MECHANISMS OF MYCOPLASMA INDUCED ARTHRITIS

关节炎支原体引起一种自然发生的，迁移性的 啮齿类动物的多发性关节炎， 类风湿性关节炎 M.关节炎引起的关节炎 作为感染性关节炎的模型进行了广泛的研究， 也可作为检查超抗原作用的模型 自身免疫的发展。 所有菌株的M.关节炎 被认为产生超抗原MAM，但许多MAM产生 菌株是相对无毒的，除了MAM之外的因子必须是 关节炎的发展所必需的。 我们最近确定 其中一个因素是新发现的溶原性 噬菌体MAV 1。 我们已经证明，M. 当用MAV 1溶原化时，关节炎病毒变得有毒。MAV1 DNA 整合到M.关节炎染色体上的任何一个位点， 并且整合位点与毒力无关。 因此，我们认为， 与MAV 1相关的毒力增加不是由于 MAV 1 DNA侧翼染色体基因调控的变化 插入物。 因此，我们提出MAV 1编码一个决定簇， 与关节炎的发展有关。 MAV 1是第一个 来自任何支原体的因子，已被证明与 关节炎，阐明这一因素是重要的履行 了解支原体机制的长期目标- 诱导性关节炎和细菌载体的作用 致关节炎决定因素与MAV 1编码的 决定子可能在细菌和支原体中流行， 关节炎，这些因素可能是重要的疫苗 候选人和药物设计的目标。 目前的目标是 建议是识别和表征MAV 1编码的 行列式 具体目标1是确定完整的核苷酸 16 kb MAV 1 DNA基因组的序列。 通过比较氨基 预测的MAV 1基因产物的氨基酸序列与 GenBank/EMBL数据库，候选MAV 1毒力决定簇 将被识别。 具体目标二是发展M.关节炎基因 传输系统。 用于遗传转化的程序和载体 将建立遗传物质转移机制。 具体目标3是 评价候选毒力的致关节炎意义 决定因素 将插入候选毒力决定簇 进入M。关节炎染色体和/或特异性突变为 构建将在大鼠中检查致关节炎性的菌株 模型，并用于最终确定MAV 1基因， 参与关节炎的发展。

Mycoplasma arthritidis causes a naturally-occurring, migratory polyarthritis in rodents that can bear 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 MAM-producing strains are relatively avirulent and factors other than MAM must be required for the development of arthritis. We have recently determined that one of these factors is the newly-discovered lysogenic bacteriophage MAV1. We have shown that 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. Accordingly, we propose 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 goal of the present proposal is to identify and characterize the MAV1-encoded determinant. Specific Aim 1 is to determine the complete nucleotide sequence of the 16 kb MAV1 DNA genome. By comparing the amino acid sequences of the predicted MAV1 gene products with those of the GenBank/EMBL databased, candidate MAV1 virulence determinants will be identified. Specific Aim 2 is to develop M. arthritidis gene transfer systems. Procedures for genetic transformation and vectors for transferring genetic material will be established. Specific Aim 3 is to evaluate the arthritogenic significance of the candidate virulence determinants. The candidate virulence determinants will be inserted into the M. arthritidis chromosome and/or specifically mutated to construct strains that will be examined for arthritogenicity in the rat model and used to conclusively identify the MAV1 genes that are involved in the development of arthritis.