Abstract: TH-PO0321
Multilayered Affinity Proteomics Reveal the Protein Interaction Network of IgAN
Session Information
- Glomerular Diseases: Omics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Nilges, Lars, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Hutzfeldt, Arvid D., Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Demir, Fatih, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Hengel, Felicitas E., Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Dehde, Silke, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Wulfmeyer, Vera Christine, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Kovalenko, Elina, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Billing, Anja M., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Wiech, Thorsten, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Hoxha, Elion, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Sung, Chih-Chien, National Defense Medical Center, Taipei City, Taiwan
- Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Lassé, Moritz, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Tomas, Nicola M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Rinschen, Markus M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
Background
IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and a leading cause of chronic kidney disease. Although circulating IgA-containing immune complexes are central to disease pathogenesis, how these complexes home to the glomerular mesangium and trigger injury is unresolved. Here, we present an integrated, multi-compartment proteomic atlas of active IgAN (Oxford M1E1), systematically linking circulating IgA to glomerular injury mechanisms.
Methods
We performed multi-layered functional mass spectrometry proteomic profiling of 18 patients meeting the histological criterion of M1E1 by the Oxford classification, indicative of active disease. For this analysis, we integrated the proteomes of four different IgAN patient sample types. The biopsy glomerular proteome using laser capture microdissection, the serum proteome, the affinity purified IgA proteome, and the affinity purified IgA proteome, in which the source serum was incubated in an allogenic human glomerular lysate matrix.
Results
We identify convergent activation of complement pathways, predominantly the alternative and lectin pathways, and a strong association of IgA with acute phase proteins and mesangial matrix components. Complement factor H–related protein 1 (CFHR1) and the acute phase protein Orosomucoid 1 (ORM1) emerged as central hubs connecting circulating IgA to mesangial and complement networks. Functional studies revealed that ORM1 inhibits lectin pathway activation, providing mechanistic insight into pathway imbalance in IgAN.
Conclusion
This study directly links circulating IgA to mesangial proteins and complement activation. Integrated proteomics and functional assays reveal CFHR1 and ORM1 as critical connectors between IgA, complement dysregulation, and mesangial injury. The strong convergence on alternative pathway and discovery of endogenous inhibitors of lectin and classical complement pathways provides mechanistic context for current and emerging complement-targeted treatments in IgAN. The multi-layered proteomic atlas offers a high-resolution reference to explore mechanisms behind genetic associations, and guide future therapeutic development.
Funding
- Government Support – Non-U.S.