Project Details
Description
IgA nephropathy (IgAN) is an autoimmune disease with an incompletely understood aetiology. The pathogenesis of IgAN is conceptualised by the multi-hit model. Observations studies from IgAN patients show increased production of aberrantly glycosylated galactose-deficient IgA1 (GdIgA1, hit 1), the generation of antibodies against it (hit 2), immune complex formation (hit 3), and the mechanisms of immune-complex-mediated kidney injury (hit 4). As the source of the pathogenic antibodies B cells are central, yet are absent from the multi-hit model. Recently, we identified and characterised a GdIgA1+ B cell population that is increased in the peripheral blood of IgAN patients; these B cells are the putative precursors of GdIgA1-antibody-secreting cells (ASCs). We aim to provide mechanistic insight into the pathogenesis of IgAN by unravelling the molecular determinants and developmental niches for the differentiation of these GdIgA+ B cells. We combine flow cytometry, single cell transcriptional profiling and confocal microscopy of mucosa-associated lymphoid tissue (MALT), specifically the Peyer\'s patches (PPs), to uncover the determinants of altered B cell activation in IgAN. To mechanistically interrogate the factors that lead to GdIgA1+ B cell and ASC differentiation we will use cultures of sorted B cells and in vitro PP modelling. Together this will address a major gap in knowledge with regards to the B cell source and differentiation pathways in the pathogenesis of IgAN.
Short title | FLPP-0487 |
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Status | Not started |
Effective start/end date | 1/01/25 → 31/12/27 |
Collaborative partners
- Rīga Stradiņš University (lead)
- Paula Stradina Clinical University Hospital
Total Funding
- Latvian Council of Science: €300,000.00
Keywords
- IgA nephropathy
- B cells
- autoimmunity
- mucosa associated lymphoid tissue
Field of Science
- 3.1 Basic medicine
- 3.2 Clinical medicine
Smart Specialization Area
- Biomedicine, medical technologies and biotechnology
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