Type IA or insulin dependent diabetes (T1D) results from of an autoimmune process that destroys insulin producing beta cells in the pancreatic islets. Although T lymphocytes are known to mediate the disease, we find that a large proportion of the invading cells are B lymphocytes. Recent success with B cell directed therapy in other T cell-mediated disorders has led to the recognition that B cells are more important in these diseases than previously thought. Accordingly, the goal of this project is to understand the functions of B lymphocytes that catalyze T cell interactions and promote autoimmune beta cell destruction leading to type 1 diabetes (T1D). To understand the actions of B cells in T1D, we introduced immunoglobulin (Ig) transgenes (Tg) from an insulin autoantibody (mAb125) into NOD mice and generated B cell repertoires that are skewed toward this critical islet antigen. Importantly, we discovered that anti-insulin B cells are maintained in a tolerant state in NOD mice, but despite this tolerance, anti-insulin B cells preserve B-T cell interactions that are essential for T1D. In addition, we used VH125Tg NOD mice that harbor only an H-chain Tg (VH125) to generate a polyclonal repertoire in which only a small fraction of B cells bind insulin. Unexpectedly, these polyclonal VH125Tg NOD B cells undergo expansion in the pancreas, and their autoimmune response spreads to antigens other than insulin. These findings suggest that 1) anti-insulin B cells are retained in the repertoire in a novel state of tolerance that preserves antigen presenting functions and induces the expansion of autoaggressive T cells;and 2) novel autoantigens in the pancreatic islets mediate B cell selection within the islet lesions, amplifying the risk of disease by promoting autoantigen spread. We will test these hypotheses in three aims. First, receptor structures on invading VH125Tg B cells will be used to identify the antigens that are driving the islet attack. Second, signaling pathways that maintain antigen presenting functions in tolerant B cells will be identified and we will use this information to block critical B-T cell interactions.
A third aim will directly test the potential for tolerant B cells to drive T cell mediated insulitis and diabetes in an antigen specific model of T1D.Project Narrative This project has direct clinical relevance for the management of type 1 diabetes;it will 1) improve diagnosis by identifying new target antigens;2) develop strategies to block presentation of islet antigens to T cells in T1D, and 3) facilitate therapy targeted at B lymphocytes in T1D.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051448-09
Application #
8197582
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Bourcier, Katarzyna
Project Start
2002-04-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
9
Fiscal Year
2012
Total Cost
$376,113
Indirect Cost
$131,088
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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