Systemic and Local Interleukin-17 and Linked Cytokines Associated with Sjogren's Syndrome Immunopathogenesis
Systemic and Local Interleukin-17 and Linked Cytokines Associated with Sjogren's Syndrome Immunopathogenesis
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DOI：
10.2353/ajpath.2009.090319
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发表时间：
2009-09-01
影响因子：
6
通讯作者：
Wahl, Sharon M.
中科院分区：
文献类型：
--
作者：
Katsifis, Gikas E.;Rekka, Sofia;Wahl, Sharon M.
Th 17细胞作为一种独特的CD 4（+）辅助性T细胞（Th）谱系，参与了宿主对感染的应答和自身免疫性疾病的发病机制。这种细胞因子与原发性干燥综合征（pSS）免疫病理学有关，因为pSS中循环白细胞介素（IL）-17水平升高。因此，通过免疫组织化学、RT-PCR和微珠测定法，对pSS患者的血浆和小唾液腺（MSG）中的CD 4（+）T细胞、T调节细胞、IL-17和支持细胞因子进行了评价。来自pSS患者的MSG含有IL-17表达细胞作为炎性病变内的优势群体。IL-17蛋白表达随着活检病灶评分的升高而逐渐增加（P < 0.0001），与RT-PCR检测结果平行。与对照组织中的量相比，发现转化生长因子-β、IL-6和IL-23（其是Th 17分化的必要启动子）的丰度。虽然转化生长因子-β也是免疫抑制性Foxp 3（+）T调节细胞（T细胞）的关键分化因子，但Foxp 3（+）T细胞的增加在轻度和中度炎症的活检标本中是明显的，但这种增加与晚期疾病中促炎性Th 17群体的升级不成比例。此外，Th 17中心细胞因子IL-17、IL-6、IL-23和IL-12在pSS血浆中显著升高。这些数据确定了在患病的pSS MSG内大量的IL-17生成细胞和支持细胞因子，而没有免疫调节性T细胞的代偿性增加;这种不平衡似乎促进了致病环境，其可能是浸润性损伤的病因和预测因素，并且适合于治疗干预。(Am J Pathol 2009，175：1167-1177; DOI：10.2353/ajpath.2009.090319）
Recently recognized as a distinct CD4(+) T helper (Th) lineage, Th17 cells have been implicated in host responses to infections and in pathogenesis associated with autoimmune diseases. This cytokine is implicated in primary Sjogren's syndrome (pSS) immunopathology because of the increased levels of circulating interleukin (IL)-17 in pSS. Plasma and minor salivary glands (MSGs) from patients with pSS were therefore evaluated for CD4(+) T cells, T regulatory cells, IL-17, and supporting cytokines by immunohistochemistry, RT-PCR, and microbead assays. MSGs from pSS patients contain IL-17-expressing cells as a dominant population within inflammatory lesions. IL-17 protein expression progressively increased with higher biopsy focus scores (P < 0.0001), in parallel with detection by RT-PCR. Transforming growth factor-beta, IL-6 and IL-23, which are requisite promoters of Th17 differentiation, were found in abundance compared with the amounts in control tissues. Although transforming growth factor-beta is also a pivotal differentiation factor for immunosuppressive Foxp3(+) T regulatory cells (Tregs), an increase in Foxp3(+) Tregs was evident in biopsy specimens with mild and moderate inflammation but this increase was disproportionate to escalating pro-inflammatory Th17 populations in advanced disease. Furthermore, the Th17-centric cytokines IL-17, IL-6, IL-23, and IL-12 were significantly elevated in pSS plasma. These data identify a profusion of IL-17-generating cells and supporting cytokines within diseased pSS MSGs without a compensatory increase in immunomodulatory Tregs; this imbalance seems to foster a pathogenic milieu that may be causative and predictive of infiltrative injury and amenable to therapeutic intervention. (Am J Pathol 2009, 175:1167-1177; DOI: 10.2353/ajpath.2009.090319)