Investigation Into the Mechanism of Polyclonal B Cell Activation as a Pathogenesis of Autoimmune Diseases

为探讨各种自身免疫性疾病的发病机制，我们从多方面探讨了多克隆B细胞活化的机制。我们已经利用了具有固定的mAb与CD 3分子复合物的培养系统，其中B细胞通过与T细胞接触而被非常有效地激活。首先，我们揭示了CD 18分子在该系统中T细胞-B细胞接触中起重要作用。其次，为了研究自身抗体产生的机制，通过利用固定化的抗CD 3和金黄色葡萄球菌（SA）的mAb来检查正常B细胞内IgM-RF前体和抗DNA前体的程度和性质。在用固定化抗CD 3刺激的培养物中，抗DNA产生细胞的前体频率（0.019-0.097/10 ^2 B细胞）与IgM-RF产生细胞的前体频率（0.025-0.104/10 ^2 B细胞）几乎相同。值得注意的是，在抗CD 3刺激的培养物中，SA的添加增加了IgM-RF产生细胞的前体频率，但不增加抗DNA产生细胞的前体频率。这些数据支持这样的结论，即抗DNA产生细胞的前体具有与IgM-RF产生细胞不同的活化要求。第三，检测人T细胞亚群的免疫调节功能。结果提示，人T细胞的抑制效应功能可能与T细胞亚群（如T4和T8细胞）的胸腺后分化阶段有关。此外，还表明IL 2在抑制效应T细胞的产生中起重要作用。这些观察结果可能至少部分解释了系统性红斑狼疮中抑制性T细胞活性缺陷的机制。最后，我们揭示了类风湿性关节炎患者单核细胞上Fc γ RL的表达增加。这一发现可能与IgMRF的产生有关，因为SA和Fc γ RI都结合IgG的Fc部分。

To investigate the pathogenesis of various autoimmune diseases, We have explored the mechanism of polyclonal B cell activation in several aspects. We have utilized the culture system with immobilized mAb to CD3 molecular complex, in which B cells are very potently activated through contact with T cells. First, we have revealed that the CD18 molecule plays an important role for the T cell -B cell contact in this system. Second, to investigate the mechanism of autoantibody production, the extent and nature of IgM-RF precursors and anti-DNA precursors within normal B cells were examined by utilizing immobilized mAb to CD3 and Staphylococcus aureus (SA). The precursor frequency of anti-DNA producing cells (0.019-0.097 per 10^2 B cells) were almost the same as that of IgM-RF producing cells (0.025-0.104 per 10^2 B cells) in cultures stimulated with immobilized anti-CD3. Of note, addition of SA increased the precursor frequency of IgM-RF producing cells, but not that of anti-DNA producing cells, in anti-CD3 stimulated cultures. These data support the conclusion that the precursors of anti-DNA producing cells have different activation requirement from those of IgM-RF producing cells. Third, the immunoregulatory functions of human T cell subpopulation were examined. The results suggest that the suppressor-effector function of human T cells may rather be related with the stages of the post-thymic differentiation as evidenced by the T cell subsets, such as T4 and T8 cells. Moreover, it has also been shown that IL2 plays an important role in the generation of suppressor-effector T cells. These observation may explain at least in part the mechanism of the deficient suppressor T cell activity in systemic lupus erythematosus. Finally, we have revealed that the expression of FcgammaRL on monocytes from patients with rheumatoid arthritis was increased. This finding may well be related the production of IgMRF, since both SA and FcgammaRI bind Fc portion of IgG.