CLASS I MOLECULES AND AUTOIMMUNITY

这些研究的总体目标是了解I类的作用 自身免疫性疾病中的蛋白质，具有显著的B细胞参与。 我们已经发现，缺乏I类分子的小鼠， I类轻链、β 2微球蛋白（β 2 M）缺乏， 在正常和病理上显示出显著的和意想不到的变化 其中许多过程仅在小鼠品系的背景下明显 背景其中最引人注目的是体液- 介导的疾病，如系统性红斑狼疮（SLE）。因此 β 2 M缺乏可预防SLE样综合征的发生 MRL-Fas/+、MRL-Fas/1 pr和BXSB小鼠中通常发生的免疫反应。我们 假设类I蛋白，FcRn，作为Brambell 保护受体（FcRp）负责所有这些作用。到 解决这一假设，我们将确定FcRn缺乏是否 在抗体应答和SLE发展方面， β 2 M缺乏，反之，是否转基因过度- FcRn的表达夸大了这些过程。如果这个假设 证明是正确的，FcRn将成为一种具有根本重要性的分子， 在体液免疫和自身免疫过程中， 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座，Y α/α，缺乏β 2 M， 与β 2 M相比， 完整的对照品。同样，缺乏β 2 M的SJL小鼠会产生更多的 他们不寻常的B细胞过度增殖性疾病的侵袭性形式。我们 假设缺乏有效的I类依赖机制 由T细胞介导，与FcRn不同， 加剧了这两种疾病。我们将通过以下方式解决这一假设： 研究是否使这些小鼠品系缺乏FcRn， CD 8 +T细胞、NK 1 + T细胞或常规自然杀伤细胞 概括了细胞和病理变化引起的一个 β 2 M缺乏症。总之，拟议的研究应提供 I类控制的新型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。所获得的见解有一个很好的 外推到临床情况的变化。

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.