A serum C3-activating factor: its characterization and its presence in glomerular deposits

Area of Science:

• Complement system immunology
• Nephrology
• Molecular immunology

Background:

• Membranoproliferative glomerulonephritis (MPGN) is a kidney disease characterized by immune deposits.
• The alternative complement pathway (ACP) plays a role in C3 activation and kidney inflammation.
• A non-immunoglobulin C3 activating factor (C3AF) was previously observed in MPGN patients.

Purpose of the Study:

• To elucidate the molecular structure and functional characteristics of C3AF.
• To determine the presence and significance of C3AF in renal biopsies of MPGN patients.
• To investigate the mechanism by which C3AF activates the alternative complement pathway.

Main Methods:

• Isolation and biochemical characterization of C3AF from patient serum and plasma.
• Functional assays to assess C3 activation by C3AF compared to zymosan and IgG C3 nephritic factor (C3NeF).
• Electrophoretic analysis (including beta 1H globulin mobility) and polyacrylamide gel electrophoresis.
• Immunofluorescence studies on renal biopsies from MPGN patients.

Main Results:

• C3AF activates the alternative complement pathway (ACP), with activity comparable to zymosan but less than C3NeF.
• The active C3AF isolate contains beta 1H globulin with altered electrophoretic mobility and a gamma-migrating C3AF protein.
• Immunofluorescence revealed C3AF antigen in 10 of 16 MPGN renal biopsies, co-localizing with C3 and beta 1H, but independent of immunoglobulins.
• C3AF is a high molecular weight protein (500,000-590,000) composed of two subunits, antigenically distinct from fibronectin.

Conclusions:

• C3AF activates ACP likely by interfering with beta 1H globulin function.
• The presence of C3AF in renal biopsies suggests a pathogenic role in MPGN.
• Further research into C3AF may offer new therapeutic targets for MPGN.