The classical pathway triggers pathogenic complement activation in membranous nephropathy

Area of Science:

• Nephrology
• Immunology
• Autoimmune Diseases

Background:

• Membranous nephropathy (MN) is an antibody-mediated autoimmune kidney disease.
• The initiation pathways and pathogenic role of complement activation in MN are not well understood.

Purpose of the Study:

• To investigate the complement pathways involved in MN pathogenesis.
• To assess the therapeutic potential of targeting complement in MN.

Main Methods:

• Analysis of renal biopsies from MN patients for complement components.
• Proximity ligation assays to visualize complement assembly.
• Utilizing an antigen-specific autoimmune mouse model of MN.
• Complement component C3 silencing using RNA interference.

Main Results:

• All three complement pathways (alternative, classical, lectin) are present in MN renal biopsies.
• Classical pathway activation is dominant, correlating with C1q-binding IgG subclasses.
• Complement-deficient mice exhibit reduced glomerular damage and proteinuria.
• C3 silencing significantly attenuates disease progression in a mouse model.

Conclusions:

• Complement is primarily activated via the classical pathway in MN.
• Targeting complement component C3 presents a potential therapeutic strategy for MN.