Iwakura Y, Itagaki K, Ishitsuka C, Yamasaki Y, Matsuzawa A, Yonehara S, Karasawa S, Ueda S, Saijo S
Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Japan.
J Immunol. 1998 Dec 15;161(12):6592-8.
Previously, we reported that human T cell leukemia virus type-1 env-pX region-introduced transgenic (pX-Tg) mice develop an inflammatory polyarthropathy. Although autoimmune pathogenesis was suggested, the detailed mechanisms remain to be elucidated. In this report, we examined effects of the MHC and fas genes on the development of the disease. When pX-Tg mice were backcrossed with different inbred strains, the incidence of arthritis differed among strains; 64% and 72% in BALB/cAn (H-2d), 25% and 46% in C3H/HeN (H-2k), and 0% and 2% in C57BL/6J (H-2b) background at 3 and 6 months of age, respectively. Rheumatoid factor levels in the serum correlated with the susceptibility to the disease, whereas IL-1beta and MHC gene expression were similarly elevated in all of these strains, suggesting involvement of immune regulatory genes in this strain difference. However, introduction of the H-2d locus into C57BL/6J pX-Tg mice did not increase the incidence of arthritis, and substitution of the BALB/cAn H-2 locus with the H-2b did not decrease it. The results indicate that the H-2 locus is not the major determinant of the disease. Then, since previous study indicated a defect in Fas-mediated apoptosis of transgenic T cells, the effects of fas gene modification on the disease were examined. The incidence increased when these pX-Tg mice were crossed with lpr/lpr mice, while it decreased when crossed with fas-transgenic mice. These observations suggest that aberration of Fas-mediated apoptosis of peripheral lymphocytes, rather than negative selection in the thymus, is involved in the development of autoimmune arthropathy in pX-Tg mice.
此前，我们报道过，导入人1型T细胞白血病病毒env-pX区域的转基因（pX-Tg）小鼠会发生炎性多关节炎。尽管提示有自身免疫发病机制，但详细机制仍有待阐明。在本报告中，我们研究了MHC和fas基因对该疾病发展的影响。当pX-Tg小鼠与不同的近交系回交时，各品系的关节炎发病率有所不同；3月龄和6月龄时，BALB/cAn（H-2d）品系的发病率分别为64%和72%，C3H/HeN（H-2k）品系为25%和46%，C57BL/6J（H-2b）品系为0%和2%。血清中的类风湿因子水平与疾病易感性相关，而所有这些品系中IL-1β和MHC基因表达均有类似升高，提示免疫调节基因参与了这种品系差异。然而，将H-2d基因座导入C57BL/6J pX-Tg小鼠并未增加关节炎发病率，用H-2b替代BALB/cAn的H-2基因座也未降低发病率。结果表明，H-2基因座不是该疾病的主要决定因素。然后，由于先前的研究表明转基因T细胞的Fas介导的凋亡存在缺陷，因此研究了fas基因修饰对该疾病的影响。当这些pX-Tg小鼠与lpr/lpr小鼠杂交时发病率增加，而与fas转基因小鼠杂交时发病率降低。这些观察结果表明，外周淋巴细胞Fas介导的凋亡异常，而非胸腺中的阴性选择，参与了pX-Tg小鼠自身免疫性关节炎的发展。
