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Detecting FH–anti-FH immune complexes in MGRS-C3G
Abstract   Open access   Peer reviewed

Detecting FH–anti-FH immune complexes in MGRS-C3G

Sydney S. Jellison, Sarah M. Roberts, Samantha J. Martin, Stephanie N. Cook, Carla M. Nester, Andrea Reparaz, Santiago Rodriguez de Cordoba, Richard J.H. Smith and Yuzhou Zhang
Immunobiology (1979), Vol.230(4), 153044
07/2025
DOI: 10.1016/j.imbio.2025.153044
url
https://doi.org/10.1016/j.imbio.2025.153044View
Published (Version of record) Open Access

Abstract

C3 glomerulopathy (C3G) is a complement-mediated kidney disease driven by dysregulated alternative pathway (AP) activation. In some patients (typically >50 years), a diagnosis of monoclonal gammopathy of renal significance (MGRS) reflects the presence of small B-cell or plasma cell clones producing nephrotoxic monoclonal immunoglobulins. How these proteins contribute to disease (MGRS-C3G) remains a key knowledge gap. We hypothesize that Factor H autoantibodies (FHAAs), particularly when forming immune complexes (FHICs), contribute significantly to disease. We also believe traditional ELISA-based assays have limited sensitivity in detecting circulating FHICs, especially IgM-type FHAAs. We evaluated a lateral flow assay (LFA) (1) consisting of three cassettes to detect both IgG- and IgM-type FHICs in serum from 58 C3G patients. Patients were categorized by FHAA ELISA results: Group A, FHAA >1000 Arbitrary Units (AU); n = 10 (C3G = 8; MGRS-C3G = 2, including one IgM-only case); Group B, ambiguous/equivocal levels (200–1000 AU); n = 14 (C3G = 10; MGRS-C3G = 4); Group C, MGRS-C3G lacking known acquired or genetic drivers but showing fluid-phase complement hyperactivity; FHAA <200 AU; n = 33. Group A: LFA confirmed FHIC positivity in all 10 patients, including the IgM-only case. Six others were IgM co-positive, showing enhanced LFA sensitivity over ELISA. Group B: LFA detected FHICs in 11 of 14 patients (79%), clarifying ambiguous ELISA results. All four MGRS patients were strongly positive for IgG-type FHICs. No IgM-type positives were seen. Group C: Despite negative ELISAs, LFA detected FHICs in 12 of 33 patients (36%), including four weakly IgM-FHAA co-positive. Overall, FHICs were found in 33 of 58 patients, including 18 of 39 MGRS-C3G cases. In 18 of 39 MGRS patients (46%), FHAAs were detected as the monoclonal protein driving complement dysregulation. Conventional ELISAs identified only 6, likely due to FHIC formation masking detection. These findings underscore both the pathogenic role of FHAAs in MGRS-C3G and the diagnostic value of LFA. Large-scale prospective studies are warranted to confirm and extend these observations. Supported in part by National Institutes of HealthR01 DK110023. (1) Rodrıguez de Cordoba S et al. Front. Immunol. 15:1527016. https://doi.org/10.3389/fimmu.2024.1527016.

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