Targeting Bruton’s Tyrosine Kinase alters IgA production and modulation of the microbiota 3280

Abstract Description IgA is an important mediator of immune-microbe interactions in the gut. It is unknown how B cell signaling protein Bruton’s Tyrosine Kinase (BTK) contributes to mucosal immunity. We previously found that Btk-deficiency selectively eliminates autoreactive B cells and autoantibodies, preventing type 1 diabetes (T1D) development in non-obese diabetic (NOD) mice. This disease protection is microbiome dependent; Akkermansia muciniphila (A.M.) is consistently increased in Btk-/-NOD mice protected against T1D. To test whether loss of Btk allowed improved colonization of A.M., we rederived Btk-/-NOD and WT NOD mice in a germ-free environment and monocolonized half the mice with A.M. At 12-15 weeks of age, some mice were sacrificed to evaluate IgA-A.M. interactions. B cells from small intestinal Peyer’s Patches were isolated, and single B cells were cultured, yielding supernatants containing monoclonal antibodies hypothesized to bind A.M. Several A.M.-binding antibodies have been identified. These will be utilized in future studies evaluating how IgA-binding modulates A.M. B cell receptor sequencing was also performed to investigate how Btk-deficiency alters the mucosal B cell repertoire. In the small intestine, Btk-deficiency decreased IgA production and IgA-coating of A.M. Moreover, A.M. prevented the development of T1D in Btk-/-NOD mice. Together, these findings demonstrate that targeting BTK alters mucosal immunology and IgA production, with downstream effects on T1D pathogenesis. Funding Sources Supported by NIH R01-DK-084246; T32AI007163-46; Needleman Fellowship; David and Deborah Winston Fellowship in Diabetes Research. Topic Categories Mucosal and Regional Immunology (MUC)