James W. Thomas, II, M.D.
Professor of Medicine
Division Chief Rheumatology
Vanderbilt University Medical Center
T-3219 Medical Center North
Nashville, TN 37232-2681
- M.D. - University of Tennessee, 1974
- Fellowship - Washington University Medical Center, 1981
- Residency - University of Alabama at Birmingham Health System, 1976
- Internship - University of Tennessee Health Science Center, 1975
Our laboratory investigates the mechanisms that regulate immune tolerance and why they fail in autoimmune disorders such at type 1 diabetes.
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 â€œimmune tolerance.â€ 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.
- Hoek, KL, Gordy, LE, Collins, PL, Parekh, VV, Aune, TM, Joyce, S, Thomas, JW, Van Kaer, L, Sebzda, E Follicular B cell trafficking within the spleen actively restricts humoral immune responses. Immunity, 33(2), 254-65, 2010.
- Grayson, BL, Smith, ME, Thomas, JW, Wang, L, Dexheimer, P, Jeffrey, J, Fain, PR, Nanduri, P, Eisenbarth, GS, Aune, TM Genome-wide analysis of copy number variation in type 1 diabetes. PLoS One, 5(11), e15393, 2010.
- Henry, RA, Kendall, PL, Woodward, EJ, Hulbert, C, Thomas, JW Vkappa polymorphisms in NOD mice are spread throughout the entire immunoglobulin kappa locus and are shared by other autoimmune strains. Immunogenetics, 62(8), 507-20, 2010.
- Boomershine, CS, Chamberlain, A, Kendall, P, Afshar-Sharif, AR, Huang, H, Washington, MK, Lawson, WE, Thomas, JW, Blackwell, TS, Bhowmick, NA Autoimmune pancreatitis results from loss of TGFbeta signalling in S100A4-positive dendritic cells. Gut, 58(9), 1267-74, 2009.
- Henry, RA, Acevedo-SuÃ¡rez, CA, Thomas, JW Functional silencing is initiated and maintained in immature anti-insulin B cells. J Immunol, 182(6), 3432-9, 2009.
- Kendall, PL, Moore, DJ, Hulbert, C, Hoek, KL, Khan, WN, Thomas, JW Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene. J Immunol, 183(10), 6403-12, 2009.
- Kendall, PL, Yu, G, Woodward, EJ, Thomas, JW Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J Immunol, 178(9), 5643-51, 2007.
- Acevedo-SuÃ¡rez, CA, Kilkenny, DM, Reich, MB, Thomas, JW Impaired intracellular calcium mobilization and NFATc1 availability in tolerant anti-insulin B cells. J Immunol, 177(4), 2234-41, 2006.
- Hall,T, Thomas,J, Padoa,C, Tom,C, Landin-Olsson,M , Ortqvist,E, Hampe,C. "Longitudinal Epitope Analysis of Insulin-Binding Antibodies in Type 1 Diabetes." Clin Exp Immunol., 146(1)(Oct), 9-14, 2006.
- Wetzel, JD, Barton, ES, Chappell, JD, Baer, GS, Mochow-Grundy, M, Rodgers, SE, Shyr, Y, Powers, AC, Thomas, JW, Dermody, TS Reovirus delays diabetes onset but does not prevent insulitis in nonobese diabetic mice. J Virol, 80(6), 3078-82, 2006.
- Bezbradica, JS, Stanic, AK, Matsuki, N, Bour-Jordan, H, Bluestone, JA, Thomas, JW, Unutmaz, D, Van Kaer, L, Joyce, S Distinct roles of dendritic cells and B cells in Va14Ja18 natural T cell activation in vivo. J Immunol, 174(8), 4696-705, 2005.
- Padoa,C, Crowther,N, Thomas, JW, Hall,T, Bekris,L, Torn,C, Landin-Olsson,M, Ortqvist,E, Palmer, J, Lernmark,A, Hampe,C. "Epitope Analysis of Insulin Autoantibodies Using Recombinant Fab.." J. of Clinical and Experimental Immunology. Clin Exp Immunol, 140(3), 4564-71, 2005.
- Rossini, M, Cheunsuchon, B, Donnert, E, Ma, LJ, Thomas, JW, Neilson, EG, Fogo, AB Immunolocalization of fibroblast growth factor-1 (FGF-1), its receptor (FGFR-1), and fibroblast-specific protein-1 (FSP-1) in inflammatory renal disease. Kidney Int, 68(6), 2621-8, 2005.
- Woodward, EJ, Thomas, JW Multiple germline kappa light chains generate anti-insulin B cells in nonobese diabetic mice. J Immunol, 175(2), 1073-9, 2005.
- Acevedo-SuÃ¡rez, CA, Hulbert, C, Woodward, EJ, Thomas, JW Uncoupling of anergy from developmental arrest in anti-insulin B cells supports the development of autoimmune diabetes. J Immunol, 174(2), 827-33, 2005.
- Kendall,PL, Woodward,EJ, Hulbert,C, Thomas,JW. "Peritoneal B Cells Govern the Outcome of Diabetes in Non-Obese Diabetic Mice." Eur.J.Immunol., 342387-2395, 2004.
- Kendall, PL, Woodward, EJ, Hulbert, C, Thomas, JW Peritoneal B cells govern the outcome of diabetes in non-obese diabetic mice. Eur J Immunol, 34(9), 2387-95, 2004.
- Yu, L, Eisenbarth,G, Bonifacio,E, Thomas, J, Atkinson,M, and Wasserfall,C. "Remarkable Interlaboratory Concordance for Radiobinding Assays to Identify Insulin Autoantibodies in Nonobese Diabetic Mice. The Second Murine Autoantibody Workshop.." Ann.N.Y Acad.Sci., 10051-12, 2003 (november).
- Byrd, Victor M, Kilkenny, Dawn M, Dikov, Michael M, Reich, Martha B, Rocheleau, Jonathan V, Armistead, Wade J, Thomas, James W, Miller, Geraldine G Fibroblast growth factor receptor-1 interacts with the T-cell receptor signalling pathway. Immunol Cell Biol, 81(6), 440-50, 2003.
- Rojas, Andres, Xu, Fingping, Rojas, Mauricio, Thomas, James W Structure and function of CD72 in the non-obese diabetic (NOD) mouse. Autoimmunity, 36(4), 233-9, 2003.
- DeBusk, Laura M, Chen, Ying, Nishishita, Toshihide, Chen, Jin, Thomas, James W, Lin, Pengnain Charles Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor alpha-induced angiogenesis in rheumatoid arthritis. Arthritis Rheum, 48(9), 2461-71, 2003.
- Thomas, James W, Kendall, Peggy L, Mitchell, Holly G The natural autoantibody repertoire of nonobese diabetic mice is highly active. J Immunol, 169(11), 6617-24, 2002.
- Rojas M, Hulbert C, Thomas JW "Anergy and Not Clonal Ignorance Determines the Fate of B Cells that Recognize a Physiological Autoantigen." Journal of Immunology, 1663194-3200, 2001.
- Rojas, M, Hulbert, C, Thomas, JW Anergy and not clonal ignorance determines the fate of B cells that recognize a physiological autoantigen. J Immunol, 166(5), 3194-200, 2001.
- Thomas,JW "Antigen-Specific Responses in Autoimmunity and Tolerance." Immunologic Research , 23-2/3139-148, 2001.
- Thomas, JW Antigen-specific responses in autoimmunity and tolerance. Immunol Res, 23(2-3), 235-44, 2001.
- Hulbert, C, Riseili, B, Rojas, M, Thomas, J W B cell specificity contributes to the outcome of diabetes in nonobese diabetic mice. J Immunol, 167(10), 5535-8, 2001.
- Thomas, J W, Thieu, T H, Byrd, V M, Miller, G G Acidic fibroblast growth factor in synovial cells. Arthritis Rheum, 43(10), 2152-9, 2000.
- Tikhomirov, OY, Thomas, JW "Alanine scanning mutants of rat proinsulin I show functional diversity of anti-insulin mAb." Journal of Immunology, 1653876-3882, 2000.
- Tikhomirov, OY, Thomas, JW Alanine scanning mutants of rat proinsulin I show functional diversity of anti-insulin monoclonal antibodies. J Immunol, 165(7), 3876-82, 2000.
- Byrd VM, Ballard DW, Miller GG, and Thomas JW "Fibroblast growth factor 1 (FGF1) enhances IL-2 production and nuclear translocation of NF-κB in FGF receptor-bearing T cells." Journal of Immunology, 162(10), 5853-5859, 1999.
- Byrd, VM, Ballard, DW, Miller, GG, Thomas, JW Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells. J Immunol, 162(10), 5853-9, 1999.
- Dikov, MM, Reich, MB, Dworkin, L, Thomas, JW, Miller, GG A functional fibroblast growth factor-1 immunoglobulin fusion protein. J Biol Chem, 273(25), 15811-7, 1998.
- Chu, D M, Francis, S H, Thomas, J W, Maksymovitch, E A, Fosler, M, Corbin, J D Activation by autophosphorylation or cGMP binding produces a similar apparent conformational change in cGMP-dependent protein kinase. J Biol Chem, 273(23), 14649-56, 1998.
- Dombrowski KE, Brewer KA, Maleckar JR, Kirley TL, Thomas JW, and Kapp JA "Identification and partial characterization of EctoATPase Expressed by Immortalized B Lymphocytes." Arch Biochem Biophys , 34010-18, 1997.
- Tikhomirov O. Yu. and Thomas JW "Preference for IgG mAb binding insulin in solution is related to immunoglobulin variable region structures." Journal of Autoimmunity, 10541-549, 1997.
- Tikhomirov, OY, Thomas, JW Preference for IgG mAb binding insulin in solution or on surfaces is related to immunoglobulin variable region structures. J Autoimmun, 10(6), 541-9, 1997.
- Tikhomirov OYu, , Thomas, J W Restricted V gene repertoire in the secondary response to insulin in young BALB/c mice. J Immunol, 158(9), 4292-300, 1997.
- Thomas, JW, Kralick, PM, Ewulonu, UK T cell-independent response to Brucella-insulin identifies a preimmune repertoire for insulin. J Immunol, 159(5), 2334-41, 1997.
- Thomas JW, Kralick PM, Ewulonu UK "The T cell-independent response to Brucella-insulin identifies a preimmune repertoire for insulin." Journal of Immunology , 1592334-2341, 1997.
- Chapman A, Stewart SJ, Nepom GT, Green WF, Crowe D, Thomas JW, Miller GG "Activation of CD11b+CD28-CD4+ human T cells: Activation requirements and association with HLA-DR alleles." Journal of Immunology , 1574771-4780, 1996.
- Byrd, V, Zhao, XM, McKeehan, WL, Miller, GG, Thomas, JW Expression and functional expansion of fibroblast growth factor receptor T cells in rheumatoid synovium and peripheral blood of patients with rheumatoid arthritis. Arthritis Rheum, 39(6), 914-22, 1996.
- Thomas, J.W. and Hulbert, C "Somatically mutated B cell pool provides precursors for insulin antibodies." Journal of Immunology , 157763-771, 1996.
- Thomas, JW, Hulbert, C Somatically mutated B cell pool provides precursors for insulin antibodies. J Immunol, 157(2), 763-71, 1996.
- Zhao X.M., Byrd V.M., McKeehan, W.L., Reich, M.B., Miller, G.G., and Thomas, J.W "Co-stimulation of human CD4+ T cells by fibroblast growth factor-1." Journal of Immunology, 1553504-3911, 1995.
- Zhao, XM, Byrd, VM, McKeehan, WL, Reich, MB, Miller, GG, Thomas, JW Costimulation of human CD4+ T cells by fibroblast growth factor-1 (acidic fibroblast growth factor). J Immunol, 155(8), 3904-11, 1995.
- Thomas JW and Hulbert C "Expression and regulation of clonally ignorant B cells." Annals of the New York Academy of Sciences, 764461-462, 1995.
- Thomas, JW, Hulbert, C Expression and regulation of clonally ignorant B cells. Ann N Y Acad Sci, 764461-2, 1995.
- Thomas JW and Powers AC.edited by Rich RR, Fleisher TA, Schwartz BD, Shearer WT, Strober W. St. Louis: Mosby-Year Book, Inc "Immunology of Diabetes." Clinical Immunology: Principles and Practice., Vol. II1503-1522., 1995.
- Mitchell, HC, Thomas, JW VH gene structure predicts a large potential anti-insulin repertoire. Mol Immunol, 32(5), 311-21, 1995.
- Mitchell HC and Thomas JW "VH gene structure predicts a large potential anti-insulin repertoire." Molecular Immunology , 32311-321, 1995.
- Byrd VM, Zhao XM, Miller GG, Thomas JW "Detection of T cells responsive to a vascular growth factor in rheumatoid arthritis.." Immunologic Research , 13139-144, 1994.
- Byrd, VM, Zhao, XM, Miller, GG, Thomas, JW Detection of T cells responsive to a vascular growth factor in rheumatoid arthritis. Immunol Res, 13(2-3), 139-44, 1994.
- Miller G, Nepom GT, Reich MB, and Thomas JW "Autoreactive T cells from a type I diabetic recognize multiple Class II products.." Human Immunology , 36219-226, 1993.
- Thomas J.W "V region diversity in human anti-insulin antibodies: preferential use of a VHIII gene subset.." Journal of Immunology , 1501375-1382, 1993.
- Miller, G, Nepom, GT, Reich, MB, Thomas, JW Autoreactive T cells from a type I diabetic recognize multiple class II products. Hum Immunol, 36(4), 219-26, 1993.
- Karounos, D.G., Wolinsky, J.S. and Thomas, J.W "Monoclonal antibody to rubella virus capsid protein recognizes a ?-cell antigen." Journal of Immunology , 1501-6, 1993.
- Thomas, JW V region diversity in human anti-insulin antibodies. Preferential use of a VHIII gene subset. J Immunol, 150(4), 1375-82, 1993.
- Thomas J.W "Anti-insulin and regulatory anti-idiotypic antibodies use the same germ-line VHIX gene." European Journal of Immunology , 222445-2448, 1992.
- Thomas, JW Anti-insulin and regulatory anti-idiotypic antibodies use the same germ-line VHIX gene. Eur J Immunol, 22(9), 2445-8, 1992.
- Karounos, D.G., Nell, L.J. and Thomas, J.W "Autoantibodies present at onset of type I diabetes recognize multiple islet cell antigens." Autoimmunity, 679-91, 1990.
- Karounos, D.G. and Thomas, J.W "Recognition of common islet antigens by autoantibodies from NOD mice and humans with IDDM." Diabetes, 1391085- 1090, 1990.
- Ewulonu, U.K., Nell, L.J. and Thomas, J.W "VH and VL gene usage by murine IgG antibodies that bind autologous insulin." J Immunol , 1443091- 3098, 1990.