White B
University of Maryland School of Medicine, Baltimore, USA.
Rheum Dis Clin North Am. 1996 Nov;22(4):695-708. doi: 10.1016/s0889-857x(05)70296-9.
The information outlined above can be used to generate a model of the immunopathogenesis of SSc (Fig. 3). This model includes a susceptible host, with age greater than 25 and female gender being risk factors. The model also includes exposure to exogenous agents, which could be different in different individuals and may include inhaled or ingested chemicals or infectious agents. An early event is T-cell activation, with infiltration in the skin and internal organs. Activation of the T cells is a selective process that appears to be influenced by antigen in SSc patients. The importance of a particular T-cell subpopulation may depend upon the organ involved and the stage of the disease. CD4+ T cells predominate in the skin. In contrast, CD8+ T cells are increased in the lungs of patients with alveolitis, where they are oligoclonal, showing evidence of antigen-driven selection. V delta 1+ gamma/delta T cells are increased in both the blood and lungs of SSc patients and also show evidence of selection by antigen. B cells are activated early, with polyclonal activation leading to hypergammaglobulinemia. SSc-specific autoantibodies target DNA topoisomerase I, centromeric proteins, and RNA polymerases I and III. Characteristics of autoantibodies in SSc suggest that the target antigens are presented to the immune system as native molecules or even part of a multiunit complex. There is some homology between viruses and autoantibody targets in SSc, which suggests that molecular mimicry may play a role in initiating the antibody response. Many nonspecific inflammatory cells infiltrate the tissues and show evidence of activation. These include macrophages and monocytes, mast cells, eosinophils, basophils, and natural killer cells. Soluble mediators made by these T cells, B cells, and nonspecific inflammatory cells can activate and damage fibroblasts, endothelial cells, and other vascular cells. The relative importance of the various candidate cytokines, the temporal sequence of their production, and their cellular sources remain largely to be defined. There may be some contribution of direct T-cell cytotoxicity or antibody-dependent cellular cytoxicity to the tissue damage that occurs.
上述信息可用于构建系统性硬化症免疫发病机制的模型（图3）。该模型包括一个易感宿主，年龄大于25岁且女性为风险因素。该模型还包括接触外源性因素，不同个体接触的外源性因素可能不同，可能包括吸入或摄入的化学物质或感染因子。早期事件是T细胞活化，并浸润至皮肤和内脏器官。T细胞的活化是一个选择性过程，似乎受系统性硬化症患者体内抗原的影响。特定T细胞亚群的重要性可能取决于受累器官和疾病阶段。CD4+ T细胞在皮肤中占主导。相比之下，在患有肺泡炎的患者肺部，CD8+ T细胞增多，这些细胞是寡克隆性的，显示出抗原驱动选择的证据。Vδ1+γ/δ T细胞在系统性硬化症患者的血液和肺部均增多，也显示出抗原选择的证据。B细胞早期被激活，多克隆激活导致高球蛋白血症。系统性硬化症特异性自身抗体靶向DNA拓扑异构酶I、着丝粒蛋白以及RNA聚合酶I和III。系统性硬化症自身抗体的特征表明，靶抗原作为天然分子甚至多聚体复合物的一部分呈递给免疫系统。系统性硬化症中病毒与自身抗体靶标之间存在一些同源性，这表明分子模拟可能在引发抗体反应中起作用。许多非特异性炎性细胞浸润组织并显示出活化的证据。这些细胞包括巨噬细胞和单核细胞、肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞和自然杀伤细胞。这些T细胞、B细胞和非特异性炎性细胞产生的可溶性介质可激活并损伤成纤维细胞、内皮细胞和其他血管细胞。各种候选细胞因子的相对重要性、它们产生的时间顺序以及细胞来源在很大程度上仍有待确定。直接的T细胞细胞毒性或抗体依赖性细胞毒性可能对发生的组织损伤有一定作用。
