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PO.4.91 Bank1 and IL-10+ B cells: bringing some light to the relationship between microbiota composition and autoimmunity development in a murine model of lupus
  1. M Botía-Sánchez1,
  2. G Galicia1,
  3. D Toro-Domínguez1,
  4. L Albaladejo-Maricó1 and
  5. ME Alarcón-Riquelme2
  1. 1GENYO. Centre for Genomics and Oncological Research Pfizer-University of Granada- Andalusian Regional Government ~ Granada ~ Spain
  2. 2Unit of Chronic Inflammatory Diseases, Institute of Environmental Medicine, Karolinska Institutet ~ Granada ~ Spain

Abstract

Background A new feature that seems to be decisive in autoimmune pathogenesis is the gut microbiota composition. However, its exact role remains to be determined. In systemic lupus erythematosus (SLE), an autoimmune disease characterized by persistent inflammation affecting multiple organs, the contribution of the gut microbiota is particularly elusive. The B cell scaffold with ankyrin repeats (Bank1) gene, which plays a role in TLR7 signalling, has been genetically associated with lupus in humans, and associated with a reduction in disease severity in mice. In the recent years, IL-10 producing B cells (so-called regulatory B cells) are being characterised for their immunosuppressive role in autoimmune inflammation and possible relationship with microbiota composition.

Purpose We aimed to determine the influence of the gut microbiota composition, driven by Bank1, in IL-10+ B cell induction as well as the possible role of these cells in disease severity.

Methods We have characterised the manifestations of lupus in the gut associated lymphoid tissue using an imiquimod-induced murine model of lupus (TLR7-dependent). To analyse IL-10 producing B cells, immune cells isolated from Peyer’s patches of C57Bl/6 WT mice and Bank1 -/- were stimulated with PMA/Ionomycin/Monensin and analysed by flow cytometry. To study microbiota influence in IL-10 production by B cells, we used single cage mice and littermates and sequenced the V4 region of 16S RNA gene.

Abstract PO.4.91 Figure 1

Representative intestinal tracts from WT and Bank1 KO (B1KO) mice at 20 weeks of age with (IMQ) and without (CTRL) lupus induction. It can be appreciated how the inflammation in WT mice after the treatment induces an increase in the caecal size and the Peyer’s patches dimension (normally not visible without microscopic magnification, pointed with arrows in the WT IMQ image). In B1KO mice, however, the caecum remains unaltered and the inflammation at Peyer’s patches levels is significantly lower than that achived by WT mice. Representation of three different experiments with 3–5 mice per group each experiment

Results and Conclusion The imiquimod-induced murine model of lupus leads to persistent gut inflammation with changes in microbiota composition in WT and Bank1 -/- mice. In these mice, the intestinal inflammation and local immune alterations resulted in increased gut permeability and caused intestinal blockade (image 1). This affectation is similar to that observed in human SLE patients. Mice deficient for Bank1 gene experienced a milder disease and exhibited a microbiota composition that was significantly different compared with their WT counterparts (principal components analysis). More specifically, the appearance of specific species belonging to the genus Porphyromonadaceae upon the induction of an inflammatory process only in Bank1 knock-out mice were related with reduced disease severity. To determine the contribution of gut microbiota to lupus inflammation, we induced the disease in littermate mice that inherited the Bank1 KO microbiota. We observed a normalized immune response that seems to be more alike to that observed in Bank1 KO mice grown separately from their WT counterparts. We then analysed the IL-10-producing cells in the gut and found that IL-10+ B cells readily increased in Peyer’s patches upon lupus inflammation in Bank1 deficient mice, but not in WT mice. When lupus was induced in littermates, the levels of IL-10+ B cells were normalized across WT and Bank1 KO mice, suggesting a possible role of microbiota in regulatory B cell induction. Further studies are, however, needed to determine whether Bank1 is required for IL-10 producing B cell activation or if its contribution is mediated by changes in the gut microbiota composition.

http://creativecommons.org/licenses/by-nc/4.0/

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