Pro- and anti-inflammatory cytokine production by autoimmune T cells against preproinsulin in HLA-DRB1*04, DQ8 Type 1 diabetes |
| |
| Authors: | Dr. I. Durinovic-Belló M. Schlosser M. Riedl N. Maisel S. Rosinger H. Kalbacher M. Deeg M. Ziegler J. Elliott B. O. Roep W. Karges B. O. Boehm |
| |
| Affiliation: | (1) Department of Internal Medicine I, Division of Endocrinology, University of Ulm, Robert-Koch Str. 8, 89081 Ulm, Germany;(2) Institute of Pathophysiology Karlsburg, University of Greifswald, Greifswald, Germany;(3) Medical Scientific Center, University of Tübingen, Tübingen, Germany;(4) Section Transplantation Immunology Medical Clinic, University of Tübingen, Tübingen, Germany;(5) Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada;(6) 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 (IFN , 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 IFN content. In insulin-treated Type 1 diabetic patients, naive and recently primed CD4+ cells were characterised by increasd IFN, TNF , 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.Abbreviations PPI Preproinsulin - PBMC peripheral blood mononuclear cells - Th T helper cells - Ab+ autoantibody-positive - ICA islet cell antibodies - IA-2A islet thyrosine phosphatase - SI stimulation index - Tr T regulatory cells W. Karges and B.O. Boehm contributed equally to this article |
| |
| Keywords: | Preproinsulin T cell subsets epitopes cytokines |
| 本文献已被 PubMed SpringerLink 等数据库收录！ |
|
