From HLA-B27 to spondyloarthritis: a journey through the ER.
From HLA-B27 to spondyloarthritis: a journey through the ER.
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DOI：
10.1111/j.0105-2896.2009.00865.x
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发表时间：
2010-01
影响因子：
8.7
通讯作者：
Layh-Schmitt G
中科院分区：
文献类型：
--
作者：
Colbert RA;DeLay ML;Klenk EI;Layh-Schmitt G
人类白细胞抗原-B27（HLA-B27）在脊柱关节炎易感性中的作用研究了近40年，尚未得出令人信服的答案。来自HLA-B27转基因大鼠模型的新结果现在非常令人信服地证明，CD 8 + T细胞不是炎性表型所必需的。HLA-B27重链在内质网（ER）中I类复合物的组装过程中具有错误折叠的倾向，并且在运输到细胞表面后形成异常的二硫键连接的二聚体，这一发现迫使人们产生关于其在疾病发病机制中的作用的新想法。在转基因大鼠中，HLA-B27错误折叠产生ER应激并导致未折叠蛋白反应（UPR）的激活，其显著增强响应于模式识别受体激动剂的白细胞介素-23（IL-23）的产生。这些发现导致在该动物模型中发现了显著的T辅助细胞17活化和扩增，这与从患有脊柱关节炎的人类中出现的结果以及IL 23 R作为强直性脊柱炎的额外易感基因的发现一致。总之，这些结果表明HLA-B27和辅助性T细胞17轴之间通过蛋白质错误折叠的后果的新联系，并开辟了新的研究途径，以及确定这组疾病的治疗干预的新靶点。
Almost four decades of research into the role of human leukocyte antigen-B27 (HLA-B27) in susceptibility to spondyloarthritis has yet to yield a convincing answer. New results from an HLA-B27 transgenic rat model now demonstrate quite convincingly that CD8+ T cells are not required for the inflammatory phenotype. Discoveries that the HLA-B27 heavy chain has a tendency to misfold during the assembly of class I complexes in the endoplasmic reticulum (ER) and to form aberrant disulfide-linked dimers after transport to the cell surface have forced the generation of new ideas about its role in disease pathogenesis. In transgenic rats, HLA-B27 misfolding generates ER stress and leads to activation of the unfolded protein response (UPR), which dramatically enhances the production of interleukin-23 (IL-23) in response to pattern recognition receptor agonists. These findings have led to the discovery of striking T-helper 17 cell activation and expansion in this animal model, consistent with results emerging from humans with spondyloarthritis and the discovery of IL23R as an additional susceptibility gene for ankylosing spondylitis. Together, these results suggest a novel link between HLA-B27 and the T-helper 17 axis through the consequences of protein misfolding, and open new avenues of investigation as well as identifying new targets for therapeutic intervention in this group of diseases.
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影响因子：
32.4
作者：
Dong, Gang;Wearsch, Pamela A.;Peaper, David R.;Cresswell, Peter;Reinisch, Karin M.
通讯作者：
Reinisch, Karin M.
影响因子：
9.8
作者：
Cargill, Michele;Schrodi, Steven J.;Begovich, Ann B.
通讯作者：
Begovich, Ann B.
适应和增加与错误折叠SP-C的本构表达相关的感染的敏感性。
影响因子：
7.8
作者：
Bridges, James P;Xu, Yan;Na, Cheng-Lun;Wong, Hector R;Weaver, Timothy E
通讯作者：
Weaver, Timothy E
影响因子：
4.8
作者：
Antoniou, AN;Ford, S;Powis, SJ
通讯作者：
Powis, SJ
影响因子：
29.4
作者：
DeVos, M;Mielants, H;Veys, E
通讯作者：
Veys, E