Caspi R R, Silver P B, Chan C C, Sun B, Agarwal R K, Wells J, Oddo S, Fujino Y, Najafian F, Wilder R L
National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 1996 Sep 15;157(6):2668-75.
This study examines whether genetic susceptibility vs genetic resistance to experimental autoimmune uveoretinitis (EAU) are connected to a predisposition to mount a Th1-dominated (IFN-gamma high, IL-4 low) vs a Th2-dominated (IL-4 high, lFN-gamma low) response. Lewis rats developed disease with high incidence after immunization with the uveitogenic peptide R16, whereas F344 rats were resistant. Primed lymph node cells from both strains proliferated in culture in response to R16. However, while the Lewis cultures transferred EAU to syngeneic recipients, those of F344 did not. The Lewis cultures produced substantially more IFN-gamma mRNA and protein in response to R16, than did those of F344. Both strains made low levels of IL-10 mRNA and IL-4 mRNA. Unlike the primary cultures, long-term (R16-specific) T cell lines derived from each of the strains transferred EAU equally well to their respective recipients, and produced similar, high levels of IFN-gamma mRNA and protein. Treatment of F344 with Bordetella pertussis toxin concurrently with immunization abrogated its resistance, enhanced Ag-specific IFN-gamma production in culture, and yielded a primed cell population capable of transferring EAU. Conversely, immunization of Lewis rats with R16 in IFA induced little or no disease; the primed cells produced minimal amounts of IFN-gamma and did not transfer EAU. However, addition of IL-12 into the culture resulted in a highly pathogenic, IFN-gamma-producing cell population. We conclude that genetic susceptibility to ocular autoimmunity in this model is connected to an elevated Th1 response. Genetic resistance, however, does not seem to involve an elevated Th2 response, but rather an inhibited development of Th1-like effector cells.
本研究探讨了对实验性自身免疫性葡萄膜视网膜炎（EAU）的遗传易感性与遗传抗性是否分别与倾向于产生以Th1为主导（IFN-γ高、IL-4低）或Th2为主导（IL-4高、IFN-γ低）的反应相关。用致葡萄膜炎肽R16免疫后，Lewis大鼠发病率高，而F344大鼠具有抗性。两种品系经致敏的淋巴结细胞在体外培养中对R16均有增殖反应。然而，Lewis大鼠的培养细胞能将EAU转移给同基因受体，而F344大鼠的则不能。与F344大鼠的培养细胞相比，Lewis大鼠的培养细胞对R16产生的IFN-γ mRNA和蛋白要多得多。两种品系产生的IL-10 mRNA和IL-4 mRNA水平都很低。与原代培养不同，来自每个品系的长期（R16特异性）T细胞系将EAU同等程度地转移给各自的受体，并产生相似的高水平IFN-γ mRNA和蛋白。在免疫的同时用百日咳博德特氏菌毒素处理F344大鼠可消除其抗性，增强培养物中抗原特异性IFN-γ的产生，并产生能够转移EAU的致敏细胞群体。相反，用R16在不完全弗氏佐剂（IFA）中免疫Lewis大鼠几乎不诱发疾病；致敏细胞产生的IFN-γ极少，且不能转移EAU。然而，向培养物中添加IL-12会产生高致病性、产生IFN-γ的细胞群体。我们得出结论，在该模型中，眼部自身免疫的遗传易感性与Th1反应增强有关。然而，遗传抗性似乎并不涉及Th2反应增强，而是涉及Th1样效应细胞的发育受到抑制。
