I Durinovic-Belló1, M Schlosser2, M Riedl3, N Maisel3, S Rosinger3, H Kalbacher4, M Deeg5, M Ziegler2, J Elliott6, B O Roep7, W Karges3, B O Boehm3. 1. Department of Internal Medicine I, Division of Endocrinology, University of Ulm, Robert-Koch Str. 8, 89081, Ulm, Germany. ivana.durinovic-bello@medizin.uni-ulm.de. 2. Institute of Pathophysiology Karlsburg, University of Greifswald, Greifswald, Germany. 3. Department of Internal Medicine I, Division of Endocrinology, University of Ulm, Robert-Koch Str. 8, 89081, Ulm, Germany. 4. Medical Scientific Center, University of Tübingen, Tübingen, Germany. 5. Section Transplantation Immunology Medical Clinic, University of Tübingen, Tübingen, Germany. 6. Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada. 7. Department of Immunohaematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Abstract
AIMS/HYPOTHESIS: Preproinsulin is a target T cell autoantigen in human Type 1 diabetes. This study analyses the phenotype and epitope recognition of preproinsulin reactive T cells in subjects with a high genetic risk of diabetes [HLA-DRB1*04, DQ8 with Ab+ (autoantibody-positive) or without islet autoantibodies (control subjects)], and in HLA-matched diabetic patients. METHODS: A preproinsulin peptide library approach was used to screen for cytokine profiles and epitope specificities in human peripheral blood lymphocytes, and CD4(+)CD45RA(-) and CD4(+)CD45RA(+) T cell subfractions, representing memory and naive and recently primed T cells respectively. RESULTS: In CD4(+) T cell subsets we identified immunodominant epitopes and cytokine production patterns that differed profoundly between patients, Ab+ subjects and non-diabetic HLA-matched control subjects. In Ab+ subjects, a C-peptide epitope C13-29 and insulin B-chain epitope B11-27 were preferentially recognised, whereas insulin-treated Type 1 diabetic patients reacted to native insulin and B-chain epitope B1-16. In peripheral blood lymphocytes of Ab+ subjects, an increase in T helper (Th) 1 (IFNgamma, IL-2) and Th2 (IL-4) cytokines was detectable, wheras in CD45RA(+) and CD45RA(-) subsets, IL-4 and IL-10 phenotypes dominated, compatible with the contribution of non-CD4 cells to IFNgamma content. In insulin-treated Type 1 diabetic patients, naive and recently primed CD4(+) cells were characterised by increasd IFNgamma, TNFalpha, and IL-5. CONCLUSIONS/ INTERPRETATION: Our data show that T cell reactivity to preproinsulin in CD45RA subsets is Th2-dominant in Ab+ subjects, challenging the Th1 paradigm in Type 1 diabetes. Characteristic immunodominant epitopes and cytokine patterns distinguish diabetic patients and Ab+ subjects from HLA-matched healthy individuals. This could prove useful in monitoring of T-cell immunity in clinical diabetes intervention trials.
AIMS/HYPOTHESIS: Preproinsulin is a target T cell autoantigen in humanType 1 diabetes. This study analyses the phenotype and epitope recognition of preproinsulin reactive T cells in subjects with a high genetic risk of diabetes [HLA-DRB1*04, DQ8 with Ab+ (autoantibody-positive) or without islet autoantibodies (control subjects)], and in HLA-matched diabeticpatients. METHODS: A preproinsulin peptide library approach was used to screen for cytokine profiles and epitope specificities in human peripheral blood lymphocytes, and CD4(+)CD45RA(-) and CD4(+)CD45RA(+) T cell subfractions, representing memory and naive and recently primed T cells respectively. RESULTS: In CD4(+) T cell subsets we identified immunodominant epitopes and cytokine production patterns that differed profoundly between patients, Ab+ subjects and non-diabeticHLA-matched control subjects. In Ab+ subjects, a C-peptide epitope C13-29 and insulin B-chain epitope B11-27 were preferentially recognised, whereas insulin-treated Type 1 diabeticpatients reacted to native insulin and B-chain epitope B1-16. In peripheral blood lymphocytes of Ab+ subjects, an increase in T helper (Th) 1 (IFNgamma, IL-2) and Th2 (IL-4) cytokines was detectable, wheras in CD45RA(+) and CD45RA(-) subsets, IL-4 and IL-10 phenotypes dominated, compatible with the contribution of non-CD4 cells to IFNgamma content. In insulin-treated Type 1 diabeticpatients, naive and recently primed CD4(+) cells were characterised by increasd IFNgamma, TNFalpha, and IL-5. CONCLUSIONS/ INTERPRETATION: Our data show that T cell reactivity to preproinsulin in CD45RA subsets is Th2-dominant in Ab+ subjects, challenging the Th1 paradigm in Type 1 diabetes. Characteristic immunodominant epitopes and cytokine patterns distinguish diabeticpatients and Ab+ subjects from HLA-matched healthy individuals. This could prove useful in monitoring of T-cell immunity in clinical diabetes intervention trials.
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