James W. Thomas, II, M.D.

Professor

james.w.thomas@vanderbilt.edu

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Faculty Appointments
Professor of Medicine Professor of Pathology, Microbiology and Immunology
Education
M.D., Medicine, University of Tennessee Center for Health Science, Memphis, TennesseeB.A., Biology/Chemistry, Rhodes College, Memphis, Tennessee
Office Address
1161 21st Ave, T-3113 MCN
Nashville, TN 37232-2681
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 “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.
Research Keywords
Our laboratory investigates the mechanisms that regulate immune tolerance and why they fail in autoimmune disorders such at type 1 diabetes.
Publications
Wan X, Thomas JW, Unanue ER. Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites. J. Exp. Med [print-electronic]. 2016 May 5/2/2016; PMID: 27139492, PII: jem.20151869, DOI: 10.1084/jem.20151869, ISSN: 1540-9538.

Bonami RH, Thomas JW. Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1 Diabetes-Prone Mice. J. Immunol [print-electronic]. 2015 Nov 11/15/2015; 195(10): 4730-41. PMID: 26432895, PMCID: PMC4637270, PII: jimmunol.1500438, DOI: 10.4049/jimmunol.1500438, ISSN: 1550-6606.

Williams JM, Bonami RH, Hulbert C, Thomas JW. Reversing Tolerance in Isotype Switch-Competent Anti-Insulin B Lymphocytes. J. Immunol [print-electronic]. 2015 Aug 8/1/2015; 195(3): 853-64. PMID: 26109644, PMCID: PMC4506889, PII: jimmunol.1403114, DOI: 10.4049/jimmunol.1403114, ISSN: 1550-6606.

Bonami RH, Wolfle WT, Thomas JW, Kendall PL. NFATc2 (NFAT1) assists BCR-mediated anergy in anti-insulin B cells. Mol. Immunol [print-electronic]. 2014 Dec; 62(2): 321-8. PMID: 24507801, PMCID: PMC4125564, PII: S0161-5890(14)00012-1, DOI: 10.1016/j.molimm.2014.01.003, ISSN: 1872-9142.

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 [print-electronic]. 2013 Oct 10/3/2013; 122(14): 2369-79. PMID: 23958952, PMCID: PMC3790507, PII: blood-2013-01-477505, DOI: 10.1182/blood-2013-01-477505, ISSN: 1528-0020.

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 [print-electronic]. 2013 Sep 9/15/2013; 191(6): 3169-78. PMID: 23956424, PMCID: PMC3770464, PII: jimmunol.1301106, DOI: 10.4049/jimmunol.1301106, ISSN: 1550-6606.

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 [print-electronic]. 2013 Jun 6/15/2013; 190(12): 5992-6003. PMID: 23677466, PMCID: PMC3679359, PII: jimmunol.1201359, DOI: 10.4049/jimmunol.1201359, ISSN: 1550-6606.

Kendall PL, Case JB, Sullivan AM, Holderness JS, Wells KS, Liu E, Thomas JW. Tolerant anti-insulin B cells are effective APCs. J. Immunol [print-electronic]. 2013 Mar 3/15/2013; 190(6): 2519-26. PMID: 23396943, PMCID: PMC3652276, PII: jimmunol.1202104, DOI: 10.4049/jimmunol.1202104, ISSN: 1550-6606.

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. 2012 Sep; 137(1): 56-64. PMID: 22612413, PMCID: PMC3449247, DOI: 10.1111/j.1365-2567.2012.03605.x, ISSN: 1365-2567.

Henry RA, Kendall PL, Thomas JW. Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes. Diabetes [print-electronic]. 2012 Aug; 61(8): 2037-44. PMID: 22698916, PMCID: PMC3402296, PII: db11-1746, DOI: 10.2337/db11-1746, ISSN: 1939-327X.

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 [print-electronic]. 2010 Aug 8/27/2010; 33(2): 254-65. PMID: 20691614, PMCID: PMC2929658, PII: S1074-7613(10)00281-5, DOI: 10.1016/j.immuni.2010.07.016, ISSN: 1097-4180.

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 [print-electronic]. 2010 Aug; 62(8): 507-20. PMID: 20556377, PMCID: PMC2970566, DOI: 10.1007/s00251-010-0457-9, ISSN: 1432-1211.

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. 2010; 5(11): e15393. PMID: 21085585, PMCID: PMC2981564, DOI: 10.1371/journal.pone.0015393, ISSN: 1932-6203.

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 [print-electronic]. 2009 Nov 11/15/2009; 183(10): 6403-12. PMID: 19841184, PMCID: PMC2970569, PII: jimmunol.0900367, DOI: 10.4049/jimmunol.0900367, ISSN: 1550-6606.

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 [print-electronic]. 2009 Sep; 58(9): 1267-74. PMID: 19625278, PMCID: PMC2719085, PII: gut.2008.170779, DOI: 10.1136/gut.2008.170779, ISSN: 1468-3288.

Henry RA, Acevedo-Suárez CA, Thomas JW. Functional silencing is initiated and maintained in immature anti-insulin B cells. J. Immunol. 2009 Mar 3/15/2009; 182(6): 3432-9. PMID: 19265121, PMCID: PMC3845364, PII: 182/6/3432, DOI: 10.4049/jimmunol.0803121, ISSN: 1550-6606.

Kendall PL, Yu G, Woodward EJ, Thomas JW. Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J. Immunol. 2007 May 5/1/2007; 178(9): 5643-51. PMID: 17442947, PII: 178/9/5643, ISSN: 0022-1767.

Acevedo-Suárez CA, Kilkenny DM, Reich MB, Thomas JW. Impaired intracellular calcium mobilization and NFATc1 availability in tolerant anti-insulin B cells. J. Immunol. 2006 Aug 8/15/2006; 177(4): 2234-41. PMID: 16887983, PII: 177/4/2234, ISSN: 0022-1767.

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. 2006 Mar; 80(6): 3078-82. PMID: 16501117, PMCID: PMC1395416, PII: 80/6/3078, DOI: 10.1128/JVI.80.6.3078-3082.2006, ISSN: 0022-538X.

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. 2006; 146(1)((Oct)): 9-14.

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. 2005 Dec; 68(6): 2621-8. PMID: 16316338, PII: KID734, DOI: 10.1111/j.1523-1755.2005.00734.x, ISSN: 0085-2538.

Woodward EJ, Thomas JW. Multiple germline kappa light chains generate anti-insulin B cells in nonobese diabetic mice. J. Immunol. 2005 Jul 7/15/2005; 175(2): 1073-9. PMID: 16002708, PII: 175/2/1073, ISSN: 0022-1767.

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. 2005 Apr 4/15/2005; 174(8): 4696-705. PMID: 15814694, PII: 174/8/4696, ISSN: 0022-1767.

Acevedo-Suárez 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. 2005 Jan 1/15/2005; 174(2): 827-33. PMID: 15634904, PII: 174/2/827, ISSN: 0022-1767.

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. 2005; 140((3)): 4564-71.

Kendall PL, Woodward EJ, Hulbert C, Thomas JW. Peritoneal B cells govern the outcome of diabetes in non-obese diabetic mice. Eur. J. Immunol. 2004 Sep; 34(9): 2387-95. PMID: 15307171, DOI: 10.1002/eji.200324744, ISSN: 0014-2980.

Kendall,PL, Woodward,EJ, Hulbert,C, Thomas,JW.. Peritoneal B Cells Govern the Outcome of Diabetes in Non-Obese Diabetic Mice. Eur.J.Immunol. 2004; 34: 2387-95.

Byrd VM, Kilkenny DM, Dikov MM, Reich MB, Rocheleau JV, Armistead WJ, Thomas JW, Miller GG. Fibroblast growth factor receptor-1 interacts with the T-cell receptor signalling pathway. Immunol. Cell Biol. 2003 Dec; 81(6): 440-50. PMID: 14636241, PII: 1199, DOI: 10.1046/j.1440-1711.2003.01199.x, ISSN: 0818-9641.

DeBusk LM, Chen Y, Nishishita T, Chen J, Thomas JW, Lin PC. Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor alpha-induced angiogenesis in rheumatoid arthritis. Arthritis Rheum. 2003 Sep; 48(9): 2461-71. PMID: 13130465, DOI: 10.1002/art.11213, ISSN: 0004-3591.

Rojas A, Xu F, Rojas M, Thomas JW. Structure and function of CD72 in the non-obese diabetic (NOD) mouse. Autoimmunity. 2003 Jun; 36(4): 233-9. PMID: 14563017, ISSN: 0891-6934.

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. 2003; 1005: 1-12.

Thomas JW, Kendall PL, Mitchell HG. The natural autoantibody repertoire of nonobese diabetic mice is highly active. J. Immunol. 2002 Dec 12/1/2002; 169(11): 6617-24. PMID: 12444175, ISSN: 0022-1767.

Hulbert C, Riseili B, Rojas M, Thomas JW. B cell specificity contributes to the outcome of diabetes in nonobese diabetic mice. J. Immunol. 2001 Nov 11/15/2001; 167(10): 5535-8. PMID: 11698422, ISSN: 0022-1767.

Rojas M, Hulbert C, Thomas JW. Anergy and not clonal ignorance determines the fate of B cells that recognize a physiological autoantigen. J. Immunol. 2001 Mar 3/1/2001; 166(5): 3194-200. PMID: 11207272, ISSN: 0022-1767.

Thomas JW. Antigen-specific responses in autoimmunity and tolerance. Immunol. Res. 2001; 23(2-3): 235-44. PMID: 11444388, PII: IR:23:2-3:235, DOI: 10.1385/IR:23:2-3:235, ISSN: 0257-277X.

Thomas,JW. Antigen-Specific Responses in Autoimmunity and Tolerance. Immunologic Research. 2001; 23-2/3: 139-48.

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. 2001; 166: 3194-200.

Thomas JW, Thieu TH, Byrd VM, Miller GG. Acidic fibroblast growth factor in synovial cells. Arthritis Rheum. 2000 Oct; 43(10): 2152-9. PMID: 11037874, DOI: 10.1002/1529-0131(200010)43:10<2152::AID-ANR2>3.0.CO;2-R, ISSN: 0004-3591.

Tikhomirov OY, Thomas JW. Alanine scanning mutants of rat proinsulin I show functional diversity of anti-insulin monoclonal antibodies. J. Immunol. 2000 Oct 10/1/2000; 165(7): 3876-82. PMID: 11034394, ISSN: 0022-1767.

Tikhomirov, OY, Thomas, JW. Alanine scanning mutants of rat proinsulin I show functional diversity of anti-insulin mAb. Journal of Immunology. 2000; 165: 3876-82.

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. 1999 May 5/15/1999; 162(10): 5853-9. PMID: 10229820, ISSN: 0022-1767.

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. 1999; 162((10)): 5853-9.

Dikov MM, Reich MB, Dworkin L, Thomas JW, Miller GG. A functional fibroblast growth factor-1 immunoglobulin fusion protein. J. Biol. Chem. 1998 Jun 6/19/1998; 273(25): 15811-7. PMID: 9624181, ISSN: 0021-9258.

Chu DM, Francis SH, Thomas JW, Maksymovitch EA, Fosler M, Corbin JD. Activation by autophosphorylation or cGMP binding produces a similar apparent conformational change in cGMP-dependent protein kinase. J. Biol. Chem. 1998 Jun 6/5/1998; 273(23): 14649-56. PMID: 9603983, ISSN: 0021-9258.

Tikhomirov OY, Thomas JW. Preference for IgG mAb binding insulin in solution or on surfaces is related to immunoglobulin variable region structures. J. Autoimmun. 1997 Dec; 10(6): 541-9. PMID: 9451593, PII: S0896-8411(97)90161-X, DOI: 10.1006/jaut.1997.0161, ISSN: 0896-8411.

Thomas JW, Kralick PM, Ewulonu UK. T cell-independent response to Brucella-insulin identifies a preimmune repertoire for insulin. J. Immunol. 1997 Sep 9/1/1997; 159(5): 2334-41. PMID: 9278323, ISSN: 0022-1767.

Tikhomirov OYu, Thomas JW. Restricted V gene repertoire in the secondary response to insulin in young BALB/c mice. J. Immunol. 1997 May 5/1/1997; 158(9): 4292-300. PMID: 9126991, ISSN: 0022-1767.

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. 1997; 340: 10-8.

Thomas JW, Kralick PM, Ewulonu UK. The T cell-independent response to Brucella-insulin identifies a preimmune repertoire for insulin. Journal of Immunology. 1997; 159: 2334-41.

Tikhomirov O. Yu. and Thomas JW. Preference for IgG mAb binding insulin in solution is related to immunoglobulin variable region structures. Journal of Autoimmunity. 1997; 10: 541-9.

Thomas JW, Hulbert C. Somatically mutated B cell pool provides precursors for insulin antibodies. J. Immunol. 1996 Jul 7/15/1996; 157(2): 763-71. PMID: 8752927, ISSN: 0022-1767.

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. 1996 Jun; 39(6): 914-22. PMID: 8651984, ISSN: 0004-3591.

Thomas, J.W. and Hulbert, C. Somatically mutated B cell pool provides precursors for insulin antibodies. Journal of Immunology. 1996; 157: 763-71.

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. 1996; 157: 4771-80.

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. 1995 Oct 10/15/1995; 155(8): 3904-11. PMID: 7561097, ISSN: 0022-1767.

Thomas JW, Hulbert C. Expression and regulation of clonally ignorant B cells. Ann. N. Y. Acad. Sci. 1995 Sep 9/29/1995; 764: 461-2. PMID: 7486566, ISSN: 0077-8923.

Mitchell HC, Thomas JW. VH gene structure predicts a large potential anti-insulin repertoire. Mol. Immunol. 1995 Apr; 32(5): 311-21. PMID: 7537854, PII: 016158909400159X, ISSN: 0161-5890.

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. 1995; 155: 3504-911.

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. 1995; Vol. II: 1503.

Mitchell HC and Thomas JW. VH gene structure predicts a large potential anti-insulin repertoire. Molecular Immunology. 1995; 32: 311-21.

Thomas JW and Hulbert C. Expression and regulation of clonally ignorant B cells. Annals of the New York Academy of Sciences. 1995; 764: 461-2.

Byrd VM, Zhao XM, Miller GG, Thomas JW. Detection of T cells responsive to a vascular growth factor in rheumatoid arthritis. Immunol. Res. 1994; 13(2-3): 139-44. PMID: 7539824, ISSN: 0257-277X.

Byrd VM, Zhao XM, Miller GG, Thomas JW. Detection of T cells responsive to a vascular growth factor in rheumatoid arthritis. Immunologic Research. 1994; 13: 139-44.

Miller G, Nepom GT, Reich MB, Thomas JW. Autoreactive T cells from a type I diabetic recognize multiple class II products. Hum. Immunol. 1993 Apr; 36(4): 219-26. PMID: 8340230, ISSN: 0198-8859.

Thomas JW. V region diversity in human anti-insulin antibodies. Preferential use of a VHIII gene subset. J. Immunol. 1993 Feb 2/15/1993; 150(4): 1375-82. PMID: 8432983, ISSN: 0022-1767.

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

Thomas J.W. V region diversity in human anti-insulin antibodies: preferential use of a VHIII gene subset. Journal of Immunology. 1993; 150: 1375-82.

Miller G, Nepom GT, Reich MB, and Thomas JW. Autoreactive T cells from a type I diabetic recognize multiple Class II products. Human Immunology. 1993; 36: 219-26.

Thomas JW. Anti-insulin and regulatory anti-idiotypic antibodies use the same germ-line VHIX gene. Eur. J. Immunol. 1992 Sep; 22(9): 2445-8. PMID: 1516630, DOI: 10.1002/eji.1830220938, ISSN: 0014-2980.

Thomas J.W. Anti-insulin and regulatory anti-idiotypic antibodies use the same germ-line VHIX gene. European Journal of Immunology. 1992; 22: 2445-8.

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

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. 1990; 144: 3091-8.

Karounos, D.G. and Thomas, J.W. Recognition of common islet antigens by autoantibodies from NOD mice and humans with IDDM. Diabetes. 1990; 139: 1085-90.