Innate immunity and experimental Lyme arthritis

描述（由申请人提供）：关节炎仍然是世界范围内发病率的主要来源。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起关键作用。然而，中性粒细胞介导其作用的机制尚不清楚。莱姆病是由蜱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炎症性关节炎的发展在大多数，但不是所有的患者，未经治疗的抗生素接近感染的时间。最近，使用莱姆病小鼠模型，我们证明了中性粒细胞募集到关节组织的病理发展的要求。来自关节炎易感小鼠品系的关节匀浆含有高水平的趋化剂KC，而来自关节炎耐药小鼠品系的关节匀浆则没有。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性导致中性粒细胞进入耐药和易感小鼠菌株关节的差异募集。阻断CXCR2 -/-小鼠关节组织中中性粒细胞的募集，可降低耐药和易感小鼠的关节炎严重程度。本应用特别关注Bb感染期间踝关节中kc介导的中性粒细胞募集和活化。特异性目的1将验证KC向感染关节募集中性粒细胞对于莱姆病的发展是必要和充分的假设。用KC或rKC多克隆抗体治疗bfc感染的小鼠，将检测关节炎发展中KC的需要量或充分性。在特异性目标2中，我们将确定关节组织中KC的细胞来源，并验证关节炎抵抗和关节炎易感小鼠关节内的前哨细胞对Bb刺激的反应不同的假设。来自耐药和易感小鼠株的原代滑膜成纤维细胞将与Bb共培养，并测量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和测量Bb刺激下KC的产生来确定。该建议将确定KC在介导莱姆病发展中的作用，但也解决了先天免疫反应多样性的更广泛问题。因此这些研究；可能不仅对莱姆病，而且对其他炎症性疾病都有重要意义。

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.