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Title page for ETD etd-11092015-092347


Type of Document Dissertation
Author Williams, Jonathan Murphy
Author's Email Address jonathan.m.williams@vanderbilt.edu
URN etd-11092015-092347
Title Peripheral Tolerance in Anti-Insulin B Lymphocytes
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Mark Boothby Committee Chair
Eric Sebzda Committee Member
James W. Thomas Committee Member
Luc Van Kaer Committee Member
Maureen Gannon Committee Member
Keywords
  • Autoimmunity
  • Tolerance
  • B cells
  • Insulin
  • Type 1 Diabetes
Date of Defense 2015-10-27
Availability unrestricted
Abstract
Overall, these studies examine how peripheral tolerance is governed for autoreactive B lymphocytes that bind the relevant autoAg, insulin. CSR-competent anti-insulin B cells enter mature compartments but are anergic, demonstrated by impaired proliferation to stimulation by a panel of B cell mitogens in vitro and total lack of IgG anti-insulin antibody production following TD immunization of VH125SD B6 mice. Reversal of anti-insulin B cell anergy is demonstrated by proliferation to insulin plus LPS in vitro and IgG2a antibody production following immunization of VH125SD mice with insulin conjugated to a type 1 TI antigen. This combined BCR/TLR co-stimulation effect in vivo is accompanied by entry of insulin-binding B cells into GCs, in contrast to expectations that such TI-mediated responses would arise in extrafollicular sites. In GCs, anti-insulin L chains are not discarded but rather selected from the pre-immune repertoire. These studies reveal a new pathway to drive loss of tolerance for CSR-competent anti-insulin B cells.
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