Type 1 diabetes (T1D) results from a complex cascade of events that breaks immune tolerance and culminates in the destruction of islet 2 cells. B lymphocytes (B cells) play a critical role in disease development, probably via antigen-presentation to pathogenic T cells. B cell contribution to the development of diabetes depends upon multiple factors, including loss of tolerance to self antigen. This tolerance is mediated by cellular responses to antigen-binding via the B cell receptor (BCR). Bruton's tyrosine kinase (BTK) is a central component of the BCR-triggered signaling pathway. Understanding cell signaling components underlying B cell-driven diabetes development will advance the field toward specific targeting of pathogenic B cells. We have introgressed btk-deficiency onto the nonobese diabetic (NOD) mouse model of T1D, and found that this results in significant protection against the development of diabetes. In addition, btk-deficiency interferes with B cell related breaches of immune tolerance, as evidenced by the loss of insulin-specific IgG autoantibodies in wild type NOD mice, and reduction of insulin-binding B cells in a transgenic anti-insulin BCR model. The specific hypothesis underlying this proposal is that BTK-mediated propagation of BCR signals contributes to 1) selection and survival of autoreactive B lymphocytes, and 2) disease- promoting functional properties of these B cells. To understand the mechanisms of action of BTK in breaking B lymphocyte tolerance and promoting disease in autoimmune diabetes, we propose to: 1) discover how BTK participates in the selection and retention of autoreactive B lymphocytes, using use new tools that include a conditional, B cell-specific BTK knockout model and small molecule BTK- inhibitors, 2) determine which domains of the BTK molecule are responsible for autoreactive B lymphocyte selection and function, by systematically restoring independent components responsible for the kinase and linking functions, and 3) investigate the mechanisms of btk-deficiency in preventing T1D by examining effects on B cell subsets, antigen-presenting outcomes, and regulatory parameters. This project has direct clinical importance in understanding how BCR-signaling supports the selection, survival and function of autoreactive B cells in T1D, as a necessary step in developing therapeutic interventions.

Public Health Relevance

Autoreactive B lymphocytes are essential to the development of type 1 diabetes. The goal of this project is to understand how B cell signaling, mediated by Bruton's tyrosine kinase, supports the breach of immunologic tolerance that occurs in this disease. These discoveries will provide new avenues of intervention for the specific targeting of autoreactive, pathogenic B cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084246-02
Application #
8215848
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Spain, Lisa M
Project Start
2011-01-27
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$327,406
Indirect Cost
$115,032
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
Nyhoff, Lindsay E; Crofford, Leslie J; Kendall, Peggy L (2016) How will Bruton's tyrosine kinase inhibitors affect rheumatoid arthritis? Arthritis Rheumatol :
Kendall, Peggy L (2016) New Players in the Field of T1D: Anti-Peripherin B Lymphocytes. Diabetes 65:1794-6
Nyhoff, Lindsay E; Barron, Bridgette L; Johnson, Elizabeth M et al. (2016) Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex-Mediated Inflammatory Arthritis. Arthritis Rheumatol 68:1856-68
Crofford, Leslie J; Nyhoff, Lindsay E; Sheehan, Jonathan H et al. (2016) The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy. Expert Rev Clin Immunol 12:763-73
Hemler, Jonathan A; Phillips, Elizabeth J; Mallal, Simon A et al. (2015) The evolving story of human leukocyte antigen and the immunogenetics of peanut allergy. Ann Allergy Asthma Immunol 115:471-6
Case, James B; Bonami, Rachel H; Nyhoff, Lindsay E et al. (2015) Bruton's Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells in Nonobese Diabetic Mice. J Immunol 195:61-70
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
Bonami, Rachel H; Sullivan, Allison M; Case, James B et al. (2014) Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells. J Immunol 192:1459-70
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

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