Turner Matthew J, Sowders Dawn P, DeLay Monica L, Mohapatra Rajashree, Bai Shuzhen, Smith Judith A, Brandewie Jaclyn R, Taurog Joel D, Colbert Robert A
William S. Rowe Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
J Immunol. 2005 Aug 15;175(4):2438-48. doi: 10.4049/jimmunol.175.4.2438.
The mechanism by which the MHC class I allele, HLA-B27, contributes to spondyloarthritis pathogenesis is unknown. In contrast to other alleles that have been examined, HLA-B27 has a tendency to form high m.w. disulfide-linked H chain complexes in the endoplasmic reticulum (ER), bind the ER chaperone BiP/Grp78, and undergo ER-associated degradation. These aberrant characteristics have provided biochemical evidence that HLA-B27 is prone to misfold. Recently, similar biochemical characteristics of HLA-B27 were reported in cells from HLA-B27/human beta2-microglobulin transgenic (HLA-B27 transgenic) rats, an animal model of spondyloarthritis, and correlated with disease susceptibility. In this study, we demonstrate that the unfolded protein response (UPR) is activated in macrophages derived from the bone marrow of HLA-B27 transgenic rats with inflammatory disease. Microarray analysis of these cells also reveals an IFN response signature. In contrast, macrophages derived from premorbid rats do not exhibit a strong UPR or evidence of IFN exposure. Activation of macrophages from premorbid HLA-B27 transgenic rats with IFN-gamma increases HLA-B27 expression and leads to UPR induction, while no UPR is seen in cells from nondisease-prone HLA-B7 transgenic or wild-type (nontransgenic) animals. This is the first demonstration, to our knowledge, that HLA-B27 misfolding is associated with ER stress that results in activation of the UPR. These observations link HLA-B27 expression with biological effects that are independent of immunological recognition, but nevertheless may play an important role in the pathogenesis of inflammatory diseases associated with this MHC class I allele.
主要组织相容性复合体（MHC）I类等位基因HLA - B27促成脊柱关节炎发病机制的具体方式尚不清楚。与其他已检测的等位基因不同，HLA - B27倾向于在内质网（ER）中形成高分子量的二硫键连接的重链复合物，结合ER伴侣BiP/Grp78，并经历内质网相关降解。这些异常特征提供了生化证据，表明HLA - B27易于错误折叠。最近，在脊柱关节炎动物模型HLA - B27/人β2-微球蛋白转基因（HLA - B27转基因）大鼠的细胞中也报道了HLA - B27的类似生化特征，且与疾病易感性相关。在本研究中，我们证明在患有炎症性疾病的HLA - B27转基因大鼠骨髓来源的巨噬细胞中，未折叠蛋白反应（UPR）被激活。对这些细胞的微阵列分析还揭示了一种IFN反应特征。相比之下，来自未发病大鼠的巨噬细胞没有表现出强烈的UPR或IFN暴露的证据。用IFN - γ激活未发病的HLA - B27转基因大鼠的巨噬细胞会增加HLA - B27的表达并导致UPR诱导，而在不易患疾病的HLA - B7转基因或野生型（非转基因）动物的细胞中未观察到UPR。据我们所知，这是首次证明HLA - B27错误折叠与ER应激相关，ER应激导致UPR激活。这些观察结果将HLA - B27的表达与独立于免疫识别的生物学效应联系起来，但仍可能在与该MHC I类等位基因相关的炎症性疾病发病机制中发挥重要作用。
