Advisory Committee Chair
John F Kearney
Advisory Committee Members
David D Chaplin
Louis B Justement
Moon Nahm
Hubert M Tse
Document Type
Dissertation
Date of Award
2012
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Type I diabetes (T1D) is an autoimmune disease in which ß cells are destroyed by the immune system; however, role of infections in type I diabetes (T1D) pathogenesis is unclear. Reports suggesting that childhood Group A Streptococcal (GAS) infections protected against T1D prompted us to study how antibodies to N-acetyl-D-glucosamine (GlcNAc), which are induced by GAS infection, influenced T1D development. We found that GlcNAc-specific antibodies reacted with ß cell secretory granules, and neonatal NOD mice immunized with GAS or given GAS-immune sera were protected from spontaneous diabetes. Monoclonal GlcNAc-specific IgM blocked activation and effector responses to islet antigens by diabetogenic T cells. Immunization with GAS inhibited BDC2.5 T cell activation in pancreatic lymph nodes, and passive transfers of monoclonal GlcNAc-specific antibodies to neonatal NOD.Rag-2 KO recipients delayed diabetes induced by BDC2.5 Tg splenocyte transfer. To understand how neonatal exposure to environmental antigens, such as GAS, shapes humoral responses in adulthood, we utilized a novel flow cytometric method to identify and phenotype ultra-low frequency GlcNAc-specific B cells in wildtype C57BL/6 mice. After secondary re-challenge in adulthood, neonatal immunization with GAS led to increased production of GlcNAc-specific antibodies with distinct idiotype reactivities compared to those generated in mice given PBS as neonates, suggesting that the clonal composition of the GlcNAc-specific B cell repertoire was altered by early exposure to GAS. Boosted GlcNAc-specific antibody titers occurred when mice were immunized within 3-14 days of age, indicating a window in neonatal life in which the B cell repertoire is shaped by antigen exposure. Taken together, these findings indicate that GlcNAc-specific B cells, when activated by microorganism-associated antigens during a defined time in neonatal life, can protect against T1D through the production of self-reactive antibodies that impede diabetogenic CD4 T cell activation.
Recommended Citation
Dizon, Brian L., "Modulation of Autoimmune Diabetes by B Cells Specific for N-acetyl-D-glucosamine" (2012). All ETDs from UAB. 1532.
https://digitalcommons.library.uab.edu/etd-collection/1532