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George Eisenbarth, M.D., Ph.D.

Genetics of diabetes mellitus and endocrine autoimmune disorders


 

The main focus of our laboratory is to understand the pathogenesis of autoimmune endocrine disorders and to develop the means to predict and prevent type 1 diabetes mellitus. Our studies focus on a major animal model of type 1 diabetes, namely the NOD mouse, and on families with the disorder. Type 1 diabetes is associated in families with a number of autoimmune disorders, including celiac disease, thyroid disease, and Addison's disease. The major genetic determinant of these disorders is genes within the major histocompatibility complex. Genes outside of this complex are also important. Our working hypothesis is that immune response genes within the major histocompatibility complex determine organ targeting while non-MHC genes are associated with more general abnormalities of immune function. These abnormalities of immune function lead to increased susceptibility to multiple disorders. It is likely that in different families with type 1 diabetes different non-MHC genes will underlie disease susceptibility.

At present with a combination of HLA typing and determination of anti-islet autoantibodies risk for type 1 diabetes, celiac disease and Addison's disease is predictable. It is likely that genetic prediction will be improved as non-MHC genetic loci are defined. It is also likely that the major determinants of disease are T lymphocytes, and detailed study of MHC, peptide presented by MHC molecules, and the T cell receptors of autoreactive lymphocytes will improve disease prediction. In animal models, insulin appears to be a very important target molecule, and peptides of insulin are recognized by pathogenic as well as protective T lymphocytes. The genetic control of responses to insulin peptides is a major area of current investigation.

 

Publications

Eisenbarth, GS, P Wilson, F Ward, HE Lebovitz. HLA type and disease occurrence in familial polyglandular failure. New Engl J Med 298:92 94, 1978.

Eisenbarth, GS, R Walsh, M Nirenberg. Monoclonal antibody to a plasma membrane antigen of neurons. Proc Natl Acad Sci (USA) 76:4913 4917, 1979.

Jackson, RA, MA Morris, BF Haynes, GS Eisenbarth. Increased circulating Ia antigen bearing T cells in Type I diabetes mellitus. New Engl J Med 306:785 788, 1982.

Srikanta, S, OP Ganda, GS Eisenbarth, JS Soeldner. Islet cell antibodies and beta cell function in monozygotic triplets and twins initially discordant for Type I diabetes mellitus. New Engl J Med 308:322 325, 1983.

Srikanta, S, OP Ganda, JS Soeldner, GS Eisenbarth. First degree relatives of patients with Type I diabetes mellitus: Islet cell antibodies and abnormal insulin secretion. New Engl J Med 313:461 464, 1985.

Hattori, M, JB Buse, RA Jackson, L Glimcher, S Makino, K Moriwaki, M Korff, M Minami, H Kuzuya, H Imura, JG Seidman, GS Eisenbarth. The NOD mouse: Recessive diabetogenic gene within the major histocompatibility complex. Science 231:733 735, 1986.

Kaye, WA, MNS Adri, JS Soeldner, SL Rabinowe, CR Kahn, B Bistrian, S Srikanta, OP Ganda, GS Eisenbarth. Acquired interleukin 2 production defect in patients with Type I diabetes mellitus. New Engl J Med 315:920 924, 1986.

Pietropaolo, M, L Castaño, S Babu, R Buelow, S Martin, A Martin, A Powers, M Prochazka, J Naggert, EH Leiter, GS Lipes, MA, A Rosenzweig, KN Tan, G Tanigawa, D Ladd, JG Seidman, GS Eisenbarth. Progression to diabetes in nonobese diabetic (NOD) mice with transgenic T cell receptors. Science 259:1165 1169, 1993.

Rewers, M, TL Bugawan, JM Norris, A Blair, B Beaty, M Hoffman, RS McDuffie, RF Hamman, G Klingensmith, GS Eisenbarth, and HA Erlich. Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 39:807-812, 1996.

Verge, CF, R Gianani, L Yu, M Pietropaolo, RA Jackson, HP Chase, GS Eisenbarth. Prediction of type I diabetes in first degree relatives using a combination of insulin, glutamic acid decarboxylase and ICA512 autoantibodies. Diabetes 45:926-933, 1996.

Simone E, D Daniel, N Schloot, P Gottlieb, S Babu, E Kawasaki, D Wegmann, GS Eisenbarth. T cell receptor restriction of diabetogenic autoimmune NOD T cells. Proc Natl Acad Sci (USA) 94:2518-2521, 1997.

Pugliese A, M Zeller, A Fernandez, LJ Zalcberg, RJ Bartlett, C Ricordi, M Pietropaolo, GS Eisenbarth, ST Bennett, DD Patel. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the IDDM2 susceptibility locus for type I diabetes. Nature Genetics 15:293-297, 1997.

Verge C, P Vardi, S Babu, H Erlich, T Bugawan, L Yu, GS Eisenbarth, PR Fain. Evidence for oligogenic inheritance of type 1A diabetes in a large Bedouin Arab family. J Clin Invest 102(8):1569-1575, 1998.

Yu L KW Brewer S Gates, A Wu, T Wang, SR Babu, PA Gottlieb, BM Freed, J Noble, HA Erlich, MJ Rewers, GS Eisenbarth. DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison’s disease. J Clin Endocrinol Metab 84:328-335, 1999.

Redondo M, M Rewers, L Yu, S Garg, CC Pilcher, RB Elliott, GS Eisenbarth. Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study. BMJ 318:698-702, 1999.

L Yu, D Robles, N Abiru, P Kaur, M Rewers, K Keleman, and GS Eisenbarth. Early expression of anti-insulin autoantibodies of man and the NOD mouse: evidence for early determination of subsequent diabetes. Proc Natl Acad Sci 97:1701-1706, 2000.

KW Wucherpfennig, GS Eisenbarth: Type 1 Diabetes. Nature Immunology 2:1-3, 2001

N Abiru, AK Maniatis, L Yu, D Miao, H Moriyama, D Wegmann, GS Eisenbarth. Peptide and major histocompatibility complex-specific breaking of humoral tolerance to native insulin with the B9-23 peptide in diabetes-prone and normal mice. diab 50:1274-1281, 2001

A Pugliese, D Brown, D Garza, M Zeller, MJ Redondo, GS Eisenbarth, DD Patel, and C Ricordi. Self-Antigen Presenting Cells Expressing Islet Cell Molecules in Human Thymus and Peripheral Lymphoid Organs: Phenotypic Characterization and Implications for Immunological Tolerance and Type 1 Diabetes. J Clin Invest 107:555-564, 2001.

H Moriyama, L Wen, N Abiru, E Liu, L Yu, D Miao, R Gianani, FS Wong, GS Eisenbarth. Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide. Proc Natl Acad Sci U S A 99:5539-5544, 2002.

E Liu, H Moriyama, N Abiru, D Miao, L Yu, RM Taylor, F Finkelman, GS Eisenbarth. Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9-23 and B:13-23. J Clin Invest 110:1021-1027, 2002.

H Moriyama, N Abiru, J Paronen, K Sikora, E Liu, D Miao, D Devendra, J Belike, R Gianani, RG Gill, and GS Eisenbarth. Evidence for a primary islet autoantigen (preproinsulin 1 ) of the NOD mouse. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10376-81.

E Liu, H Moriyama, J Paronen, N Abiru, D Miao, L Yu, RM Taylor, and GS Eisenbarth. Nondepleting anti-CD4 monoclonal antibody prevents diabetes and blocks induction of insulin autoantibodies following insulin peptide B:9-23 immunization in the NOD mouse. Journal of Autoimmunity 2003;21(3):213-219.

Norris JM, Barriga K, Klingensmith G, Hoffman M, Eisenbarth GS, Erlich HA, Rewers M: Timing of cereal exposure in infancy and risk of islet autoimmunity. JAMA 290:1713-1720, 2003.

Hutton JC, Eisenbarth, GS. A pancreatic (beta)-cell-specific homolog of glucose-6-phosphatase emerges as a major target of cell-mediated autoimmunity in diabetes. Proc Natl Acad Sci USA 100:86826-8628, 2003.

Hoffenberg EJ, Mackenzie T, Barriga KJ, Eisenbarth GS, Bao F, Haas JE, Erlich H, Bugawan TI T, Sokol RJ, Taki I, Norris JM, Rewers M: A prospective study of the incidence of childhood celiac disease. J Pediatr 143/3: 308-314, 2003.

Robles DT, Eisenbarth GS, Dailey NJ, Peterson LB, Wicker LS: Insulin autoantibodies are associated with islet inflammation but not always related to diabetes progression in NOD congenic mice. Diabetes 52:882-886, 2003.

Tiberti C, Bao F, Bonamico M, Verrienti A, Picarelli A, DiTola M, Ferri M, Vecci E, Dotta F, Eisenbarth GS, DiMario U: Celaic disease-associated transglutaminase autoantibody target domains at diagnosis are age and sex dependent. Clinical Immunology 109:318-324, 2003.

Eisenbarth GS, Kotzin BL. Enumerating autoreactive T cells I peripheral blood: a big step in diabetes prediction. J. Clin Invest 111:1-4, 2003.

Stene LC, Barriga KJ, Norris JM, Hoffman M, Klingensmith G, Erlich HA, Eisenbarth GS, Rewers M: Pregnancy complications and development of islet autoimmunity in early childhood. The Diabetes Autoimmunity Study in the Young (DAISY). J Epidemiology. In press

Paronen,J.; Liu,E.; Moriyama,H.; Devendra,D.; Ide,A.; Taylor,R.; Yu,L; Miao,D.; Melanitou,E.; Eisenbarth,G.S. Genetic differentiation of Poly:IC from B:9-23 peptide induced experimental autoimmune diabetes. Journal of Autoimmunity, In Press

Eisenbarth, G.S. Genetic Counseling for Autoimmune Type 1 Diabetes in Therapy for Diabetes Mellitus and Related Disorders, Lebovitz, H. ed, American Diabetes Association, 2004 In Press

Bottini N; Muscumeci L; Alonso A; Rahmouni S; Nika K; Rostamkhari M; MacMurray,J; Meloni,GF; Lucarelli,P; Pellechia,M; Eisenbarth,GS; Comings,D; Mustelin,T Nature Genetics 36: 337-338, 2004.

Eisenbarth GS, Gottlieb P. Autoimmune Polyendocrine Syndromess. New Engl J Med, In Press May 2004.

Barker J, Goehrig SH, Barriga K, Hoffman M, Slover R, Eisenbarth G, Norris J, Klingensmith GJ, and Rewers M. Clinical Characteristics of Type 1 Diabetic Children Identified by a Genetic Screening and Intensive Follow-up Program. Diabetes Care, In Press 2004.

Stanley HM, Norris JM, Barriga K, Hoffman M, Yu L, Miao D, Erlich HA, Eisenbarth GS, Rewers M. Is presence of islet autoantibodies at birth associated with development of persistent islet autoimmunity? The Diabetes Autoimmunity Study in the Young (DAISY). Diabetes Care. 2004 Feb;27(2):497-502.

Paronen,J.; Liu,E.; Moriyama,H.; Devendra,D.; Ide,A.; Taylor,R.; Yu,L; Miao,D.; Melanitou,E.; Eisenbarth,GS. Genetic differentiation of Poly:IC from B:9-23 peptide induced experimental autoimmune diabetes. Journal of Autoimmunity, 2004 22:307-313.

Redondo,M.J.; Fain,PR; Krischer,J; Yu,L; Cuthbertson,D; Winter,WE; Eisenbarth,GS. Expression of beta-cell autoimmunity does not differ between dizygotic twins and siblings of patients with type I diabetes. Journal of Autoimmunity, 2004 In Press

Yu J, Ho Shin C, Yang SW, Park M, Eisenbarth GS. Analysis of Children with Type 1 Diabetes in Korea: High Prevalence of Specific Anti-Islet Autoantibodies, Immunogenetic Similarities to Wester Populations with "Unique" Haplotypes, and Lack of Discrimination by Aspartic Acid at Population 57 of DQB. Clinical Immunology. 2004 In Press

Eisenbarth, GS and Gottlieb,P Autoimmune Polyendocrine Syndromes, New England J Med, 2004, 350:36-47

Links

Barbara Davis Center for Childhood Diabetes