MECHANISMS OF MYCOPLASMA-INDUCED ARTHRITIS

说明(申请人摘要)：关节炎支原体致病原因 啮齿类动物的一种自然发生的迁移性多发性关节炎， 组织学上与人类类风湿性关节炎相似。M. 关节炎诱导的关节炎已经被广泛研究为一种 由感染性病原体引起的关节炎，也是研究 超抗原在自身免疫发展中的作用(S)。所有菌株都是M. 关节炎被认为会产生超抗原MAM，但许多MAM 必须是发展成关节炎所必需的。其中一个因素是 溶原性噬菌体MAV1。节炎分枝杆菌无毒株成为 用MAV1裂解后致病。MAV1 DNA整合到M。 节炎菌染色体位于众多位置中的任何一个，以及整合的位置 与毒力无关。因此，毒力的增加 与MAV1相关的不是由于染色体调节的变化 MAV1 DNA插入片段两侧的基因。我们已经建议MAV1编码一个 与关节炎的发生有关的决定因素。MAV1是 任何支原体的第一因子已被证明与 关节炎，而阐明这一因素对于实现 了解支原体诱导的机制的长期目标 关节炎与噬菌体作为致炎细菌载体的作用 决定因素。类似于MAV1编码的行列式的因子可以是 普遍存在于导致人类关节炎的细菌和支原体中，而这些 作为候选疫苗和药物设计的目标，这些因素可能是重要的。 本申请的目标是识别和表征 MAV1编码的决定簇并开始研究以阐明其功能。从… 16kb的MAV1基因组的核苷酸序列，我们已经鉴定出一个 预测编码细胞膜的候选毒力决定簇 脂蛋白。具体目标1是最终确定特定的MAV1 节炎支原体毒力相关基因(S)。具体目标2是 确定MAV1毒力因子是细胞质还是细胞膜 蛋白质，并在体内产生。具体目标3是探索MAV1的作用 在疾病的发病机制上。MAV1对关节炎支原体的溶原化作用 将检查关节炎疾病的进展情况。通过使用 免疫受损的动物，我们将解决MAV1是否 通过影响与节炎分枝杆菌的相互作用而增加其毒力 宿主因素，如B和T细胞及补体。因此，这一过程 将开始剖析MAV1在毒力中的功能。

DESCRIPTION ( applicant's abstract): Mycoplasma arthritidis causes a naturally-occurring, migratory polyarthritis in rodents that bears a close histological resemblance to rheumatoid arthritis of humans. M. arthritidis-induced arthritis has been extensively studied as a model for arthritides caused by infectious agents and also as a model for examining the role(s) of superantigens in the development of autoimmunity. All strains of M. arthritidis are thought to produce the superantigen MAM, but many an MAM must be required for the development of arthritis. One of these factors is the lysogenic bacteriophage MAV1. Avirulent strains of M. arthritidis become virulent when lysogenized with MAV1. MAV1 DNA integrates into the M. arthritidis chromosome at any of numerous sites, and the site of integration does not correlate with virulence. Therefore, the increase in virulence associated with MAV1 does not result from changes in regulation of chromosomal genes flanking MAV1 DNA inserts. We have proposed that MAV1 encodes a determinant that is involved with the development of arthritis. MAV1 is the first factor from any mycoplasma that has been shown to be associated with arthritis, and elucidation of this factor is important for fulfillment of the long-range goals of understanding the mechanisms of mycoplasma-induced arthritis and the role of phages as carriers of bacterial arthritogenic determinants. Factors analogous to the MAV1-encoded determinant may be prevalent in bacteria and mycoplasmas that cause arthritis in humans, and these factors may be important as vaccine candidates and as targets for drug design. The goals of the present application are to identify and characterize the MAV1-encoded determinant and initiate studies to elucidate its function. From the nucleotide sequence of the 16-kb MAV1 genome, we have identified a candidate virulence determinant that is predicted to encode a membrane lipoprotein. Specific Aim 1 is to conclusively identify the particular MAV1 gene(s) associated with virulence of M. arthritidis. Specific Aim 2 is to determine whether the MAV1 virulence factor is a cytoplasmic or membrane protein and is produced in vivo. Specific Aim 3 is to explore the role of MAV1 in disease pathogenesis. How lysogenization of M. arthritidis by MAV1 affects the progression of arthritic disease will be examined. Through the use of immunocompromised animals, we will address the question of whether MAV1 contributes to the virulence of M. arthritidis by affecting interactions with host factors such as B and T cells and complement. Thus, the process of dissecting the function of MAV1 in virulence will be begun.