HLA-DR1001 presents "altered-self" peptides derived from joint-associated proteins by accepting citrulline in three of its binding pockets.
HLA-DR1001 presents "altered-self" peptides derived from joint-associated proteins by accepting citrulline in three of its binding pockets.
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DOI：
10.1002/art.27594
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发表时间：
2010-10
影响因子：
--
通讯作者：
Kwok, William W.
中科院分区：
文献类型：
--
作者：
James, Eddie A.;Moustakas, Antonis K.;Bui, John;Papadopoulos, George K.;Bondinas, George;Buckner, Jane H.;Kwok, William W.
HLA-DRB1*1001(DR1001)是类风湿性关节炎的共同表位等位基因。这项研究的目的是评估DR1001在其结合口袋中容纳瓜氨酸的能力，并鉴定来自联合结合蛋白的瓜氨酸T细胞表位。测定了含有瓜氨酸、精氨酸和其他氨基酸取代基的多肽衍生物的结合力。然后开发了一种预测算法来从瓜氨酸化时优先与DR1001结合的关节相关蛋白中识别含有精氨酸的序列。这些序列的未经修饰和瓜氨酸版本被合成并用于刺激来自健康受试者和类风湿性关节炎患者的CD4+T细胞。通过MHC-II类四聚体染色检测应答，并通过分离CD4+T细胞克隆来确认应答。DR1001的三个固定口袋可以接受瓜氨酸，但不能接受精氨酸。预测算法识别出优先与DR1001结合的序列，其中精氨酸被瓜氨酸取代。这些序列中有三个激发了CD4+T细胞反应。针对这些序列的T细胞克隆只有在对瓜氨酸肽有反应时才会增殖。精氨酸转化为瓜氨酸会产生可被DR1001结合和呈递的“改变自我”的多肽。对这些多肽的反应涉及相应的蛋白(纤维蛋白原α、纤维蛋白原β和软骨中间层蛋白)作为相关抗原。对瓜氨酸序列的优先反应表明，这种翻译后修饰引起的肽结合亲和力的改变可能是类风湿关节炎发生或发展的一个重要因素。因此，测量对这些多肽的反应性可能有助于免疫监测。
HLA-DRB1*1001 (DR1001) is a shared epitope allele associated with rheumatoid arthritis. The objectives of this study were to assess the capacity of DR1001 to accommodate citrulline in its binding pockets and to identify citrullinated T cell epitopes derived from joint associated proteins. The binding of peptide derivatives containing citrulline, arginine, and other amino acid substitutions was measured. A prediction algorithm was then developed to identify arginine containing sequences from joint associated proteins that preferentially bind to DR1001 upon citrullination. Unmodified and citrullinated versions of these sequences were synthesized and utilized to stimulate CD4+ T cells from healthy subjects and rheumatoid arthritis patients. Responses were measured by MHC class II tetramer staining and confirmed by isolating CD4+ T cell clones. DR1001 accepted citrulline, but not arginine in three of its anchoring pockets. The prediction algorithm identified sequences that preferentially bound to DR1001 with arginine replaced by citrulline. Three of these sequences elicited CD4+ T cell responses. T cell clones specific for these sequences proliferated only in response to citrullinated peptides. Conversion of arginine to citrulline generates ‘altered-self’ peptides that can be bound and presented by DR1001. Responses to these peptides implicate the corresponding proteins (fibrinogen α, fibrinogen β and cartilage intermediate layer protein) as relevant antigens. Preferential responses to citrullinated sequences suggests that altered peptide binding affinity due to this post-translational modification may be an important factor in the initiation or progression of RA. As such, measuring responsiveness to these peptides may be useful for immune monitoring.
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影响因子：
56.9
作者：
Fremont, DH;Hendrickson, WA;Kappler, J
通讯作者：
Kappler, J
影响因子：
15.9
作者：
Novak, EJ;Liu, AW;Kwok, WW
通讯作者：
Kwok, WW
影响因子：
--
作者：
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通讯作者：
Jaraquemada, Dolores
影响因子：
5.4
作者：
JONES, CM;LAKE, RA;FAITH, A
通讯作者：
FAITH, A
影响因子：
7.2
作者：
Liu, GY;Liao, YF;Hung, HC
通讯作者：
Hung, HC