Thymic Expression Of Ocular Proteins--Autoimmune Uveitis

实验性自身免疫性葡萄膜炎（Experimental autoimmune uveitis，EAU）是人类眼内炎性疾病或葡萄膜炎的良好建立的模型，并且容易在易感动物物种中通过用视网膜蛋白如感光细胞间类视色素结合蛋白（interphotoreceptor retinoid binding protein，IRBP）和S-抗原（S-Antigen，SAg）免疫而诱导。不同动物种属和品系对EAU诱导的敏感性存在显著差异，但这些差异的原因尚不完全清楚。小鼠通常对EAU具有抗性，而大多数大鼠品系是敏感的。了解EAU耐药或眼蛋白耐受诱导的基本机制可能有助于治疗或预防眼部炎症性疾病。在1996-1997财政年度，我们证明，有很强的相关性之间的组成性表达的眼自身抗原在胸腺（mRNA和蛋白质）和抵抗EAU。在种属（小鼠与大鼠或猴）和亚种水平（品系间差异）均观察到这种相关性。在1997-1998财政年度，我们发现SAg在人胸腺中表达，因此可以作为葡萄膜炎易感性的有用指标。我们现在已经将这一分析扩展到已知在啮齿动物中诱导葡萄膜炎的其他视网膜蛋白。这些结果表明，除了SAg，IRBP，视蛋白和恢复蛋白在人胸腺中表达。然而，这些抗原在个体和群体中的表达水平存在显著的变异性。现在，重要的努力是针对开发非侵入性的方法，获得胸腺活检和敏感的实时RT-PCR测定，以定量胸腺表达的推定的自身抗原的水平。目标是量化发展任何器官特异性自身免疫性疾病的风险。

Experimental autoimmune uveitis (EAU) is a well established model of human intraocular inflammatory diseases or uveitis and is easily induced in susceptible animal species by immunization with retinal proteins, such as interphotoreceptor retinoid binding protein (IRBP) and S-Antigen (SAg). Marked differences exist among different animal species and strains in their susceptibility to EAU induction but the cause for these differences is not completely clear. Mice are generally resistant to EAU while most rat strains are susceptible. Knowledge about the basic mechanisms underlying resistance to EAU or tolerance induction to ocular proteins may prove beneficial for the treatment or prevention of ocular inflammatory diseases. In FY 1996-1997 we demonstrated that there is strong correlation between constitutive expression of ocular autoantigens in the thymus (mRNA and protein) and resistance to EAU. This correlation was noted both at the species (mice vs. rats or monkeys) and sub-species levels (differences among strains). In 1997-1998 fiscal year we found that SAg is expressed in human thymi and may therefore serve as a useful indicator of susceptibility to uveitis. We have now extended this analysis to other retinal proteins known to induce uveitis in rodents. These results reveal that in addition to SAg, IRBP, opsin and recoverin are expressed in the human thymus. However, there is significant variability in the level of expression of these antigens in an individual and in the population. Significant effort is now directed at developing non-invasive methods of obtaining thymic biopsy and sensitive real-time RT-PCR assays to quantify levels of thymic expression of putative autoantigens. The goal is to quantify risk of developing any organ-specific autoimmune disease.