MYOCYTE RESPONSES DURING EXPERIMENTAL MYASTHENIA GRAVIS

乙酰胆碱受体（AChR）在肌肉膜上表达，并且负责接收来自刺激肌肉收缩的神经的信号。 重症肌无力（MG）是一种神经肌肉疾病，是由针对AChR的自身抗体引起的肌肉收缩受损的结果。然而，抗AChR抗体的循环血清滴度与MG患者的疾病严重程度没有很好的相关性，这种相关性的缺乏导致了对可能有助于确定最终疾病严重程度的其他因素的研究。 因此，我们的假设是，肌肉不是MG疾病症状发展的被动参与者，事实上，通过产生免疫调节因子，可以影响免疫系统对肌肉的最终免疫病理学影响，发挥着非常重要的积极作用。MG的实验大鼠模型将用于检验这一假设。 因此，将用纯化的AChR免疫刘易斯大鼠，这导致抗AChR抗体和实验性自身免疫性重症肌无力（EAMG）的产生。研究将集中在EAMG大鼠肌肉细胞产生的细胞因子和对细胞因子的反应。 在这方面，在存在或不存在源自刘易斯大鼠的抗AChR抗体的情况下，将肌细胞系体外暴露于选定的细胞因子。 读出将是具有免疫调节活性的肌细胞产物的诱导（即，细胞因子、趋化因子、膜相互作用分子）。 类似地，将评价来自已知对EAMG诱导具有抗性的大鼠品系（Wistar Furth）的肌细胞细胞系的肌细胞反应差异，这将解释疾病易感性的差异。 基于体外观察的结论将在AChR免疫的刘易斯大鼠的免疫应答诱导阶段得到验证，以及在接受了已知具有不同诱导疾病症状能力的预先形成的抗AChR抗体的大鼠中得到验证。

Acetylcholine receptors (AChR) are expressed on muscle membranes and are responsible for the reception of signals from nerves that stimulate muscle contraction. Myasthenia gravis (MG) is a neuromuscular disease that is the result of impaired muscle contraction caused by autoantibodies directed at the AChR. However, circulating serum titers of anti-AChR antibodies do not correlate well with disease severity in patients with MG and this lack of correlation has led to the search for other factors which may help determine eventual disease severity. Therefore, it is our hypothesis that muscle is not a passive participant in the development of disease symptoms in MG and, in fact, plays a very important active role by producing immunomodulating factors that can influence the eventual immunopathological impact of the immune system on muscle. The experimental rat model for MG is to be used to test this hypothesis. Accordingly, Lewis rats are to be immunized with purified AChR which results in the production of anti-AChR antibodies and Experimental Autoimmune Myasthenia Gravis (EAMG). Studies will focus on the production of, and responses to, cytokines by muscle cells in rats with EAMG. In this regard, muscle cell lines will be exposed in vitro to selected cytokines in the presence or absence of anti-AChR antibodies derived from Lewis rats. The readout will be the induction of myocyte products with immunomodulating activities (i.e., cytokines, chemokines, membrane interaction molecules). Similarly, myocyte cell lines derived from a rat strain known to be resistant to the induction of EAMG (Wistar Furth) will be evaluated for differences in myocyte responses that would explain differences in disease susceptibility. Conclusions based on in vitro observations will then be verified in AChR-immunized Lewis rats during the induction phase of the immune response, as well as in rats that have received pre-formed anti-AChR antibodies known to possess differing abilities to induce disease symptoms.