Purpose The purpose of this work was to determine the role of the Bank1 gene in the gut B cell response and its influence in gut microbiota composition during lupus inflammation. The BANK1 gene is a susceptibility gene for SLE and in lupus-prone B6.Sle1.yaa mice the absence of Bank1 resulted in diminished disease severity concomitant with reduced total IgG, anti-dsDNA IgG antibody production and type I interferon signaling. Furthermore, BANK1 was demonstrated to be implicated in the TLR signaling in B cells as BANK1 binds MyD88 and TRAF6 through its TIR domain and TRAF6-binding motifs, respectively. We thus hypothesized that the gut B cell response in steady state and in lupus inflammation may be altered in Bank1 deficient mice. Consequently, the altered microbiome composition may impact lupus pathogenesis.
Methods In this work we used two TLR7-mediated models of lupus: the spontaneous TLR7Tg lupus prone-mice and the induced-model with TLR7 agonist (imiquimod), both in C57Bl/6 Bank1-sufficient and Bank1-deficient mice. Mice were either raised in separate cages by genotype (single cage) or both genotypes together in the same cage (littermates). The B cell populations in the gut 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 TLR7tg lupus-prone mice, the absence of Bank1 diminishes disease severity with a concomitant reduction in serum pathogenic IgG antibodies. Bank1 KO mice have reduced frequency of CD19+B220+ and IgA+B220- B cell populations in the gut. Fecal free IgA was also reduced, and these differences in B cell populations were not observed after the development of lupus, however lupus inflammation increased gut permeability in the TLR7.Tg mice, but reduced in TLR7Tg.Bank1 KO mice. Additionally, single cage Bank1 KO mice had altered the baseline composition of their gut microbiome compared with control mice. These changes were more pronounced after lupus development. Particularly, we found significantly increased abundance of Parabacteroides distasonis in the fecal microbiome of Bank1 KO mice. Moreover, in littermate animals, which had homogeneous microbiome composition, the disease severity was equal in both, Bank1 KO and WT mice and was lower compared to WT single cage animals. Also, the abundance of Parabacteroides distasonis was similar in both Bank1 KO and WT mice.
Conclusions Our results link a susceptibility gene for lupus with the abnormalities in the microbiome composition of the gut and the production of IgA. Interestingly, we identified Parabacteroides distasonis as a prevalent species associated with less severe inflammation in lupus. However, we still need to determine the mechanism behind the changes in the migration of B cells to the gut immune tissue, the production of IgA, and the microbiome composition as well as the role of P. distasonis in lupus inflammation.
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