Abstract: FR-PO811
Deciphering Complement Activation Mechanisms in Childhood IgA Nephropathy
Session Information
- Glomerular Diseases: Inflammation and Immunology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Sahu, Srishti, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
- Patey, Natalie, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
- Bonnefoy, Arnaud, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
- Troyanov, Stephan, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada
- Lapeyraque, Anne-Laure, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
- Alexandra, Cambier, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
Group or Team Name
- Cambier's Laboratory.
Background
The complement pathway plays a crucial role in the development of IgA nephropathy (IgAN), as evidenced by the association of complement C3 with IgA deposits. However, the specific mechanisms that trigger complement pathway activation remain poorly understood. Recent research has implicated soluble CD89 (sCD89) in kidney inflammation among childhood IgAN (cIgAN) patients. Thus, this study seeks to understand how sCD89 activates collectin 11—a crucial initiator of the lectin pathway—ultimately resulting in the formation of C5b-9 and subsequent kidney inflammation.
Methods
A prospective cohort of cIgAN patients was enrolled in the study (n=52). The levels of soluble C5b-9 (sC5b-9) and collectin-11 (C-11) were determined in both the urine and plasma of these patients using ELISA. These levels were correlated with biological, histological and clinical data. Kidney biopsies were assessed for inflammation and C5b-9 deposition. Next, we evaluated the expression and secretion of C-11 in human mesangial cells (HMCs) using RT-PCR and ELISA respectively. HMCs were stimulated with cIgAN plasma or recombinant sCD89 (rsCD89). Additionally, to detect the presence of C-11 within circulating immune complexes (CICs) we used sCD89 immunoprecipitation.
Results
Our research findings demonstrate several significant associations in cIgAN patients. sC5b-9 correlates with lower eGFR and increased proteinuria. Elevated levels of sC5b-9 were also linked to cellular inflammation, glomerulosclerosis and fibrotic crescents. Notably, we found that plasma sC5b-9 is linked to endocapillary deposition of C5b-9 in kidney glomeruli. Furthermore, C-11 levels are elevated in cIgAN patients compared to healthy controls. There exists a positive correlation between plasma C5b-9 and C-11 levels. Our in vitro results indicate that C-11 is expressed and secreted by the HMCs, with its upregulation upon stimulation by cIgAN plasma and rsCD89. Interestingly, we also observe the presence of C-11 within the CICs.
Conclusion
Our study indicates that both sC5b-9 and C-11 are associated with disease severity in cIgAN. They show promise as prognostic markers for cIgAN, potentially obviating the need for invasive kidney biopsy procedures. Additionally, the interplay between C-11 and sCD89 may provide insights into the underlying mechanisms of complement pathway activation in cIgAN.