All ETDs from UAB

Advisory Committee Chair

John F Kearney

Advisory Committee Members

Alex J Szalai

David E Briles

Frances E Lund

Hubert M Tse

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Type 1 Diabetes suppression in diabetes prone mice following immunization with Group A Streptococcus correlates with the B lymphocyte response to N-acetyl-D-glucosamine (GlcNAc) present in the Group A Carbohydrate cell wall polysaccharide. GlcNAc-specific B cells recognize cryptic GlcNAc-epitopes in beta cells. Following exposure of GlcNAc-modified antigens on beta cells during cellular apoptosis, GlcNAc-specific IgM antibodies opsonize these epitopes and mediate classical complement pathway activation. In vitro, opsonization of apoptotic beta cells with GlcNAc-specific IgM increases their uptake by dendritic cells, while suppressing the subsequent presentation of beta cell-derived antigens to diabetogenic T lymphocytes. Passive administration of Group A Streptococcus antisera to naïve NOD mice transferred Type 1 diabetes protection, indicating a central role for GlcNAc-specific IgM in preventing the precipitation of diabetes in this model. Moreover, relative to healthy individuals, human Type 1 diabetes patients exhibit aberrations in the B cell clonotypes represented within their GlcNAc-reactive B cell compartment, suggesting certain GlcNAc-reactive B cell clonotypes may inhibit progression of T1D in humans. The development of innate-like GlcNAc-reactive B cells is dependent on exogenous antigen, and the content of the intestinal microbiota directly influences the GlcNAc-reactive B cell clonal repertoire. Moreover, colonization by the microbiota during early life is an important factor in the establishment of conserved GlcNAc-reactive B cell clonotypes in mice. Interactions with microbiota derived antigens not only influence clonal selection of GlcNAc-reactive B cells, but result in their localization to the small intestinal lamina propria. Here, GlcNAc-reactive B cells secrete immunoglobulin A into the intestinal lumen, which opsonizes luminal GlcNAc-bearing microbes. Modeling of GlcNAc-reactive B cell development in the immunoglobulin heavy chain transgenic VH HGAC39 mouse indicates that endogenous antigens suppress the development of GlcNAc-reactive B cells at peripheral tolerance checkpoints during adult lymphopoiesis. Thus, the establishment of natural antibody producing GlcNAc-reactive B cells with the potential to suppress Type 1 Diabetes is highly influenced by colonization with the microbiota during early life, which results in clonal expansion at selection checkpoints in precursors to these cells. These data are of significance for the design of therapeutics aimed towards boosting natural antibody repertoire deficiencies in Type 1 Diabetes patients.

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