Ostlie N S, Karachunski P I, Wang W, Monfardini C, Kronenberg M, Conti-Fine B M
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, St. Paul, MN 55108, USA.
J Immunol. 2001 Apr 15;166(8):4853-62. doi: 10.4049/jimmunol.166.8.4853.
Ab to the acetylcholine receptor (AChR) cause experimental myasthenia gravis (EMG). Th1 cytokines facilitate EMG, whereas Th2 cytokines might be protective. IL-10 inhibits Th1 responses but facilitates B cell proliferation and Ig production. We examined the role of IL-10 in EMG by using wild-type (WT) C57BL/6 mice and transgenic (TG) C57BL/6 mice that express IL-10 under control of the IL-2 promoter. We immunized the mice with doses of AChR that cause EMG in WT mice or with low doses ineffective at causing EMG in WT mice. After low-dose AChR immunization, WT mice did not develop EMG and had very little anti-AChR serum Ab, which were mainly IgG1, whereas TG mice developed EMG and had higher levels of anti-AChR serum Ab, which were mainly IgG2, in addition to IgG1. At the higher doses, TG mice developed EMG earlier and more frequently than WT mice and had more serum anti-AChR Ab. Both strains had similar relative serum concentrations of anti-AChR IgG subclasses and IgG and complement at the muscle synapses. CD8(+)-depleted splenocytes from all AChR-immunized mice proliferated in the presence of AChR and recognized a similar epitope repertoire. CD8(+)-depleted splenocytes from AChR-immunized TG mice stimulated in vitro with AChR secreted significantly more IL-10, but less of the prototypic Th1 cytokine IFN-gamma, than those from WT mice. They secreted comparable amounts of IL-4 and slightly but not significantly reduced amounts of IL-2. This suggests that TG mice had reduced activation of anti-Torpedo AChR Th1 cells, but increased anti-AChR Ab synthesis, that likely resulted from IL-10-mediated stimulation of anti-AChR B cells. Thus, EMG development is not strictly dependent on Th1 cell activity.
针对乙酰胆碱受体（AChR）的抗体可引发实验性重症肌无力（EMG）。Th1细胞因子会促进EMG，而Th2细胞因子可能具有保护作用。白细胞介素-10（IL-10）会抑制Th1反应，但会促进B细胞增殖和免疫球蛋白产生。我们通过使用野生型（WT）C57BL/6小鼠和在白细胞介素-2启动子控制下表达IL-10的转基因（TG）C57BL/6小鼠，研究了IL-10在EMG中的作用。我们用能在WT小鼠中引发EMG的AChR剂量或用在WT小鼠中引发EMG无效的低剂量对小鼠进行免疫。低剂量AChR免疫后，WT小鼠未出现EMG，且抗AChR血清抗体极少，主要为IgG1，而TG小鼠出现了EMG，且除IgG1外，抗AChR血清抗体水平更高，主要为IgG2。在高剂量时，TG小鼠比WT小鼠更早且更频繁地出现EMG，且血清抗AChR抗体更多。两种品系在肌肉突触处抗AChR IgG亚类、IgG和补体的相对血清浓度相似。所有接受AChR免疫的小鼠中去除CD8(+)的脾细胞在有AChR存在时会增殖，并识别相似的表位库。与WT小鼠相比，用AChR在体外刺激AChR免疫的TG小鼠中去除CD8(+)的脾细胞分泌的IL-10明显更多，但原型Th1细胞因子干扰素-γ更少。它们分泌的IL-4量相当，IL-2量略有减少但不显著。这表明TG小鼠中抗电鳐AChR Th1细胞的活化减少，但抗AChR抗体合成增加，这可能是由IL-10介导的抗AChR B细胞刺激所致。因此，EMG的发展并不严格依赖于Th1细胞活性。
