Lehuen A, Bendelac A, Bach J F, Carnaud C
INSERM U25, Hôpital Necker, Paris, France.
J Immunol. 1990 Mar 15;144(6):2147-51.
Nonobese diabetic (NOD) mice present concomitant signs of cell-mediated and humoral autoimmunity. Whereas the involvement of the cell-mediated manifestations in the pathogenesis of diabetes has been clearly demonstrated, the origin and the relevance of the humoral manifestations is still unclear. In the present study, we have tried to determine whether the humoral manifestations observed in NOD mice were secondary to the cell-mediated antiislet reaction, or whether they resulted from an autonomous polyclonal activation of B cells, a possibility suggested by the notorious presence of antilymphocyte antibodies with thymocytotoxic properties, in the serum of old NOD females. To discriminate between the two alternatives, we have followed the titers of thymocytotoxic autoantibodies in aging males and females, as well as in F1 hybrids where the organ-specific disease is recessive, and in back-crossed mice where the susceptibility genes responsible for insulitis and diabetes have segregated. In addition to thymocytotoxic antibodies, we have also screened the sera of these animals for hyperglobulinemia, antiinsulin, and anti-DNA autoantibodies that are classically associated with polyclonal B cell activation in autoimmune strains of mice. The results indicate that these humoral anomalies are clearly disconnected from the occurrence of diabetes and even of insulitis. Lymphocytotoxic antibodies appear several weeks after the onset of insulitis in NOD mice, are not correlated with disease occurrence and have no predictive value for its onset. The humoral manifestations that include, beside thymocytotoxic antibodies, antiinsulin antibodies, hyperglobulinemia, but no anti-DNA antibodies, are found at the same frequency in F1 mice as in parental mice in spite of the fact that the former are practically free of insulitis lesions. These anomalies are also randomly distributed among back-crossed mice independently of the presence and the severity of the organ-specific lesions. Altogether, these results suggest that NOD mice, like other autoimmune strains, suffer from a genetically inherited defect of B cell regulation resulting in the hyperproduction of natural autoantibodies.
非肥胖型糖尿病（NOD）小鼠呈现出细胞介导和体液自身免疫的伴随症状。虽然细胞介导的表现形式在糖尿病发病机制中的作用已得到明确证实，但体液表现形式的起源及其相关性仍不清楚。在本研究中，我们试图确定在NOD小鼠中观察到的体液表现是细胞介导的抗胰岛反应的继发结果，还是由B细胞的自主多克隆激活导致的，老年NOD雌性小鼠血清中存在具有胸腺细胞毒性的抗淋巴细胞抗体提示了这种可能性。为了区分这两种可能性，我们追踪了衰老雄性和雌性NOD小鼠、器官特异性疾病为隐性的F1杂种小鼠以及负责胰岛炎和糖尿病的易感基因已分离的回交小鼠中胸腺细胞毒性自身抗体的滴度。除了胸腺细胞毒性抗体，我们还检测了这些动物血清中的高球蛋白血症、抗胰岛素和抗DNA自身抗体，这些抗体在小鼠自身免疫品系中通常与多克隆B细胞激活相关。结果表明，这些体液异常与糖尿病甚至胰岛炎的发生明显无关。淋巴细胞毒性抗体在NOD小鼠胰岛炎发作数周后出现，与疾病发生无关，对其发作也没有预测价值。除胸腺细胞毒性抗体外，还包括抗胰岛素抗体、高球蛋白血症但无抗DNA抗体的体液表现，在F1小鼠中的出现频率与亲本小鼠相同，尽管前者实际上没有胰岛炎病变。这些异常在回交小鼠中也是随机分布的，与器官特异性病变的存在和严重程度无关。总之，这些结果表明，NOD小鼠与其他自身免疫品系一样，存在B细胞调节的遗传缺陷，导致天然自身抗体过度产生。
