Dalakas M C
Medical Neurology Branch, NINDS, NIH, Bethesda, MD 20892-1382, USA.
Ann Neurol. 1995 May;37 Suppl 1:S2-13. doi: 10.1002/ana.410370703.
The neurological diseases with definite or putative immune pathogenesis include myasthenia gravis; Lambert-Eaton myasthenic syndrome; IgM monoclonal anti-myelin-associated glycoprotein-associated demyelinating polyneuropathy; Guillain-Barré syndrome; chronic inflammatory demyelinating polyneuropathy; multifocal motor neuropathy with or without GM1 antibodies; multiple sclerosis; inflammatory myopathies; stiff-man syndrome; autoimmune neuromyotonia; paraneoplastic neuronopathies and cerebellar degeneration; and neurological diseases associated with systemic autoimmune conditions, vasculitis, or viral infections. The events that lead to these autoimmune diseases are not clear but the following sequential steps are critical: (a) the breaking of tolerance, a process in which cytokines, molecular mimicry, or superantigens may play a role in rendering previously anergic T cells to recognize neural autoantigens; (b) antigen recognition by the T-cell receptor complex and processing of the antigen via the major histocompatibility complex class I or II; (c) costimulatory factors especially B7 and B7-binding proteins (CD28, CTLA-4) and intercellular adhesion molecule (ICAM)-1 and its leukocyte function-associated (LFA)-1 ligand; (d) traffic of the activated T cells across the blood-brain or blood-nerve barrier via a series of adhesion molecules that include selectins, leukocyte integrins (LFA-1, Mac-1, very late activating antigen [VLA]-4) and their counterreceptors (ICAM-1, vascular cell adhesion molecule [VCAM]) on the endothelial cells; and (e) tissue injury when the activated T cells, macrophages, or specific autoantibodies find their antigenic targets on glial cells, myelin, axon, calcium channels, or muscle. In designing specific immunotherapy, the main players involved in every step of the immune response need to be considered. Targets for specific therapy in neurological diseases include agents that (a) interfere or compete with antigen recognition or stimulation, (b) inhibit costimulatory signals or cytokines, (c) inhibit the traffic of the activated cells to tissues, and (d) intervene at the antigen recognition sites in the targeted organ. The various immunomodulating procedures and immunosuppressive drugs currently used for nonselective neuroimmunotherapy are discussed in the context of their interference with the above-described immune mediators.
具有明确或推测性免疫发病机制的神经系统疾病包括重症肌无力、兰伯特-伊顿肌无力综合征、IgM单克隆抗髓鞘相关糖蛋白相关脱髓鞘性多发性神经病、吉兰-巴雷综合征、慢性炎症性脱髓鞘性多发性神经病、伴或不伴GM1抗体的多灶性运动神经病、多发性硬化症、炎性肌病、僵人综合征、自身免疫性神经性肌强直、副肿瘤性神经病和小脑变性，以及与全身性自身免疫性疾病、血管炎或病毒感染相关的神经系统疾病。导致这些自身免疫性疾病的事件尚不清楚，但以下连续步骤至关重要：(a) 免疫耐受的打破，在此过程中细胞因子、分子模拟或超抗原可能在使先前无反应性的T细胞识别神经自身抗原中起作用；(b) T细胞受体复合物对抗原的识别以及通过主要组织相容性复合体I类或II类对抗原的加工；(c) 共刺激因子，尤其是B7及其结合蛋白（CD28、CTLA-４）和细胞间黏附分子（ICAM）-1及其白细胞功能相关抗原（LFA）-1配体；(d) 活化的T细胞通过一系列黏附分子穿过血脑屏障或血神经屏障，这些黏附分子包括选择素、白细胞整合素（LFA-１、Mac-1、极晚期活化抗原 [VLA]-4）及其在内皮细胞上的反受体（ICAM-1、血管细胞黏附分子 [VCAM]）；以及(e) 当活化的T细胞、巨噬细胞或特异性自身抗体在神经胶质细胞、髓鞘、轴突、钙通道或肌肉上找到其抗原靶点时发生组织损伤。在设计特异性免疫疗法时，需要考虑免疫反应每个步骤中涉及的主要因素。神经系统疾病特异性治疗的靶点包括以下药物：(a) 干扰或竞争抗原识别或刺激；(b) 抑制共刺激信号或细胞因子；(c) 抑制活化细胞向组织的转运；以及(d) 在靶器官的抗原识别位点进行干预。目前用于非选择性神经免疫治疗的各种免疫调节程序和免疫抑制药物将在其对上述免疫介质的干扰背景下进行讨论。
