Clinical Relevance of Anti-C3 and Anti-C4 Autoantibodies in Lupus Nephritis

IntroductionComplement system overactivation is pivotal in LN pathophysiology. As anti-C3 autoantibodies play a significant role in LN pathophysiology, we explored them as disease activity biomarkers and compared them to the ones against the homologous protein C4.MethodsWe investigated the presence of anti-C3 and anti-C4 IgG autoantibodies in a LN cohort (n=85 patients) and monitored their changes over time. We correlated autoantibody presence with clinical parameters. We conducted cross-sectional and longitudinal analyses (n=295 samples, 8 years follow-up) to explore associations between autoantibodies and disease progression. Antigen-specific anti-C3 or anti-C4 IgG were purified from plasma by affinity chromatography and their reactivity was tested for cross-reactivity against purified C3 or C4 by ELISA.ResultsThe reactivity against C3 was independent of C4. Our study revealed distinct roles for anti-C3 and anti-C4 in LN. Anti-C3 IgG exhibited stronger clinical correlations than anti-C4, showing associations with hypocomplementemia, anti-dsDNA, class IV LN, and active disease according to BILAG Renal score. In a longitudinal analysis, anti-C3 positivity at initial sampling predicted present and future disease exacerbation alone and even better when combined with anti-dsDNA, as indicated by a transition to BILAG category A.ConclusionsOur research provides insights into anti-C3/C3b and anti-C4 auto-antibodies in LN, revealing that they are often not cross-reactive. Anti-C3 utility as disease activity biomarkers is underscored by its stronger clinical associations and predictive value for future flares. Combining anti-C3 and anti-dsDNA out-performs the two factors alone, suggesting that the incorporation of anti-C3/C3b quantification into routine clinical practice could improve LN management.