Mechanisms of Mycoplasma-Induced Arthritis

描述（由申请人提供）：支原体关节炎在啮齿类动物中引起自然发生的迁移性多关节炎，与人类类风湿关节炎具有密切的组织学相似性。M. arthritis -induced arthritis -被广泛研究为感染性因子引起的关节炎模型，也作为超抗原在自身免疫发展中的作用模型。所有的关节炎分枝杆菌菌株都被认为产生超抗原MAM，但是许多产生MAM的菌株是相对无毒的。因此，除了MAM之外，关节炎的发展还需要其他因素。我们最近发现了一种自发突变（菌株158-1）的关节炎分枝杆菌，它是无毒的，在感染的最初几个小时内迅速从小鼠体内清除。与毒力强的亲本菌株相比，突变体具有主要的抗原性差异。亲本158菌株具有一种名为MIA（支原体免疫优势抗原）的蛋白，该蛋白具有23个8个氨基酸串联重复序列。在它的位置上，158-1具有相同的蛋白质（ORF 619基因产物），但有31个串联重复序列。本提案的主要目标是确定MAM和MIA是否是关节炎发展的毒力因素。鉴定关节炎支原体毒力因子是实现了解支原体诱导关节炎发病机制这一长期目标的第一步。类似于MAM和MIA的因素可能在引起人类关节炎的微生物中普遍存在，这些因素可能是重要的候选疫苗和药物设计靶点。我们与TIGR合作确定了该物种的完整基因组序列，这将有助于我们构建关节炎分枝杆菌突变体，其中感兴趣的基因（例如编码MAM和MIA）已被破坏（Specific Aim 1）。Aim 2是对Aim 1中产生的突变体进行补充，比较突变体和被补充突变体的毒力，从而确定MAM和MIA是否为毒力因子。目的3是继续我们对158-1的研究，以确定为什么它能从感染小鼠体内迅速清除。对158-1无法抵抗宿主防御的理解可能为探索支原体与先天免疫之间的相互作用提供了一个独特的机会。

DESCRIPTION (provided by applicant): 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 MAM-producing strains are relatively avirulent. Thus, factors in addition to MAM must be required for the development of arthritis. We have recently identified a spontaneous mutant (strain 158-1) of M. arthritidis that is avirulent and is rapidly cleared from the mouse in the first few hours of infection. The mutant has a major antigenic difference when compared to the virulent parent strain. The parent 158 strain has a protein designated MIA (mycoplasma immunodominant antigen) that has 23 copies of a 8-amino acid tandem repeat sequence. In its place, 158-1 has the same protein (the ORF 619 gene product) but with 31 tandem repeats. A primary goal of this proposal is to determine whether MAM and MIA are virulence factors for the development of arthritis. The identification of M. arthritidis virulence factors is a first step towards fulfillment of the long-range goal of understanding the pathogenesis of mycoplasma-induced arthritis. Factors analogous to MAM and MIA may be prevalent in microorganisms that cause arthritis in humans, and these factors may be important as vaccine candidates and as targets for drug design. We have in collaboration with TIGR determined the complete genome sequence of this species, which will assist us in the construction of mutants of M. arthritidis in which genes of interest (e.g., encoding MAM and MIA) have been disrupted (Specific Aim 1). Aim 2 is to complement the mutants generated in Aim 1 and compare the virulence of the mutants and the complemented mutants, thus determining whether MAM and MIA are virulence factors. Aim 3 is to continue our studies on 158-1 to determine why it is rapidly cleared from infected mice. An understanding of the inability of 158-1 to resist host defenses may offer an unique opportunity to explore interactions between the mycoplasma and innate immunity.