Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients.
Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients.
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DOI：
10.1002/art.30445
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发表时间：
2011-10
影响因子：
--
通讯作者：
Buckner, Jane H.
中科院分区：
文献类型：
--
作者：
Snir, Omri;Rieck, Mary;Gebe, John A.;Yue, Betty B.;Rawlings, Crystal A.;Nepom, Gerald;Malmstrom, Vivianne;Buckner, Jane H.
针对滑膜抗原波形蛋白的瓜氨酸化形式的抗体对类风湿性关节炎（RA）具有特异性，并与HLA DRB 1 *0401相关。这表明，对HLA-DRB 1 *0401背景下的瓜氨酸波形蛋白衍生肽特异的T细胞可能有助于RA的发病机制。在这里，我们的目的是确定免疫显性表位从瓜氨酸波形蛋白提出的HLADRB 1 *0401和表征所产生的T细胞反应。我们首先基于DRB 1 *0401的结合基序预测瓜氨酸波形蛋白的HLA结合T细胞表位，然后证实其亲和力。构建了一种负载cit-vim 59 -78的MHC II类四聚体，并用于筛选DRB 1 *0401转基因小鼠、RA患者和健康对照中的特异性T细胞。此外，通过流式细胞术和基于Luminex的分析，在患者和健康受试者中分析cit-vim 59 -78激发后的细胞因子输出。瓜氨酸化形式的vim 59 -78与HLA-DRB 1 *0401结合，而天然形式不能。随后，使用MHC II类四聚体、CD 154上调和细胞内细胞因子测量，在免疫小鼠和HLA-DR*0401健康对照和RA受试者的外周中检测cit-vim 59 -78特异性T细胞。与健康对照相比，细胞培养物上清液显示出细胞因子的产生增强，其中最突出的是响应于cit-vim 59 -78的来自RA衍生细胞的IFNγ。在这里，我们描述了一种翻译后修饰的RA候选自身抗原，对DRB 1 *0401限制性T细胞可以发现在RA患者和健康对照，但其中的促炎反应是唯一的发现与RA受试者。
Antibodies towards the citrullinated form of the synovial antigen vimentin are specific for rheumatoid arthritis (RA) and associated with HLADRB1*0401. This suggests that T cells specific for peptides derived from citrullinated-vimentin presented in the context of HLA-DRB1*0401 may contribute to the etiopathogenesis of RA. Here, we aimed to identify immunodominant epitopes from citrullinated-vimentin presented by HLADRB1*0401 and characterize the resulting T cell responses. We first predicted an HLA-binding T cell epitope from citrullinated vimentin based on the binding motif of DRB1*0401, and then confirmed its affinity. An MHC class-II tetramer loaded with cit-vim59-78 was constructed and used to screen for specific T cells in DRB1*0401 transgenic mice, RA patients and healthy controls. Additionally, the cytokine output following cit-vim59-78 challenge was analyzed in patients and healthy subjects by multicolor flow cytometry and luminex-based analysis. The citrullinated form of vim59-78 bound to HLA-DRB1*0401 while the native version could not. Subsequently, cit-vim59-78-specific T cells were detected in immunized mice and in the periphery of both HLA-DR*0401 healthy controls and RA subjects, using MHC class-II tetramers, CD154 upregulation and intracellular cytokine measurements. Cell culture supernatants demonstrated an enhanced production of cytokines, most prominent of which was IFNγ from RA-derived cells in response to cit-vim59-78 in comparison to healthy controls. Here, we describe a posttranslational modification of an RA candidate autoantigen towards which DRB1*0401-restricted, T cells can be found in both RA patients and healthy controls, but for which a proinflammatory response is uniquely found among subjects with RA.
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影响因子：
--
作者：
Lundstrom, Erneli;Kallberg, Henrik;Alfredsson, Lars;Klareskog, Lars;Padyukov, Leonid
通讯作者：
Padyukov, Leonid
影响因子：
--
作者：
James, Eddie A.;Moustakas, Antonis K.;Bui, John;Papadopoulos, George K.;Bondinas, George;Buckner, Jane H.;Kwok, William W.
通讯作者：
Kwok, William W.
影响因子：
15.9
作者：
Novak, EJ;Liu, AW;Kwok, WW
通讯作者：
Kwok, WW
影响因子：
14.8
作者：
Chattopadhyay, Pratip K.;Yu, Joanne;Roederer, Mario
通讯作者：
Roederer, Mario
DOI：
10.1073/pnas.95.13.7574
发表时间：
1998-06-23
影响因子：
11.1
作者：
Andersson, EC;Hansen, BE;Fugger, L
通讯作者：
Fugger, L