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.