Background/Purpose: Mucosa-associated commensal bacteria have been shown to be involved in the pathogenesis of systemic lupus erythematosus (SLE). However, its exact role remains to be determined. The BANK1 gene is a susceptibility gene for SLE implicated in TLR7 signaling in B cells. In lupus prone B6.Sle1.yaa mice the absence of Bank1 resulted in diminished disease severity concomitant with reduced anti-dsDNA IgG antibody production. B cells play a critical role in the microbiota-immune system crosstalk. Thus, the purpose of this work was to determine the role of the Bank1 gene in the gut B-cell response and its influence on gut microbiota composition in steady-state and during disease.

Methods: Two TLR7-mediated models of lupus were used: the spontaneous TLR7Tg lupus prone-mice and the model induced with treatment with a TLR7 agonist Imiquimod, both in C57Bl/6 Bank1-sufficient and Bank1-deficient mice. Animals were either raised in separate cages by genotype (single cage) or both genotypes together (littermates). B cell populations resident in the gut associated lymphoid tissue (GALT) were characterized by flow cytometry, and immunoglobulin determination in serum and fecal matter were quantified by ELISA. Microbiome composition was determined by sequencing the V4 region of 16sRNA. Gut permeability was measured with FITC-Dextran.

Results: In the imiquimod model, Bank1 KO mice showed in steady-state, reduced frequency of CD19⁺B220⁺ and IgA⁺B220^– B cell populations in the gut with lower levels of fecal free IgA. These differences between Bank1 KO and WT mice in B cell populations were not observed after lupus development. Conversely, IL-10-producing B cells in the gut readily increased in Peyer’s patches upon gut inflammation in Bank KO mice, but not in WT mice, correlating with lower splenomegaly. The absence of Bank1 also diminished disease severity in the TLR7tg lupus-prone mice with a concomitant reduction in serum pathogenic IgG antibodies and lower gut permeability. When analyzing microbiota composition, single cage Bank1 KO mice had the baseline and composition of their gut microbiome altered as compared with control mice. The appearance of specific species belonging to the genera Parabacteroides and Bacteroides upon the induction of lupus only in Bank1 KO mice was related with reduced disease severity. To determine the contribution of gut microbiota to lupus inflammation, the imiquimod-induced model in littermate mice that inherited the Bank1 KO microbiota was used. The results were similar to those observed in Bank1 KO mice grown separately from their WT counterparts. 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.

Conclusion: These results indicate a link between Bank1 and microbiome composition in the gut. Interestingly, specific species of microbiota were identified as associated with less severe lupus inflammation only in Bank1 deficient mice. The specific mechanisms behind changes in the migration of B cells to the GALT and microbiota composition remains to be determined, but this is the first link between Bank1 and environmental factors in the lupus context.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bank1-signaling-shapes-the-gut-microbiota-composition-by-controlling-the-gut-mucosal-b-cell-response-in-lupus/