Thymic Expression Of Ocular Proteins--Autoimmune Uveitis

实验性自身免疫性葡萄膜炎(EAU)是一种公认的人类眼内炎症性疾病或葡萄膜炎的模型，用视网膜蛋白如光感受器间视黄醇结合蛋白(IRBP)和S抗原(SAG)免疫易感动物。不同动物种类和品系对EAU诱导的敏感性存在显着差异，但这些差异的原因尚不完全清楚。小鼠一般对EAU具有抵抗力，而大多数大鼠品系对EAU敏感。了解EAU抵抗或眼蛋白耐受的基本机制可能有助于眼炎性疾病的治疗或预防。在1996-1997财年，我们证明了眼部自身抗原在胸腺中的结构性表达(信使核糖核酸和蛋白质)与对EAU的抵抗有很强的相关性。这种相关性在物种(小鼠与大鼠或猴子)和亚种水平(品系之间的差异)都得到了注意。在1997-1998财政年度，我们发现SAG在人的胸腺中表达，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其他已知的诱发啮齿动物葡萄膜炎的视网膜蛋白。这些结果表明，除SAG外，人胸腺中还表达IRBP、视蛋白和恢复素。然而，这些抗原在个体和群体中的表达水平存在显著差异。目前主要致力于开发非侵入性的胸腺活检方法和灵敏的实时RT-PCR分析方法，以量化胸腺假定自身抗原的表达水平。目标是量化发生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.