Complement activation drives a compartmentalized innate immune response in C3 glomerulopathy contributing to the disease phenotype.

Abstract

C3 glomerulopathy is a rare kidney disease resulting from dysregulation of the complement alternative pathway. The mechanistic diversity of alternative pathway activation, the heterogeneous immunological and clinical profiles limit a comprehensive understanding of the disease. Here, we characterize mechanisms of complement-mediated immune response within the kidney. We studied a retrospective cohort of 47 patients diagnosed with C3 glomerulopathy and profiled systemic and intra-kidney complement activation and characterized intra-kidney immune infiltrates. The immune infiltrate of the kidney showed distinct compositions between the glomerular and interstitial compartments, with most neutrophils and macrophages in the glomeruli versus a majority of B and T lymphocytes and macrophages in the interstitium. The presence of a neutrophil-rich glomerular infiltrate appeared to be associated with stronger markers of complement activation in both systemic and intra-kidney compartments. However, interstitial immune infiltrates were not associated with a specific complement activation profile. The presence of a neutrophil-rich glomerular infiltrate correlated with a better response of the kidney to treatment and kidney survival, while patients with higher interstitial infiltrate had poor kidney survival. Our study highlights a link between the intra-kidney immune response, complement activation profile, and the phenotypic expression of the disease, which contributes to improving our understanding of the disease.