Pathogenic Mechanisms in Spondyloarthritis

脊柱关节炎的发病机制

基本信息

批准号：
8746517
负责人：
Robert Colbert
金额：
$ 287.56万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8746517
关键词：
Accounting Adolescent Adrenal Cortex Hormones Adult Affect Age Alleles Ankylosing spondylitis Arthritis Autophagocytosis Biological Biopsy Categories Cells Characteristics Child Childhood Chronic Chronic Childhood Arthritis Clinical Clinical Trials Collaborations Colon Crohn&apos s disease Cross-Sectional Studies Data Development Disease Drug usage Enrollment Excision Gene Expression Genes Goals HLA-B Antigens HLA-B27 Antigen HLA-B7 Antigen Health Status Heritability Homeostasis IL12B gene Immune Individual Inflammation Inflammatory Interferon Type II Interferon-beta Interferons Interleukin-1 Interleukin-17 International Joints Knowledge Lead Lesion Link Measures Mediating Modeling Molecular Molecular Immunology National Institute of Arthritis and Musculoskeletal and Skin Diseases Non-Steroidal Anti-Inflammatory Agents Onset of illness Osteoblasts Osteoclasts Osteogenesis Outcome Pain Pain intensity Paper Pathogenesis Pathway interactions Patients Peripheral Phenotype Physical Function Physicians Play Population Predisposition Production Proteins Psoriatic Arthritis Published Comment Publishing Rattus Refractory Registries Reporting Research Research Personnel Rheumatology Role STAT3 gene Series Spondylarthritis Stimulus Stress Symptoms System T-Lymphocyte TYK2 Tissue Sample Tissues Transgenic Model Transgenic Organisms Tumor Necrosis Factor-alpha Undifferentiated Up-Regulation Uveitis Variant Work Writing bone cell type cytokine disease characteristic gastrointestinal human TNF protein improved in vivo interleukin-22 interleukin-23 lymph nodes macrophage mineralization monocyte natural killer cell protein 44-kDa osteoclastogenesis overexpression protective effect protein misfolding response small molecule ward young adult

项目摘要

Pain and Health Status in ERA In collaboration with Pam Weiss (CHOP) and other Childhood Arthritis and Rheumatology Research Alliance (CARRA) investigators, we conducted a cross-sectional study using data from 2,571 children with JIA enrolled in the CARRA Registry to determine whether clinical characteristics of JIA were associated with pain intensity, physical function, and health status. Pain intensity, physical function, and health status differed significantly between JIA subtypes. Subjects with ERA reported worse pain and function in comparison to other categories of JIA. In multivariable analyses, higher active joint count and current use of nonsteroidal anti-inflammatory drugs (NSAIDs), biologics, or corticosteroids were associated with worse scores on all patient-reported measures. ERA subtypes and older age were associated with greater pain intensity and poorer health status. Enthesitis, sacroiliac tenderness, and NSAID use were independently associated with increased pain intensity in ERA, whereas systemic JIA and uveitis were significantly associated with worse health status. The correlation was low between physician global assessment of disease activity and patient-reported pain intensity, physical function, and health status. These data indicate that there are significant differences in pain intensity, physical function, and health status among JIA categories, and they suggest that current treatments may not be equally effective for particular disease characteristics more common in specific JIA categories, such as enthesitis or sacroiliac tenderness in ERA. Biological Effects of HLA-B27 Misfolding HLA-B27 misfolding can generate ER stress and activate the unfolded protein response (UPR), which promotes the production of certain cytokines including IL-23 and IFNβ in macrophages. In rats transgenic for HLA-B27, SpA-like disease is strongly associated with expansion and activation of IL-23-responsive CD4+ Th17 T cells in the colon, joints, and draining lymph nodes. We are currently using this model to evaluate the role of HLA-B27 misfolding as an upstream innate immune stimulus in causing this disease. We recently demonstrated that TNF- alpha enhances the development of osteoclasts (OCs) 2.5-fold in transgenic rat monocytes expressing HLA-B27, but not HLA-B7, or cells from wild type rats. TNF-alpha-induced HLA-B expression, which exacerbated misfolding and resulted in ER stress and UPR activation in B27-expressing, but not B7-expressing, or wild type cells. ER stress and UPR activation was associated with enhanced IL-1-alpha and IFN- beta production. Interestingly, we found that these cytokines were promoting (IL-1-alpha) and inhibiting (IFN-beta) OC formation, with the net effect being greater osteoclastogenesis under the conditions studied. When IFN-beta was neutralized, OC formation was almost 4-fold higher in the HLA-B27 transgenic cells. We have additional preliminary data suggesting that rat osteoblasts expressing HLA-B27 become refractory to the inhibitory effects of TNF-alpha when they are also exposed to IFN-gamma. Mineralization is inhibited under these conditions in HLA-B7 and wild type osteoblasts, whereas HLA-B27 expressing cells mineralize normally. The biological effect is associated with robust UPR activation, but the molecular mechanism is still unclear. Together, these results implicate HLA-B27 misfolding in altering bone homeostasis in transgenic rats under pro-inflammatory conditions, and suggest that it may contribute to the unique SpA phenotype through downstream pathways such as altering the response of cells to TNF-alpha. Evidence for Autophagy in HLA-B27+ Ankylosing Spondylitis Francesco Ciccia and colleagues have shown previously that IL-23 is upregulated in ileal biopsy tissue samples from AS patients with chronic, but sub-clinical, gastrointestinal inflammation. Unlike Crohns disease, IL-23 upregulation is not associated with IL-17A overexpression, and they have some evidence that this may be due to a tissue protective effect of IL-22-expressing NKp44+ cells. In a collaborative effort we have recently shown that gene expression (ATG16L, IRGM, MAP1LC3A) and protein markers of autophagy (LC3II, ATG5, ATG12) are expressed in chronic inflammatory ileal lesions from AS patients, similar to Crohns disease, but that the UPR is not activated. HC-10 reactive (unfolded/misfolded) HLA class I heavy chains were prominent in the tissue samples from AS patients, and co-localized with HRD-1 (SYVN or synoviolin gene), a marker of ER-associated degradation (ERAD) that has been shown to assist in the removal of misfolded HLA class I heavy chains. These results provided strong evidence for in vivo HLA-B27 misfolding, and suggest a model where ongoing ERAD may not be sufficient and could lead to activation of autophagy pathways rather than UPR activation. The IL-23/IL-17 Axis in Spondyloarthritis This years efforts include an invited review article on HLA-B27 misfolding and AS published in part with a special series in Molecular Immunology on the pathogenesis of spondyloarthritis. This article highlights the contribution of protein misfolding and its consequences to the pathogenesis of this immune-mediated inflammatory disease, and in particular non-canonical pathways linking ER stress to activation of the IL-23/IL-17 axis. I also wrote an invited commentary (co-authored with Dr. Michael Ward, NIAMS) on a clinical trial being published in The Lancet providing the first evidence that targeting the IL-23/IL-17 axis may be beneficial in the treatment of AS. This is likely to represent the beginning of a number of papers that will appear over the next several years exploring the efficacy of biologics and small molecules that target components of the IL-23/IL-17 pathway in AS. We were the first to discover activation of this axis in the HLA-B27 transgenic model of SpA in a paper published in 2009, and moreover provided critical evidence linking HLA-B27 to this pathway.

时代的痛苦和健康状况与Pam Weiss（CHOP）和其他儿童期关节炎和风湿病研究联盟（CARRA）研究人员合作，我们使用来自2,571名JIA JIA患有CARRA注册的儿童的数据进行了横断面研究，以确定JIA的临床特征是否与疼痛强度，身体功能和健康状况有关。 JIA亚型之间的疼痛强度，身体功能和健康状况显着不同。与其他类别的JIA相比，具有ERA的受试者报告的疼痛和功能较差。在多变量分析中，在所有患者报告的措施上，生物制剂或皮质类固醇的当前使用非甾体类抗炎药（NSAID），生物制剂或皮质类固醇的使用较差。 ERA亚型和年龄较大，与更大的疼痛强度和健康状况较差有关。肠炎，s骨压痛和NSAID使用与ERA的疼痛强度增加有关，而全身性的JIA和葡萄膜炎与健康状况较差显着相关。在全球对疾病活动的评估与患者报告的疼痛强度，身体机能和健康状况之间的相关性较低。这些数据表明，JIA类别之间的疼痛强度，身体机能和健康状况存在显着差异，它们表明当前的治疗可能对特定的JIA类别中更常见的特定疾病特征同样有效，例如ERA中的肠胃炎或Sacroiliac压痛。 HLA-B27错误折叠的生物学作用 HLA-B27错误折叠可以产生ER应力并激活未折叠的蛋白质反应（UPR），该反应促进了巨噬细胞中某些细胞因子在内的某些细胞因子的产生。在HLA-B27的大鼠转基因中，水疗样疾病与结肠，关节和排水淋巴结中IL-23反应性CD4+ Th17 T细胞的扩张和激活密切相关。目前，我们正在使用该模型来评估HLA-B27错误折叠的作用，因为它是引起这种疾病的上游先天免疫刺激。我们最近证明，TNF-Alpha增强了表达HLA-B27但不能HLA-B7的转基因大鼠单核细胞中的破骨细胞（OCS）2.5倍，而不是野生型大鼠的细胞。 TNF-Alpha诱导的HLA-B表达加剧了错误折叠，并导致了表达B27的ER应力和UPR激活，但没有表达B7或野生型细胞。 ER应力和UPR激活与增强的IL-1-Alpha和IFN-beta产生有关。有趣的是，我们发现这些细胞因子正在促进（IL-1-α）并抑制（IFN-β）OC的形成，在所研究的条件下，净作用较大的破骨细胞生成更大。当IFN-β被中和时，HLA-B27转基因细胞中的OC形成近4倍。我们还有其他初步数据，表明表达HLA-B27的大鼠成骨细胞在TNF-Alpha也暴露于IFN-GAMMA时会对TNF-Alpha的抑制作用产生难治性。在HLA-B7和野生型成骨细胞中，在这些条件下抑制了矿化化，而HLA-B27表达细胞正常矿化。生物学效应与鲁棒的UPR激活有关，但分子机制尚不清楚。总之，这些结果暗示HLA-B27在促炎条件下改变转基因大鼠的骨体内平衡时的HLA-B27错误折叠，并表明它可能通过下游途径有助于独特的SPA表型，例如改变细胞对TNF-Alpha的反应。 HLA-B27+强直性脊柱炎的自噬的证据 Francesco CICCIA及其同事先前已经表明，来自慢性但临床上胃肠道炎症患者的回肠活检组织样本中IL-23上调。与克罗恩斯疾病不同，IL-23上调与IL-17A过表达无关，并且有证据表明这可能是由于表达IL-22的NKP44+细胞的组织保护作用。在协作努力中，我们最近表明，自噬的基因表达（ATG16L，IRGM，MAP1LC3A）和自噬的蛋白质标志物（LC3II，ATG5，ATG12）在AS患者的慢性炎症性回肠病变中表达，类似于Crohns疾病，但未经Crohns病，但未经激活的UPR。 HC-10反应性（展开/错误折叠）HLA I类重链在AS患者的组织样本中突出，并与HRD-1（SYVN或Synoviolin Gene）共定位，这是ER相关降解（ERAD）的标志物（ERAD）的标记，已显示出有助于将Misfla cermfla cermfla classefla classefla classefted Chains拆除。这些结果为体内HLA-B27的折叠式折叠式错误提供了有力的证据，并提出了一个模型，即持续的ERAD可能不够，并且可能导致自噬途径激活而不是UPR激活。脊椎关节炎中的IL-23/IL-17轴今年的努力包括一篇有关HLA-B27错误折叠的评论文章，部分发表了有关脊椎关节炎发病机理的分子免疫学特殊系列。本文强调了蛋白质错误折叠的贡献及其对这种免疫介导的炎症性疾病的发病机理的影响，尤其是将ER应力与IL-23/IL-17轴激活联系起来的非经典途径。我还撰写了一份邀请的评论（与Niams的Michael Ward博士合着），对柳叶刀发表的临床试验提供了第一个证据，即针对IL-23/IL-17轴的第一个证据可能对AS的治疗可能是有益的。这很可能代表了许多论文的开头，这些论文将在未来几年中探讨靶向IL-23/IL-17途径的生物制剂和小分子的功效。我们是第一个在2009年发表的论文中发现SPA的HLA-B27转基因模型中该轴激活的人，此外提供了将HLA-B27与该途径联系起来的关键证据。