Nucleotide sequencing of psoriatic arthritis tissue before and during methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest they drive the inflammatory process by recognizing autoantigens
Nucleotide sequencing of psoriatic arthritis tissue before and during methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest they drive the inflammatory process by recognizing autoantigens
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DOI：
10.4049/jimmunol.172.3.1935
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发表时间：
2004-02-01
影响因子：
4.4
通讯作者：
Winchester, R
中科院分区：
文献类型：
--
作者：
Curran, SA;FitzGerald, OM;Winchester, R
银屑病关节炎是一种有趣的MHC I类等位基因相关自身免疫性疾病，其损伤可能完全由T细胞介导。我们使用TCR β链核苷酸测序来深入了解导致这种损伤的适应性免疫事件，并确定这种疾病的众多寡克隆扩增是否代表了识别自身抗原的驱动克隆中的极端决定性扩散，还是非ag驱动的炎症相关扩增。由于甲氨蝶呤抑制但不能消除这种炎症，我们假设在甲氨蝶呤治疗期间持续存在的克隆可能会导致炎症。活性组织中76%的T细胞克隆是多克隆和未扩增的，占转录本的31%。甲氨蝶呤大大降低了它们的含量。引人注目的是，炎症关节中的大多数扩增克隆在甲氨蝶呤治疗期间没有持续存在，仅在炎症部位发现，彼此没有结构同源性，并且谱系中要么是CD4，要么是CD8，这表明它们是非自身抗原驱动的炎症相关扩增。扩增的克隆中只有12%的克隆组可以被归类为结构上同源的CDR3 β链氨基酸基序，提示Ag驱动。它们在谱系中仅为CD8，在给予甲氨蝶呤期间持续存在，并且存在于关节液和血液中，这表明它们是识别自身抗原的候选驱动克隆。然而，一组假定的驱动克隆表现出先前描述的ebv特异性β链基序，强调该疾病的主要特征是多个克隆的激活，显然缺乏对刺激性自身抗原的特异性。
Psoriatic arthritis is an interesting MHC class I allele associated autoimmune disease where injury is likely mediated exclusively by T cells. We used TCR beta-chain nucleotide sequencing to gain insight into the adaptive immune events responsible for this injury and determine whether the numerous oligoclonal expansions of this disease represent extreme determinant spreading among driving clones that recognize autoantigen or were non-Ag-driven, inflammation-related expansions. Because methotrexate suppresses but does not eliminate this inflammation, we hypothesized that clones persisting during methotrexate treatment would likely drive the inflammation. Seventy-six percent of the T cell clones in active tissue were polyclonal and unexpanded, accounting for 31 % of transcripts. They were decreased greatly by methotrexate. Strikingly, most expanded clones in the inflamed joint did not persist during methotrexate treatment, were found only in inflammatory sites, exhibited no structural homology to one another, and were either CD4 or CD8 in lineage, suggesting they were non-autoantigen-driven, inflammation-related expansions. Only 12% of the expanded clones could be grouped into clonal sets distinguished by structurally homologous CDR3 beta-chain amino acid motifs suggesting Ag drive. These were exclusively CD8 in lineage, persisted during methotrexate administration, and were present in both joint fluid and blood implying they were candidate driver clones that recognized an autoantigen. However, a major set of putative driver clones exhibited a previously described EBV-specific beta-chain motif, emphasizing that the dominant feature of the disease was activation of multiple clones apparently lacking specificity for an inciting autoantigen.