Innate immunity and experimental Lyme arthritis

描述（由申请人提供）：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，中性粒细胞介导其作用的机制仍不清楚。莱姆病是由蜱传播的螺旋体伯氏疏螺旋体（Bb）感染引起的。这种疾病的一个主要并发症是在大多数但不是全部的患者中发展炎性关节炎，这些患者在感染时未经抗生素治疗。最近，使用莱姆病的小鼠模型，我们证明了需要中性粒细胞募集到关节组织的病理发展。关节炎易感小鼠品系的关节匀浆含有高水平的化学引诱物KC，而关节炎抗性小鼠品系的关节匀浆则没有。这表明，在最初的主机响应Bb感染的常驻细胞在关节组织内的多态性导致的差异招聘中性粒细胞进入关节的耐药和敏感的小鼠品系。在CXCR 2-/-小鼠中阻断中性粒细胞向关节组织中的募集导致抗性和易感小鼠品系的关节炎严重程度降低。本申请特别关注Bb感染期间踝关节中KC介导的中性粒细胞的募集和激活。具体目标1将检验这样的假设，即KC将中性粒细胞募集到感染的关节中对于莱姆关节炎的发展是必要的和充分的。用KC或rKC的多克隆抗体处理Bfc感染的小鼠将测试KC对于关节炎发展的需要或充分性。在具体目标2中，我们将确定关节组织中KC的细胞来源，并测试关节炎抗性和易感小鼠关节内的哨兵细胞对Bb刺激的反应不同的假设。将来自抗性和易感小鼠品系的原代滑膜成纤维细胞与Bb共培养，并测量KC的产生。炎症反应的中性粒细胞调节也将通过中性粒细胞与滑膜成纤维细胞的共培养和测量响应于Bb刺激的KC的产生来确定。该提案将定义KC在介导莱姆病关节炎发展中的作用，但也解决了先天免疫反应中更广泛的多样性问题。因此，这些研究可能不仅对莱姆病，而且对其他炎症性疾病具有重要意义。

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.