may also be involved in the production of nephritogenic GdIgA1. It is still inconclusive whether APRIL or BAFF is more closely involved in the production of nephritogenic GdIgA1. Phenotypes in transgenic animal models suggest BAFF involvement, however, a genome wide association study (GWAS) analysis of human IgAN has identified APRIL, not BAFF, as a candidate gene. Based on the above background, several international clinical trials are underway for drugs such as TLR regulators (hydroxychloroquine), anti-APRIL drugs, anti-BAFF drugs, APRIL/BAFF receptor (TACI) binding inhibitors, and cytoreductive drugs (proteasome inhibitors, anti-CD38 antibodies) to inhibit nephritogenic GdIgA1 production in responsible B cells. This session will provide an overview of the responsible B cells, their GdIgA1 production mechanism, and ongoing drugs.