TARGETS FOR AUTOANTIBODIES FROM SYNOVIAL LESIONS IN CHRONIC LYME ARTHRITIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 虽然莱姆病的病原体确切地被认为是壁虱传播的螺旋体，伯氏疏螺旋体(BB)，但随后在一组患者中发生的慢性关节炎症的病因学仍然不太清楚。在螺旋体明显根除后，关节炎的持续表明原始细菌感染下游的一种自身免疫反应。我们已经从受影响的关节炎关节内的滑膜病变中产生了重组抗体探针，试图在损伤部位概括与疾病相关的抗原结合特异性。使用这组关节内探针以及来自患者外周血的抗体片段，我们已经确定存在于滑膜微血管内皮细胞中的细胞角蛋白10(CK10)是慢性、抗生素治疗耐药的莱姆关节炎的靶配体和假定的自身抗原。此外，CK10与一种重要的BB抗原--外表面蛋白A(OspA)之间存在交叉反应。在炎症诱导的组织损伤的背景下，自身蛋白质的释放和由此产生的对它的原位反应可能启动一个前馈循环，从而放大炎症过程，从而使其成为慢性和自我持续的，即使在没有煽动病原体的情况下也是如此。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. While the causative agent of Lyme disease is definitively known to be the tick-borne spirochete, Borrelia burgdorferi (Bb), the etiology of chronic joint inflammation that ensues in a subset of patients remains less well understood. Persistence of arthritis after apparent eradication of the spirochete suggests an autoimmune reaction downstream of the original bacterial infection. We have generated recombinant antibody probes from synovial lesions within affected arthritic joints in an attempt to recapitulate disease-relevant antigen binding specificities at the site of injury. Using this panel of intraarticular probes, as well as antibody fragments derived from patient peripheral blood, we have identified cytokeratin 10 (CK10), present in synovial microvascular endothelium, as a target ligand and a putative autoantigen in chronic, antibiotic treatment-resistant Lyme arthritis. Further, there is cross-reactivity between CK10 and a prominent Bb antigen, Outer Surface Protein A (OspA). Release of the self protein in the context of inflammation-induced tissue injury and the resulting in situ response to it could set in motion a feed-forward loop, which amplifies the inflammatory process, thereby rendering it chronic and self-perpetuating, even in the absence of the inciting pathogen.