Factor H autoantibodies in membranoproliferative glomerulonephritis

Area of Science:

• Immunology
• Nephrology
• Complement System Biology

Background:

• Factor H autoantibodies are identified in approximately 10% of atypical hemolytic uremic syndrome (aHUS) patients, often linked to factor H-related proteins 1/3 deficiency and binding to the C-terminal domain.
• Membranoproliferative glomerulonephritis (MPGN) shares complement activation pathways with aHUS, prompting investigation into a potential association with Factor H autoantibodies.

Purpose of the Study:

• To investigate the hypothesis that Factor H autoantibodies are associated with MPGN.
• To characterize the binding site and functional significance of Factor H autoantibodies in MPGN patients.

Main Methods:

• Enzyme-linked immunosorbent assay (ELISA) was used to screen sera from 16 MPGN patients and 100 controls for IgG Factor H autoantibodies.
• Multiplex ligation-dependent probe amplification (MLPA) was employed to measure complement factor H-related protein (CFHR) 1/3 copy number.
• Functional assays using purified patient IgG were conducted to assess the impact on complement-mediated hemolysis.

Main Results:

• Two MPGN patients (one with type II DDD MPGN and C3NeF, another with type I MPGN without C3NeF) tested positive for high-titer IgG Factor H autoantibodies.
• The autoantibodies predominantly bound to the N-terminal complement regulatory domain of Factor H.
• Both patients had a normal complement factor H-related protein (CFHR) 1/3 copy number (2 copies each).
• Purified patient IgG demonstrated increased hemolysis in normal human sera, indicating functional significance.

Conclusions:

• This study identified functionally significant Factor H autoantibodies in two MPGN patients.
• These findings suggest that screening for Factor H autoantibodies should be considered in all MPGN patients.
• Antibody-depleting therapy may represent a potential treatment strategy for MPGN patients with these autoantibodies.