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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Bourcier, Katarzyna
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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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
Lee, Keunwook; Heffington, Lindsey; Jellusova, Julia et al. (2013) Requirement for Rictor in homeostasis and function of mature B lymphoid cells. Blood 122:2369-79
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
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
Colonna, Lucrezia; Catalano, Geoffrey; Chew, Claude et al. (2010) Therapeutic targeting of Syk in autoimmune diabetes. J Immunol 185:1532-43
Kendall, Peggy L; Moore, Daniel J; Hulbert, Chrys et al. (2009) Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene. J Immunol 183:6403-12
Kendall, Peggy L; Yu, Guowu; Woodward, Emily J et al. (2007) Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J Immunol 178:5643-51