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Title page for ETD etd-03172009-162023


Type of Document Dissertation
Author Henry, Rachel Anne
URN etd-03172009-162023
Title Immune Tolerance for Insulin in Developing B Lymphocytes
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Luc Van Kaer Committee Chair
Alexander Lawton Committee Member
Cathleen Pettepher Committee Member
Eugene Oltz Committee Member
James W. Thomas Committee Member
Sebastian Joyce Committee Member
Keywords
  • Diabetes -- Etiology
  • Insulin -- Physiological effect
  • Immunological tolerance
  • B Cells
  • Insulin
  • Anergy
  • Receptor Editing
  • Tolerance
  • Autoimmune diseases -- Etiology
Date of Defense 2009-03-06
Availability unrestricted
Abstract
The bulk of the developing B cell repertoire consists of autoreactive specificities; accordingly, effective maintenance of immune tolerance at this stage is critical for the prevention of autoimmune disease, the third most prevalent disease category in the U.S. Using bone marrow culture, we provide the first evidence that functional silencing, manifested by reduced surface IgM, impaired Ca2+ mobilization, and impaired proliferation, occurs in developing anti-insulin B cells exposed to insulin, a key type 1 diabetes autoantigen. This form of anergy occurs following short-term insulin exposure, and removal of antigen restores normal immature B cell function, suggesting that a high degree of functional elasticity is maintained. Development of a novel Igê-targeted BCR transgenic model reveals that a second mechanism of tolerance, receptor editing, can additionally censor immature anti-insulin B cells by replacing the autoreactive BCR specificity. These data therefore indicate that low concentrations of small molecules trigger developing B cell tolerance and highlight a potential therapeutic window for insulin autoimmunity, as the involvement of B cells in type 1 diabetes is increasingly appreciated.
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