Biomedical Research Education & Training
Faculty Member

Thomas, James W., M.D.
Director, Division of Rheumatology & Clinical Immunology
Professor of Medicine
Professor of Pathology, Microbiology and Immunology

Lab Url: http://www.mc.vanderbilt.edu/root/vumc.php?site=thomaslab&doc

Phone Number: 615-322-4746

Email Address: james.w.thomas@vanderbilt.edu

Thomas, James's picture
Academic history
B.A., Southwestern at Memphis, Memphis, TN (Rhodes College)
M.D., University of Tennessee, Memphis, TN

Office Address   Mailing Address

T-3219 Medical Center North

T-3219 MCN 2681


Research Specialty
Our laboratory investigates the mechanisms that regulate immune tolerance and why they fail in autoimmune disorders such at type 1 diabetes.

Research Description
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 a??immune tolerance.a?? 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
Cho, SH, Raybuck, A, Wei, M, Erickson, J, Nam, KT, Cox, RG, Trochtenberg, A, Thomas, JW, Williams, J, Boothby, M. B Cell-Intrinsic and -Extrinsic Regulation of Antibody Responses by PARP14, an Intracellular (ADP-Ribosyl)Transferase. J Immunol, 191(6), 3169-78, 2013

Henry-Bonami, RA, Williams, JM, Rachakonda, AB, Karamali, M, Kendall, PL, Thomas, JW. B lymphocyte "original sin" in the bone marrow enhances islet autoreactivity in type 1 diabetes-prone nonobese diabetic mice. J Immunol, 190(12), 5992-6003, 2013

Kendall, PL, Case, JB, Sullivan, AM, Holderness, JS, Wells, KS, Liu, E, Thomas, JW. Tolerant anti-insulin B cells are effective APCs. J Immunol, 190(6), 2519-26, 2013

Lee, K, Heffington, L, Jellusova, J, Nam, KT, Raybuck, A, Cho, SH, Thomas, JW, Rickert, RC, Boothby, M. Requirement for Rictor in homeostasis and function of mature B lymphoid cells. Blood, 2013

Briney, BS, Willis, JR, Hicar, MD, Thomas, JW, Crowe, JE. Frequency and genetic characterization of V(DD)J recombinants in the human peripheral blood antibody repertoire. Immunology, 137(1), 56-64, 2012

Henry, RA, Kendall, PL, Thomas, JW. Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes. Diabetes, 61(8), 2037-44, 2012

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 PMCID:2981564

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 PMCID:2970566

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 PMCID:2981564

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 PMCID:2719085

Henry, RA, Acevedo-Su?!rez, CA, Thomas, JW. Functional silencing is initiated and maintained in immature anti-insulin B cells. J Immunol, 182(6), 3432-9, 2009 PMCID:2719085

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 PMCID:2970569

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-Su?!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 PMCID:1395416

Acevedo-Su?!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

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

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

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, 2387-2395, 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., 1005, 1-12, 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

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

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

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

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

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, 166, 3194-3200, 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. Immunol Res, 23(2-3), 235-44, 2001

Thomas,JW. Antigen-Specific Responses in Autoimmunity and Tolerance. Immunologic Research , 23-2/3, 139-148, 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, 165, 3876-3882, 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

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

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

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 , 340, 10-18, 1997

Thomas JW, Kralick PM, Ewulonu UK. The T cell-independent response to Brucella-insulin identifies a preimmune repertoire for insulin. Journal of Immunology , 159, 2334-2341, 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

Tikhomirov O. Yu. and Thomas JW. Preference for IgG mAb binding insulin in solution is related to immunoglobulin variable region structures. Journal of Autoimmunity, 10, 541-549, 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

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

Byrd V, Zhao X-M, McKeehan WL, Miller GG, and Thomas JW: Expression and functional expansion of fibroblast growth factor receptor T cells are in rheumatoid synovium and peripheral blood of patients with rheumatoid arthritis. Arthritis Rheum 39:914-922, 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

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 , 157, 4771-4780, 1996

Thomas, J.W. and Hulbert, C. Somatically mutated B cell pool provides precursors for insulin antibodies. Journal of Immunology , 157, 763-771, 1996

Thomas, JW, Hulbert, C. Somatically mutated B cell pool provides precursors for insulin antibodies. J Immunol, 157(2), 763-71, 1996

Mitchell HC and Thomas JW. VH gene structure predicts a large potential anti-insulin repertoire. Molecular Immunology , 32, 311-321, 1995

Mitchell, HC, Thomas, JW. VH gene structure predicts a large potential anti-insulin repertoire. Mol Immunol, 32(5), 311-21, 1995

Thomas JW and Hulbert C. Expression and regulation of clonally ignorant B cells. Annals of the New York Academy of Sciences, 764, 461-462, 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. II, 1503-1522., 1995

Thomas, JW, Hulbert, C. Expression and regulation of clonally ignorant B cells. Ann N Y Acad Sci, 764, 461-2, 1995

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, 155, 3504-3911, 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

Byrd VM, Zhao XM, Miller GG, Thomas JW. Detection of T cells responsive to a vascular growth factor in rheumatoid arthritis.. Immunologic Research , 13, 139-144, 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

Karounos, D.G., Wolinsky, J.S. and Thomas, J.W. Monoclonal antibody to rubella virus capsid protein recognizes a ?-cell antigen. Journal of Immunology , 150, 1-6, 1993

Miller G, Nepom GT, Reich MB, and Thomas JW. Autoreactive T cells from a type I diabetic recognize multiple Class II products.. Human Immunology , 36, 219-226, 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

Thomas J.W. V region diversity in human anti-insulin antibodies: preferential use of a VHIII gene subset.. Journal of Immunology , 150, 1375-1382, 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 , 22, 2445-2448, 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

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 , 144, 3091- 3098, 1990

Karounos, D.G. and Thomas, J.W. Recognition of common islet antigens by autoantibodies from NOD mice and humans with IDDM. Diabetes, 139, 1085- 1090, 1990

Karounos, D.G., Nell, L.J. and Thomas, J.W. Autoantibodies present at onset of type I diabetes recognize multiple islet cell antigens. Autoimmunity, 6, 79-91, 1990


Postdoctoral Position Available
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Postdoctoral Position Details
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Updated Date
08/15/2011