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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, Radziszewska A, Peckham H, Ciurtin C, Rosser E
  • Date:
  • Name of Conference:
    B cell UK 2022, British Society for Immunology
  • Conference place:
    Holiday Inn Bloomsbury, London, UK
  • Conference start date:
  • Conference finish date:
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 725-dihydroxycholesterol – is critical in regulating the movement of B cells into extrafollicular sites and the early initiation of plasmablast responses in mice. Here, we demonstrate that patients with juvenile-onset SLE (JSLE), who have a more severe disease than adult-onset SLE patients, have a reduction in GPR183-expressing memory B cells in peripheral blood compared to matched healthy individuals. This reduction is associated with an expansion in antibody-producing plasmablasts. Using a mouse model of experimental lupus, we show that, prior to the development of nephritis, there is an increase in the expression of cholesterol 25-hydroxylase (ch25h) – a key rate limiting enzyme in the production of GPR183’s ligand 725-dihydroxycholesterol – in splenic stromal cells and gpr183 expression in splenic B cells. Blocking GPR183 with the small molecule antagonist NIBR189 suppresses extrafollicular B cell differentiation by driving B cells into the germinal centre, which, in turn, suppresses the severity of lupus-like disease. These data identify GPR183-725-dihydroxycholesterol interactions as a therapeutically relevant pathway that contributes to aberrant extrafollicular B cell differentiation in SLE.
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