B cell targeting in IgA nephropathy

Area of Science:

• Nephrology
• Immunology
• Pathophysiology

Background:

• IgA nephropathy (IgAN) is linked to the "multi-hit theory," originating with galactose-deficient IgA1 (GdIgA1).
• Chronic complement pathway activation (alternative and lectin) drives glomerular damage, leading to proteinuria and fibrosis.
• GdIgA1 production mechanisms and targeted therapies are under active investigation.

Purpose of the Study:

• To review the role of responsible B cells in GdIgA1 production.
• To elucidate the molecular mechanisms underlying GdIgA1 synthesis.
• To provide an overview of ongoing therapeutic strategies targeting GdIgA1 production.

Main Methods:

• Review of clinical and basic research findings on IgAN pathogenesis.
• Analysis of molecular mechanisms involving Toll-like receptors (TLRs), APRIL, and BAFF.
• Summary of ongoing international clinical trials for novel IgAN therapies.

Main Results:

• Nephritogenic GdIgA1 is likely polymeric IgA1 of mucosal origin, produced by differentiated B cells.
• Mucosal innate immunity, including TLRs (TLT9, TLR7), and cytokines APRIL/BAFF, are implicated in GdIgA1 production.
• Clinical trials are evaluating TLR regulators, anti-APRIL/BAFF agents, and cytoreductive drugs.

Conclusions:

• Understanding GdIgA1 production by B cells is crucial for IgAN treatment.
• Targeting GdIgA1 production represents a promising therapeutic avenue for IgAN.
• Ongoing research and clinical trials are advancing IgAN management.