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 #
5R01AI051448-08
Application #
7992388
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
2010-12-01
Budget End
2011-11-30
Support Year
8
Fiscal Year
2011
Total Cost
$376,113
Indirect Cost
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
Raybuck, Ariel L; Cho, Sung Hoon; Li, Jingxin et al. (2018) B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity. J Immunol 200:2627-2639
Cho, Sung Hoon; Raybuck, Ariel L; Stengel, Kristy et al. (2016) Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537:234-238
Wan, Xiaoxiao; Thomas, James W; Unanue, Emil R (2016) Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites. J Exp Med 213:967-78
Packard, Thomas A; Smith, Mia J; Conrad, Francis J et al. (2016) B Cell Receptor Affinity for Insulin Dictates Autoantigen Acquisition and B Cell Functionality in Autoimmune Diabetes. J Clin Med 5:
Bonami, Rachel H; Thomas, James W (2015) Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1 Diabetes-Prone Mice. J Immunol 195:4730-41
Williams, Jonathan M; Bonami, Rachel H; Hulbert, Chrys et al. (2015) Reversing Tolerance in Isotype Switch-Competent Anti-Insulin B Lymphocytes. J Immunol 195:853-64
Bonami, Rachel H; Wolfle, William T; Thomas, James W et al. (2014) NFATc2 (NFAT1) assists BCR-mediated anergy in anti-insulin B cells. Mol Immunol 62:321-8
Kendall, Peggy L; Case, James B; Sullivan, Allison M et al. (2013) Tolerant anti-insulin B cells are effective APCs. J Immunol 190:2519-26
Henry-Bonami, Rachel A; Williams, Jonathan M; Rachakonda, Amita B et al. (2013) B lymphocyte ""original sin"" in the bone marrow enhances islet autoreactivity in type 1 diabetes-prone nonobese diabetic mice. J Immunol 190:5992-6003
Cho, Sung Hoon; Raybuck, Ariel; Wei, Mei et al. (2013) B cell-intrinsic and -extrinsic regulation of antibody responses by PARP14, an intracellular (ADP-ribosyl)transferase. J Immunol 191:3169-78

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