CLASS I MOLECULES AND AUTOIMMUNITY

这些研究的总体目标是理解I类的作用 B细胞显著参与的自身免疫性疾病中的蛋白质。 我们已经发现，由于缺乏I类分子，小鼠 I类轻链缺乏，β2微球蛋白(β2M)， 在正常和病理上表现出显著和意想不到的变化 其中许多过程只在小鼠紧张的情况下才明显 背景。其中最引人注目的是体液方面的异常- 媒介疾病，如系统性红斑狼疮(SLE)。因此，一个 β2M缺乏可阻止系统性红斑狼疮样综合征的发展 这通常发生在MRL-Fas/+、MRL-Fas/1PR和BXSB小鼠身上。我们 假设类I蛋白FcRN充当Brambell 保护受体(FcRp)负责所有这些效应。至 针对这一假设，我们将确定FcRN是否存在缺陷 在抗体反应和系统性红斑狼疮发生上引起相同的表型 是否存在Beta2M缺陷，反之，转基因是否过度- FcRN的表达夸大了这些过程。如果这个假设 事实证明是正确的，FcRN将成为一个具有根本重要性的分子 在体液免疫和自身免疫过程中，具有新颖和耐人寻味的 临床干预的可能性。与其他SLE相反- 易感品系，携带Y染色体连锁的BXSB小鼠 自身免疫加速器基因YAlpha/Alpha和缺乏Beta2M可发展为 与Beta2M相比，过早且更具侵袭性的系统性红斑狼疮 完整的对照。同样，缺乏Beta2M的SJL小鼠发展成更多 他们罕见的B细胞过度增殖性疾病的侵袭性形式。我们 假设不存在一个有效的依赖于I类的机制 由T细胞介导，与FcRN不同，负责 加剧了这两种疾病。我们将通过以下方式解决这一假设 调查是否使这些品系的小鼠缺乏FcRN， CD8+T细胞、NK1+T细胞或常规自然杀伤细胞 重述了由一种 β2M缺乏症。总而言之，拟议的研究应该提供 对I类控制的新的病理生物学途径的关键见解 分子，一个加速，另一个限制B细胞- 介导的自身免疫性疾病。所获得的洞察力具有极好的 根据临床情况进行外推的变化。

The overall goal of these studies is to understand the role of class I proteins in autoimmune diseases with a significant B cell involvement. We have found that mice lacking class I molecules by virtue of a deficiency in the class I light chain, beta2 microglobulin (beta2M), show remarkable and unexpected changes in normal and pathological processes many of which are only apparent in the context of mouse strain backgrounds. Among the most striking are aberrations in humorally- mediated diseases, such as systemic lupus erythematosus (SLE). Thus, a deficiency in beta2M prevents the development of the SLE-like syndromes that normally occur in MRL-Fas/+, MRL-Fas/1pr, and BXSB mice. We hypothesize that the class I-like protein, FcRn, acting as the Brambell protection receptor (FcRp), is responsible for all of these effects. To address this hypothesis, we will determine whether a deficiency in FcRn elicits the same phenotype on antibody responses and SLE development as does a deficiency in beta2M, and conversely, whether transgenic over- expression of FcRn exaggerates these processes. If this hypothesis proves correct, FcRn will emerge as a molecule of fundamental importance in humoral immune and autoimmune processes, with novel and intriguing possibilities for clinical intervention. Contrary to other SLE- predisposed strains, BXSB mice carrying the Y-chromosome linked Autoimmune Accelerator locus, Yalpha/alpha, and lacking beta2M develop a premature and much more aggressive form of SLE compared with beta2M- intact controls. Similarly, SJL mice lacking beta2M develop a much more aggressive form of their unusual B cell hyperproliferative disease. We hypothesize that the absence of a potent class I-dependent mechanism mediated by T cells and distinct from FcRn is responsible for exacerbating these two diseases. We will address this hypothesis by investigating whether rendering these strains of mice deficient in FcRn, CD8+T cells, NK1+ T cells, or conventional natural killer cells recapitulates the cellular and pathological changes elicited by a deficiency in beta2M. Altogether, the proposed studies should provide key insights into novel pathobiological pathways controlled by class I molecules, one which accelerates and the other which limits B cell- mediated autoimmune diseases. The insights gained have an excellent changes of extrapolation to clinical situations.