期刊
JOURNAL OF PROTEOME RESEARCH
卷 16, 期 1, 页码 355-365出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.6b00617
关键词
rheumatoid arthritis; peptidylarginine deiminase; shared epitope; autoimmunity; autoantigen; hydrogen-deuterium exchange; mass spectrometry; antigen pressing; antigen presentation; epitope
资金
- Jerome L. Greene Foundation
- Sibley Memorial Hospital Mackley Fund
- Johns Hopkins Arthritis Center Discovery Fund
- Camille Julia Morgan Arthritis Research and Education Fund
- Johns Hopkins Institute for Clinical and Translational Research [UL1 TR001079]
- National Institutes of Health [P30-AR053503, MH084512, GM084041, R01AI063764, R21AI101987]
Proteolysis of autoantigens can alter normal MHC class II antigen processing and has been implicated in the induction of autoimmune diseases. Many autoantigens are substrates for the protease granzyme B (GrB), but the mechanistic significance of this association is unknown. Peptidylarginine deiminase 4 (PAD4) is a frequent target of autoantibodies in patients with rheumatoid arthritis (RA) and a substrate for GrB. RA is strongly associated with specific MHC class II alleles, and elevated levels of GrB and PAD4 are found in the joints of RA patients, suggesting that GrB may alter the presentation of PAD4 by RA-associated class II alleles. In this study, complementary proteomic and immunologic approaches were utilized to define the effects of GrB cleavage on the structure, processing, and immunogenicity of PAD4. Hydrogen-deuterium exchange and a cell-free MHC class II antigen processing system revealed that proteolysis of PAD4 by GrB induced discrete structural changes in PAD4 that promoted enhanced presentation of several immunogenic peptides capable of stimulating PAD4-specific CD4+ T cells from patients with RA. This work demonstrates the existence of PAD4-specific T cells in patients with RA and supports a mechanistic role for GrB in enhancing the presentation of autoantigenic CD4+ T cell epitopes.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据