T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin.

Content Provider	Semantic Scholar
Author	Congia, Mauro Patel, Sarju D. Cope, Andrew P. Virgiliis, Stefano De Sønderstrup, Grete
Copyright Year	1998
Abstract	Approximately one-half of Caucasians with newly diagnosed insulin-dependent diabetes mellitus (IDDM) have autoantibodies to insulin, and the majority of those express the HLA-DR4 genotype [Ziegler, R., Alper, C. A., Awdeh, Z. L., Castano, L., Brink, S. J., Soeldner, J. S., Jackson, R. A. & Eisenbarth, G. S. (1991) Diabetes 40, 709-714]. However, it has been difficult to demonstrate T cell proliferative responses to human insulin in IDDM patients [Durinovic-Bello, I., Hummel, M. & Ziegler, A. G. (1996) Diabetes 45, 795-800]. We have immunized transgenic mice expressing the susceptible HLA-DR (alpha1*0101,beta1*0401) (hereafter called DRB1*0401) and human CD4 molecules on a murine major histocompatibility complex class II null background, with human preproinsulin (PPI), proinsulin (PI), and insulin and derived large panels of T cell hybridomas to determine the immunogenic epitopes of these proteins. These results show that the prohormones PI or PPI carry the major immunogenic T cell epitope in the DRB1*0401 transgenic mice. The PPI/PI immunodominant epitope LALEGSLQK was localized at the C-peptide/A-chain junction. This T cell epitope PPI/PI LALEGSLQK is unusual because, normally, it is proteolytically destroyed during the maturation of the insulin molecule. Additionally, this T cell epitope is both processed and presented by human DRB1*0401-positive Epstein-Barr virus transformed B cells, and it can also stimulate T cells from the peripheral blood of HLA-DR4-positive patients with type 1 diabetes. These findings may partly explain why susceptibility to type 1 diabetes is associated with HLA-DR4-positive individuals and why T cell responses to the mature insulin protein are rarely detected in IDDM patients.
Starting Page	2173
Ending Page	2176
Page Count	4
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://www.pnas.org/content/95/7/3833.full.pdf
PubMed reference number	9520453v1
Volume Number	95
Issue Number	7
Journal	Proceedings of the National Academy of Sciences of the United States of America
Language	English
Access Restriction	Open
Subject Keyword	Biologic Development C-Peptide Chronic Lymphocytic Leukemia Diabetes Mellitus Diabetes Mellitus, Insulin-Dependent Epitopes Epstein-Barr Virus HLA Antigens HLA-DQ Antigens HLA-DR Antigens Histocompatibility Antigens Class II Hybridomas INS gene Isoelectric Point Leukemia, B-Cell Major Histocompatibility Complex Patients Proinsulin, human Proton Pump Inhibitors peripheral blood preproinsulin
Content Type	Text
Resource Type	Article