Etiology of autoimmune thyroiditis and diabetes
Postdoctoral Fellow: Angela Lombardi, Cheuk wun Li
Research Personnel: Erlinda Concepcion, Mihaela Stefan,
Summary of Research Studies:
The laboratory of Dr. Tomer studies the mechanisms leading to the development of autoimmune thyroiditis and diabetes. Current projects include: (1) Genetic and epigenetic studies in thyroid autoimmunity. The Tomer lab discovered that the presence of arginine at position 74 of the peptide binding groove of HLA-DR is critical for disease susceptibility. In collaboration with Dr. Osman's group from the Department Structural and Chemical biology they identified a specific HLA-DR pocket structure that is associated with thyroid autoimmunity. The group is now analyzing which immunogenic peptides can bind to these pockets and induce thyroid autoimmunity, since blocking these peptides from binding to the DR pockets can be used as a novel therapeutic approach. Dr. Tomer’s group also identified several non-MHC genetic polymorphisms that are associated with thyroid autoimmunity including variants in the CD40 and thyroglobulin genes. Current studies focus on the genetic and epigenetic mechanisms, by which these variants contribute to disease. The group is using tissue cultures to examine the effects of genetic variants on gene regulation and splicing, as well as transgenic and chimeric mouse models. (2) Genetic analysis of autoimmune (type 1) diabetes and thyroiditis. The Tomer lab is analyzing genes that confer shared susceptibility to the development of type 1 diabetes and autoimmune thyroiditis in the same individual. The lab has shown that the CTLA-4 and FOXP3 genes play a major role in this shared susceptibility and they are currently studying the mechanisms by which these genes predispose to both diseases. In addition the group is mapping additional genes conferring this shared susceptibility. (3) Environmental factors and thyroid autoimmunity. It is well known that certain infections, specifically hepatitis C, are associated with thyroid autoimmunity. In addition, interferon alpha therapy of hepatitis C can cause thyroiditis in a significant percentage of patients. Using tissue cultures and mouse models Dr. Tomer’s lab is studying the mechanisms by which hepatitis C infection, and interferon alpha therapy cause thyroiditis.
Li CW, Menconi F, Osman R, Mezei M, Jacobson EM, Concepcion E, David CS, Kastrinsky DB, Ohlmeyer M, Tomer Y. Identifying a small molecule blocking antigen presentation in autoimmune thyroiditis. The Journal of biological chemistry 2015 Dec;.
Lipner EM, Tomer Y, Noble JA, Monti MC, Lonsdale JT, Corso B, Greenberg DA. Linkage Analysis of Genomic Regions Contributing to the Expression of Type 1 Diabetes Microvascular Complications and Interaction with HLA. Journal of diabetes research 2015 Oct; 2015.
Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and Hepatitis C: A Two-Way Association. Frontiers in endocrinology 2015 Sep; 6.
Lee HJ, Li CW, Hammerstad SS, Stefan M, Tomer Y. Immunogenetics of autoimmune thyroid diseases: A comprehensive review. Journal of autoimmunity 2015 Jul;.
Tomer Y, Dolan LM, Kahaly G, Divers J, D'Agostino RB, Imperatore G, Dabelea D, Marcovina S, Black MH, Pihoker C, Hasham A, Hammerstad SS, Greenberg DA, Lotay V, Zhang W, Monti MC, Matheis N. Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. Journal of autoimmunity 2015 Apr;.
Li CW, Concepcion E, Tomer Y. Dissecting the role of the foxp3 gene in the joint genetic susceptibility to autoimmune thyroiditis and diabetes: A genetic and functional analysis. Gene 2014 Dec;.
Lombardi A, Barlow Inabnet W, Owen R, Ellen Farenholtz K, Tomer Y. ENDOPLASMIC RETICULUM STRESS AS A NOVEL MECHANISM IN AMIODARONE-INDUCED DESTRUCTIVE THYROIDITIS. The Journal of clinical endocrinology and metabolism 2014 Oct;.
Stefan M, Wei C, Lombardi A, Li CW, Concepcion ES, Inabnet WB, Owen R, Zhang W, Tomer Y. Genetic-epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity. Proceedings of the National Academy of Sciences of the United States of America 2014 Aug; 111(34): 12562-12567.
Villano MJ, Huber AK, Greenberg DA, Golden BK, Concepcion E, Tomer Y. Autoimmune thyroiditis and diabetes: Dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocrinol Metab 2009; 94: 1458-1466.
Akeno N, Blackard JT, Tomer Y. HCV E2 protein binds directly to thyroid cells and induces IL-8 production: A new mechanism for HCV induced thyroid autoimmunity. J Autoimmun 2008; 31: 339-344.
Huber A, Menconi F, Corathers S, Jacobson EM, Tomer Y. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis; From epidemiology to mechanisms. Endocr Rev 2008; 29: 697-725.
Ban Y, Greenberg DA, Davies TF, Jacobson E, Concepcion E, Tomer Y. Linkage analysis of thyroid antibody production: Evidence for shared susceptibility to clinical autoimmune thyroid disease. J Clin Endocrinol Metab 2008; 93: 3589-3596.
Menconi F, Monti MC, Greenberg DA, Oashi T, Osman R, Davies TF, Ban Y, Jacobson EM, Concepcion ES, Li CW, Tomer Y. Molecular amino acid signatures in the MHC class II peptide binding pocket predispose to autoimmune thyroiditis in humans and in mice.. Proc Natl Acad Sci USA 2008; 105: 14034-14039.