Innate immunity and experimental Lyme arthritis

描述(申请人提供)：关节炎仍然是全球发病率的主要来源。在大多数关节炎模型中，中性粒细胞已被证明在发病机制的发展中发挥关键作用。然而，中性粒细胞调节其作用的机制仍不清楚。莱姆病是由壁虱传播的伯氏疏螺旋体(BB)感染引起的。这种疾病的一个主要并发症是大多数(但不是所有)患者在感染时未使用抗生素治疗而发展为炎症性关节炎。最近，利用莱姆病的小鼠模型，我们证明了中性粒细胞重新聚集到关节组织中是病理发展所必需的。来自易患关节炎的小鼠品系的关节匀浆含有高水平的化学诱导剂KC，而来自抗关节炎品系的关节匀浆含有高水平的趋化物质KC。这表明，关节组织内驻留细胞对BB感染的初始宿主反应的多态导致中性粒细胞在耐药和敏感品系的小鼠关节中的不同招募。阻断中性粒细胞在CXCR2-/-小鼠关节组织中的募集，导致抵抗和敏感小鼠的关节炎严重程度降低。这项应用特别关注在BB感染期间KC介导的中性粒细胞在踝关节的募集和激活。具体目标1将检验这样一种假设，即KC将中性粒细胞重新募集到感染关节是莱姆关节炎发展所必需的，也是充分的。用抗KC或RKC的多克隆抗体治疗BFC感染的小鼠，将测试KC对关节炎发展的需求或充足。在特定的目标2中，我们将确定关节组织中KC的细胞来源，并测试关节炎抵抗和敏感小鼠关节内的前哨细胞对BB刺激的不同反应的假设。将抗性和易感品系小鼠的滑膜成纤维细胞与BB共培养，并测定KC的产生。中性粒细胞对炎症反应的调节也将通过中性粒细胞与滑膜成纤维细胞的共培养以及测量对BB刺激的KC的产生来确定。这项建议将定义KC在调节莱姆关节炎发展中的作用，但也解决了先天免疫反应中的多样性这一更广泛的问题。因此，这些研究不仅对莱姆病有重要意义，而且对其他炎症性疾病也有重要意义。

DESCRIPTION (provided by applicant): Arthritis continues to be a major source of morbidity worldwide. In most models of arthritis, neutrophils have been demonstrated to play a key role in the development of pathogenesis. The mechanism by which neutrophils mediate their effect, however, remains unknown. Lyme disease is caused by infection with the tick borne spirochete Borrelia burgdorferi (Bb). One major complication of this disease is the development of an inflammatory arthritis in most, but not all, patients untreated with antibiotics near the time of infection. Recently, using a mouse model of Lyme disease, we demonstrated a requirement for neutrophil recruitment into the joint tissue for the development of pathology. Joint homogenates from arthritis-susceptible mouse strains contained high levels of the chemoattractant KC, whereas joint homogenates from arthritis-resistant mouse strains did not. This suggested that polymorphisms in the initial host response to Bb infection by resident cells within the joint tissue led to the differential recruitment of neutrophils into the joints of resistant and susceptible mouse strains. Blocking the recruitment of neutrophils into the joint tissue in CXCR2 -/- mice resulted in a decrease in arthritis severity in both resistant and susceptible mouse strains. This application focuses specifically on the KC-mediated recruitment and activation of neutrophils in the ankle joint during Bb infection. Specific Aim 1 will test the hypothesis that recruitment of neutrophils into the infected joint by KC is necessary and sufficient for development of Lyme arthritis. Treatment of Bfc-infected mice with polyclonal antibody to KC or rKC will test for the requirement or sufficiency of KC for arthritis development. In Specific Aim 2 we will identify the cellular source of KC in joint tissue and test the hypothesis that sentinel cells within the joints of arthritis-resistant and -susceptible mice respond differently to Bb stimulation. Primary synovial fibroblasts from resistant and susceptible mouse strains will be co-cultured with Bb and the production of KC measured. Neutrophil modulation of the inflammatory response will also determined by the co-culture of neutrophils with synovial fibroblasts and measuring the production of KC in response to Bb stimulation. This proposal will define the role of KC in mediating the development of Lyme arthritis, but also addresses the broader issue of diversity within the innate immune response. As such these studies; may have important implications not only for Lyme disease, but for other inflammatory diseases as well.