Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis.
Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis.
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DOI：
10.1021/acs.jproteome.6b00617
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发表时间：
2017-01-06
影响因子：
4.4
通讯作者：
Rosen, Antony
中科院分区：
文献类型：
--
作者：
Darrah, Erika;Kim, AeRyon;Zhang, Xi;Boronina, Tatiana;Cole, Robert N.;Fava, Andrea;Giles, Jon T.;Bingham, Clifton O., III;Chalmers, Michael J.;Griffin, Patrick R.;Sadegh-Nasseri, Scheherazade;Rosen, Antony
关键词：
自身抗原的蛋白水解可以改变正常的MHC II类抗原加工，并与自身免疫性疾病的诱导有关。许多自身抗原是蛋白酶颗粒酶B （GrB）的底物，但这种关联的机制意义尚不清楚。肽精氨酸脱亚胺酶4 （PAD4）是类风湿性关节炎（RA）患者自身抗体的常见靶标，也是GrB的底物。RA与特定的MHC II类等位基因密切相关，在RA患者的关节中发现GrB和PAD4水平升高，提示GrB可能通过RA相关的II类等位基因改变PAD4的表现。在这项研究中，利用互补的蛋白质组学和免疫学方法来确定GrB切割对PAD4结构、加工和免疫原性的影响。氢-氘交换和无细胞MHC II类抗原处理系统显示，GrB对PAD4的蛋白水解诱导了PAD4的离散结构变化，从而促进了几种能够刺激RA患者PAD4特异性CD4+ T细胞的免疫原性肽的呈递。这项工作证明了RA患者中存在pad4特异性T细胞，并支持GrB在增强自身抗原CD4+ T细胞表位呈递中的机制作用。
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.
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