POS-017 A POPULATION PERSPECTIVE OF NEPHRITIC FACTORS AS SYSTEMIC DRIVERS OF COMPLEMENT DYSREGULATION IN C3 GLOMERULOPATHY

Abstract

IntroductionC3 Glomerulopathy (C3G) is an ultra-rare renal disease mediated by dysregulation of the alternative pathway (AP) of the complement system. Rare and novel genetic variation in complement genes and autoantibodies to complement proteins are commonly identified in the C3G population and thought to drive complement dysregulation. Most commonly identified are C3 and C5 nephritic factors that bind to and stabilize the AP C3 and C5 convertases, respectively. The rare and heterogeneous nature of C3G makes understanding how these genetic and immunologic factors may influence disease progression difficult. We hypothesize that C3 and C5 nephritic factors drive systemic complement dysregulation in vivo and play a role in driving C3G disease progression.MethodsThe Molecular Otolaryngology and Renal Research laboratories (MORL) C3G cohort (n=554) was retrospectively evaluated to understand the relationship between in vivo complement biomarkers, genetic drivers of disease, and complement autoantibodies. Autoantibodies were detected using hemolytic and ELISA-based assays. Biomarkers were detected using radial immunodiffusion and ELISA-based methods. Rare genetic variation was screened for in 8 disease-associated genes (CFH, CFI, CD46, CFB, CFHR5, C3, THBD, DGKE).ResultsSubjects in the C3G cohort who were positive for an immunologic driver of disease were at a significantly higher risk of expressing a biomarker profile indicative of complement dysregulation (p < 5.8e-09). The magnitude of C3 and C5 nephritic factor stabilization capacity directly correlated with the magnitude of in vivo complement dysregulation. Conversely, patients negative for all immunologic drivers of were more likely to have a normal biomarker profile.ConclusionsOur data support C3 and C5 nephritic factors as robust drivers of systemic complement dysregulation and the C3G phenotype. Further characterization is needed to understand how nephritic factors change over time and they may ultimately influence disease outcome. This study highlights the continued need for discovery-based research to identify novel drivers of disease. Approximately 40% of the MORL C3G cohort lacks an identified driver of disease, and this subset of patients most frequently carries a profile of normal to mildly dysregulated complement biomarkers. These data suggest the presence of unknown, potentially local (rather than systemic) drivers of disease affecting complement dysregulation in the glomerulus.No conflict of interest IntroductionC3 Glomerulopathy (C3G) is an ultra-rare renal disease mediated by dysregulation of the alternative pathway (AP) of the complement system. Rare and novel genetic variation in complement genes and autoantibodies to complement proteins are commonly identified in the C3G population and thought to drive complement dysregulation. Most commonly identified are C3 and C5 nephritic factors that bind to and stabilize the AP C3 and C5 convertases, respectively. The rare and heterogeneous nature of C3G makes understanding how these genetic and immunologic factors may influence disease progression difficult. We hypothesize that C3 and C5 nephritic factors drive systemic complement dysregulation in vivo and play a role in driving C3G disease progression. C3 Glomerulopathy (C3G) is an ultra-rare renal disease mediated by dysregulation of the alternative pathway (AP) of the complement system. Rare and novel genetic variation in complement genes and autoantibodies to complement proteins are commonly identified in the C3G population and thought to drive complement dysregulation. Most commonly identified are C3 and C5 nephritic factors that bind to and stabilize the AP C3 and C5 convertases, respectively. The rare and heterogeneous nature of C3G makes understanding how these genetic and immunologic factors may influence disease progression difficult. We hypothesize that C3 and C5 nephritic factors drive systemic complement dysregulation in vivo and play a role in driving C3G disease progression. MethodsThe Molecular Otolaryngology and Renal Research laboratories (MORL) C3G cohort (n=554) was retrospectively evaluated to understand the relationship between in vivo complement biomarkers, genetic drivers of disease, and complement autoantibodies. Autoantibodies were detected using hemolytic and ELISA-based assays. Biomarkers were detected using radial immunodiffusion and ELISA-based methods. Rare genetic variation was screened for in 8 disease-associated genes (CFH, CFI, CD46, CFB, CFHR5, C3, THBD, DGKE). The Molecular Otolaryngology and Renal Research laboratories (MORL) C3G cohort (n=554) was retrospectively evaluated to understand the relationship between in vivo complement biomarkers, genetic drivers of disease, and complement autoantibodies. Autoantibodies were detected using hemolytic and ELISA-based assays. Biomarkers were detected using radial immunodiffusion and ELISA-based methods. Rare genetic variation was screened for in 8 disease-associated genes (CFH, CFI, CD46, CFB, CFHR5, C3, THBD, DGKE). ResultsSubjects in the C3G cohort who were positive for an immunologic driver of disease were at a significantly higher risk of expressing a biomarker profile indicative of complement dysregulation (p < 5.8e-09). The magnitude of C3 and C5 nephritic factor stabilization capacity directly correlated with the magnitude of in vivo complement dysregulation. Conversely, patients negative for all immunologic drivers of were more likely to have a normal biomarker profile. Subjects in the C3G cohort who were positive for an immunologic driver of disease were at a significantly higher risk of expressing a biomarker profile indicative of complement dysregulation (p < 5.8e-09). The magnitude of C3 and C5 nephritic factor stabilization capacity directly correlated with the magnitude of in vivo complement dysregulation. Conversely, patients negative for all immunologic drivers of were more likely to have a normal biomarker profile. ConclusionsOur data support C3 and C5 nephritic factors as robust drivers of systemic complement dysregulation and the C3G phenotype. Further characterization is needed to understand how nephritic factors change over time and they may ultimately influence disease outcome. This study highlights the continued need for discovery-based research to identify novel drivers of disease. Approximately 40% of the MORL C3G cohort lacks an identified driver of disease, and this subset of patients most frequently carries a profile of normal to mildly dysregulated complement biomarkers. These data suggest the presence of unknown, potentially local (rather than systemic) drivers of disease affecting complement dysregulation in the glomerulus.No conflict of interest Our data support C3 and C5 nephritic factors as robust drivers of systemic complement dysregulation and the C3G phenotype. Further characterization is needed to understand how nephritic factors change over time and they may ultimately influence disease outcome. This study highlights the continued need for discovery-based research to identify novel drivers of disease. Approximately 40% of the MORL C3G cohort lacks an identified driver of disease, and this subset of patients most frequently carries a profile of normal to mildly dysregulated complement biomarkers. These data suggest the presence of unknown, potentially local (rather than systemic) drivers of disease affecting complement dysregulation in the glomerulus.