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Publication Detail
Interaction of GPR183 with its ligand 7a25-dihydroxycholesterol drives pathogenic extrafollicular B cell responses in systemic lupus erythematosus
  • Publication Type:
    Conference presentation
  • Authors:
    De Gruijter N, Jebson B, Peckham H, Radziszewska A, Ciurtin C, Rosser E
  • Date:
    08/09/2022
  • Name of Conference:
    EMBO workshop of Germinal Centre and Immune Niches
  • Conference place:
    The David Lopatie Conference Centre Weizmann Institute of Science, Rehovot, Israel
  • Conference start date:
    05/09/2022
  • Conference finish date:
    08/09/2022
Abstract
Emerging evidence suggests that inappropriate extrafollicular B cell activation plays a critical role in the generation of autoantibody-producing B cells in systemic lupus erythematosus (SLE). However, the exact mechanisms driving abnormal extrafollicular B cell responses in SLE are unclear. Previous studies have demonstrated that GPR183 – an oxysterol receptor whose main ligand is 7a25-dihydroxycholesterol – is critical in regulating the positioning of B cells into extrafollicular sites and the early initiation of plasmablast responses in mice. The contribution of this pathway to lupus pathogenesis remains unknown. Here, we demonstrate that patients with juvenile-onset SLE (JSLE), who have a more severe disease than adultonset SLE patients, have a reduction in GPR183-expressing memory B cells in peripheral blood compared to age-matched healthy individuals. In-depth analysis of GPR183-expressing B cells also demonstrated reduced expression of CXCR5, another critical lymph nodepositioning receptor, and upregulated expression of genes associated with plasma cell differentiation, in JSLE compared to healthy controls. Using the parent into F1 model of experimental lupus, we show that, prior to the development of nephritis, there is an increase in the expression of cyp7b1 – a key rate limiting enzyme in the production of GPR183’s ligand 7a25-dihydroxycholesterol – in splenic stromal cells and that suppression of GPR183-driven responses with the small molecule antagonist NIBR189 reduces both the severity of nephritis and plasmablast differentiation. Mimicking the strong female-bias in human lupus, the efficacy of GPR183-antagonism in suppressing lupus pathogenesis was only observed in female mice and could not be recapitulated using male animals. These data identify GPR183-7a25dihydroxycholesterol interactions as a potentially therapeutically relevant pathway contributing to heightened extrafollicular B cell differentiation in SLE.
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Inflammation
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