Friday, May 9, 2025
5/9/2025
Characterizing IgA-microbe interactions in type 1 diabetes - PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disease that often emerges during childhood due to T cell- mediated destruction of insulin-producing cells in the pancreas. Over the last 30 years, the incidence of T1D has increased by 3-4%, a rapid change that cannot be explained by genetics alone. Diverse environmental factors including the microbiota have been associated with the increased incidence of T1D, but the mechanisms by which the microbiota influences T1D pathogenesis are not well understood. Studies of non-obese diabetic (NOD) mice and human patients with T1D have similarly revealed associations between protection against T1D and the relative abundance of Akkermansia muciniphila (A.M.) in the gut. A.M. is a Gram-negative, mucin- degrading obligate anaerobe that exerts beneficial effects on the host gut such as increasing mucus production, goblet cells, antimicrobial peptides, and tight junction proteins. These potentially beneficial immunomodulatory effects of A.M. are exciting, but the immune-microbe interactions that mediate these effects are not fully understood. A.M. is also a potent inducer of secretory IgA (sIgA), which plays important roles in modulating microbial colonization and altering microbial gene expression. Small intestinal Peyer’s Patches (PP) are key sites at which B cells respond to the microbiota. There, B cells undergo class switching, somatic hypermutation, and affinity maturation, resulting in the downstream production of high affinity sIgA. How autoimmunity impacts sIgA production and subsequent sIgA-microbe interactions is not known. To address this gap, I will modulate B cell signaling via the genetic deletion of Bruton’s tyrosine kinase (Btk), a B cell signaling protein. We previously discovered that genetic depletion of Btk selectively eliminates autoreactive B cells, thereby preventing T1D in NOD mice. However, this phenotype is dependent on the composition of the microbiota. Monocolonization of germ free Btk-deficient mice with A.M. alone confers protection against T1D. In this setting, WT NOD mice have decreased A.M. abundance compared to Btk-deficient NOD mice. We hypothesize that Btk-deficiency protects against T1D in NOD mice by interfering with the production of sIgA that would prevent A.M. colonization. Accordingly, we seek to identify WT NOD derived IgA that binds A.M. and promotes its clearance from the gut. We will first define the contributions of BTK-mediated B cell receptor (BCR) signaling to the PP B cell repertoire. Then, we will produce monoclonal IgA from PP B cells from monocolonized mice and evaluate the functionality of this A.M.-induced sIgA. We will test the ability of this IgA to modulate A.M. in vitro and create monoclonal antibodies (mIgA) hypothesized to reduce A.M. abundance in vivo. Finally, we will test whether supplementation with mIgA reduces A.M. abundance and causes an increase in T1D in Btk-deficient NOD mice monocolonized with A.M. This work will support a new paradigm by which BTK-mediated B cell signaling modulates the microbiota, with downstream effects on T1D pathogenesis.
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