NK and NKT cells, Th1/Th2 cytokines in immune reproductive failure

本研究旨在探讨NK细胞、NKT细胞、Th1/Th2细胞因子在免疫生殖衰竭中的病理生理作用。我们发现复发性流产患者外周血中NK细胞活性升高与胎儿染色体正常的继发性流产有关。RM患者外周血中NK细胞KIR2DL1(CD158a)和T细胞亚群Th2/Tc2-SIFT表达降低。RM患者子宫内膜中CD3+细胞、CD4+干扰素-g+细胞、CD4+肿瘤坏死因子-a+细胞的比例降低。在一项前瞻性研究中，我们发现在胎儿染色体正常的散发性流产患者蜕膜上CD158a、CD94和CD244的表达降低，而Perform的表达增加。GST M1空(OR2.2)、CYP17 A2等位基因(OR2.4)、IL-6 G等位基因(OR0.46)等位基因与RM风险相关，提示RM是一种多基因疾病。我们发现，只有携带≧1A2*1F纯合子A等位基因(100-299 mg/天，300 mg/天，OR 5.2)的女性，每日咖啡因摄入量与风湿性黄斑变性的风险相关。注射完整的人免疫球蛋白和小鼠免疫球蛋白可显著降低胎儿吸收率，分别从55%降至8.5%和0%。但注射人免疫球蛋白的Fab片段并不能检测到这种抗流产作用。我们进行了各种过继移植实验，将注射免疫球蛋白的供者的脾细胞转移到注射聚(I：C)的受者身上。脾细胞过继转移和巨噬细胞的浓缩保留了抗流产作用。然而，如果移植的脾细胞中的巨噬细胞被耗尽，这种抗流产作用就完全消失了。首次证实了免疫球蛋白刺激的巨噬细胞具有抗流产作用，其中免疫球蛋白的Fc部分起着关键作用。

The aim of this study was to investigate pathophysiological roles of NK and NKT cells, Th1/Th2 cytokines in immune reproductive failure. We found that high NK cell activities in the circulation of women with recurrent miscarriage (RM) were associated with subsequent miscarriage with normal fetal chromosome. Decreases in KIR2DL1 (CD158a) expression on NK cells and in T cell population, Th2/Tc2-sift were found in the circulation of RM women. Frequencies of CD3+cells, CD4+IFN-g+cells, CD4+TNF-a+cells were decreased in the endometria of RM women. In a prospective study, we found decreases in CD158a, CD94, and CD244 expression on NK cells and increases in perform expression in the deciduas of sporadic cases of miscarriage with normal fetal chromosome.Gene polymorphisms such as GST M1 null (OR2.2), CYP17 A2 allele (OR2.4), IL-6 G allele (OR0.46) were found to be associated RM risk, suggesting that RM is a polygenetic disease. We found that daily caffeine intake was associated with RM risk only in women who carried CYP1A2^* 1F homozygous A allele (100-299 mg/day OR 1.9,≧300mg/day OR 5.2), and suggested that RM is a life-style related disease.We used poly(I:C)-induced fetal resorption prone mating of CBA/J×DBA/2J mice. Injections of intact type human Ig and mouse Ig significantly reduced fetal resorption rates from 55% to 8.5% and 0%, respectively. But this anti-miscarriage effect was not detected by injections of Fab fragments of human Ig. We performed a variety of adoptive transfer experiments in which spleen cells from Ig-injected donors were transferred to poly(I:C)-injected pregnant recipients. Adoptive transfer of spleen cells with enrichment of macrophages retained the anti-miscarriage effect. However, this anti-miscarriage effect completely disappeared, if macrophages were depleted from transferred spleen cells. It was for the first time demonstrated that Ig-stimulated macrophages carried the anti-miscarriage effects in which Fc portions of Ig playd a critical role.