Profile

Antibody production, or humoral immunity, is a highly effective mechanism for host defense because the developing B cell repertoire generates an enormous number of immune receptors that become immune effectors as antibodies. Because many of the immune receptors produced during B cell development also react with self antigens (i.e. are autoreactive), mechanisms are necessary to prevent the emergence of potentially toxic B cell clones and antibodies. The mechanisms that maintain this autoreactivity in check are broadly termed “immune tolerance.†Every immune response must first negotiate checkpoints of immune tolerance before effective host defense can be generated. In autoimmune diseases, these checkpoints fail and autoagressive clones emerge. Among these, loss of B cell tolerance as manifest by anti-insulin antibodies is a harbinger of autoimmune beta cell destruction in the pancreas that causes type 1 (insulin dependent) diabetes. To study this event at the cellular and molecular level, our laboratory has generated mice that harbor insulin autoantibodies as B cell receptor transgenes. T1D prone NOD mice that harbor an Ig heavy chain transgene permit us to investigate a population of insulin binding B cells in the repertoire. We find that these insulin specific B cells promote T1D in the NOD mouse model. In addition, we have discovered that some of these B cells invade islets and express receptors that may bind antigens other than insulin. Capturing the antigen receptors on these B cells provides a means to discover new beta cell autoantigens that are targets in T1D. Further, a new line of transgenic mice is being generated in which the anti-insulin V regions are targeted to the Ig locus. Studies in these will identify, for the first time, when and where immune tolerance is lost, allowing anti-insulin B cells to undergo class switch recombination and differentiation into antibody producing cells. Studies in the laboratory investigate how the action of helper and regulatory T cells alter this critical immune response.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. NFATc2 (NFAT1) assists BCR-mediated anergy in anti-insulin B cells. Bonami RH, Wolfle WT, Thomas JW, Kendall PL (2014) Mol Immunol 62(2): 321-8
    › Primary publication · 24507801 (PubMed) · PMC4125564 (PubMed Central)
  2. B lymphocyte "original sin" in the bone marrow enhances islet autoreactivity in type 1 diabetes-prone nonobese diabetic mice. Henry-Bonami RA, Williams JM, Rachakonda AB, Karamali M, Kendall PL, Thomas JW (2013) J Immunol 190(12): 5992-6003
    › Primary publication · 23677466 (PubMed) · PMC3679359 (PubMed Central)
  3. Tolerant anti-insulin B cells are effective APCs. Kendall PL, Case JB, Sullivan AM, Holderness JS, Wells KS, Liu E, Thomas JW (2013) J Immunol 190(6): 2519-26
    › Primary publication · 23396943 (PubMed) · PMC3652276 (PubMed Central)
  4. Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes. Henry RA, Kendall PL, Thomas JW (2012) Diabetes 61(8): 2037-44
    › Primary publication · 22698916 (PubMed) · PMC3402296 (PubMed Central)
  5. Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene. Kendall PL, Moore DJ, Hulbert C, Hoek KL, Khan WN, Thomas JW (2009) J Immunol 183(10): 6403-12
    › Primary publication · 19841184 (PubMed) · PMC2970569 (PubMed Central)
  6. Functional silencing is initiated and maintained in immature anti-insulin B cells. Henry RA, Acevedo-Suárez CA, Thomas JW (2009) J Immunol 182(6): 3432-9
    › Primary publication · 19265121 (PubMed) · PMC3845364 (PubMed Central)
  7. Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. Kendall PL, Yu G, Woodward EJ, Thomas JW (2007) J Immunol 178(9): 5643-51
    › Primary publication · 17442947 (PubMed)
  8. Impaired intracellular calcium mobilization and NFATc1 availability in tolerant anti-insulin B cells. Acevedo-Suárez CA, Kilkenny DM, Reich MB, Thomas JW (2006) J Immunol 177(4): 2234-41
    › Primary publication · 16887983 (PubMed)
  9. Multiple germline kappa light chains generate anti-insulin B cells in nonobese diabetic mice. Woodward EJ, Thomas JW (2005) J Immunol 175(2): 1073-9
    › Primary publication · 16002708 (PubMed)
  10. Uncoupling of anergy from developmental arrest in anti-insulin B cells supports the development of autoimmune diabetes. Acevedo-Suárez CA, Hulbert C, Woodward EJ, Thomas JW (2005) J Immunol 174(2): 827-33
    › Primary publication · 15634904 (PubMed)
  11. Peritoneal B cells govern the outcome of diabetes in non-obese diabetic mice. Kendall PL, Woodward EJ, Hulbert C, Thomas JW (2004) Eur J Immunol 34(9): 2387-95
    › Primary publication · 15307171 (PubMed)
  12. VH gene structure predicts a large potential anti-insulin repertoire. Mitchell HC, Thomas JW (1995) Mol Immunol 32(5): 311-21
    › Primary publication · 7537854 (PubMed)