Bruton's Tyrosine Kinase Supports Gut Mucosal Immunity and Commensal Microbiome Recognition in Autoimmune Arthritis
Bruton's tyrosine kinase (Btk) deficiency preferentially eliminates autoreactive B cells while sparing normal humoral responses, but has not been studied in mucosal immunity. Commensal microbes are essential for arthritis in K/BxN mice, used here to examine how BTK-mediated signaling interfaces with the microbiome. Btk-deficient K/BxN mice were found to have small Peyer's Patches with reduced germinal center and IgA+ B cells. Although lamina propria IgA+ plasma cells were numerically normal, intestinal IgA was low and IgA coating of commensal bacteria was reduced. IgA-seq showed a shift in microbes that are normally IgA-coated into the uncoated fraction in Btk-deficient mice. In this altered microbial milieau, the proportion of Parabacteroides distasonis was reduced in Btk-deficient K/BxN mice. To determine whether P. distasonis contributes to arthritis, it was reintroduced into antibiotic-protected K/BxN mice, where it restored disease. This suggests that P. distasonis' inability to thrive in Btk-deficient mice may be a factor in disease protection. Thus, BTK supports normal intestinal IgA development, with downstream effects on the microbiome that may contribute to autoimmunity.
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