Lachmann P J, Walport M J
Mechanisms in Tumour Immunity Unit, MRC Centre, Cambridge, UK.
Ciba Found Symp. 1987;129:149-71. doi: 10.1002/9780470513484.ch11.
It has long been the conventional wisdom that most autoimmune responses represent a pathological aberration of the immune system and a great deal of effort has been devoted to investigating how such abnormal responses may be induced. It seems likely, however, particularly in the form of autoimmunity seen in diseases like systemic lupus erythematosus (LE) and associated with immune complex disease, that it is not the induction of the autoimmune response that is primarily abnormal, but its persistence, and that this abnormal persistence is a consequence of a failure of the proper functioning of the effector mechanisms of the immune response. The strongest reason for so believing is the striking incidence of these diseases in subjects with deficiencies of the early components of the classical complement pathway. Total, homozygous deficiencies are rare and account for only a small proportion of patients with systemic LE. However, partial, heterozygous deficiency of these components is much commoner and also carries an increased susceptibility to these diseases. An explanation for this association is given. In the presence of an adequately functioning complement system immune complexes remain soluble and of relatively small size. It is proposed that this is a result of the incorporation of C4 and C3 into the antigen-antibody lattice leading to a reduction in the effective valency of antigen and antibody. The Goldberg theory of immune precipitation predicts that a reduction in valency would inhibit precipitation and the formation of large complexes. In the absence of adequate complement function this mechanism will fail and large, potentially insoluble complexes with little C4 and C3 on them will be formed. These large immune complexes without sufficient C4 and C3 bound on them will also not be bound normally to erythrocyte CR1 and will therefore be transported in the (peripheral) plasma stream rather than in the (central) erythrocyte stream. It is proposed that this will result in the deposition of immune complexes in peripheral small blood vessels rather than in the sinusoids of the liver and spleen; and that this peripheral deposition gives rise to inflammation, with the release of autoantigens and the formation of further autoantibodies. The importance of CR1 in relation to these diseases is emphasized by the reduction in CR1 numbers that accompanies their active phase. This appears to be due to proteolysis of the receptor while the immune complex-bearing erythrocyte is sequestered in the reticuloendothelial system.
长期以来，传统观点认为大多数自身免疫反应代表免疫系统的病理异常，人们投入了大量精力来研究这种异常反应是如何诱导产生的。然而，特别是在系统性红斑狼疮（LE）等疾病中出现的自身免疫形式，并与免疫复合物疾病相关联的情况下，似乎主要异常的并非自身免疫反应的诱导，而是其持续性，并且这种异常持续性是免疫反应效应机制正常功能失败的结果。如此认为的最有力理由是，在经典补体途径早期成分缺乏的个体中，这些疾病的发病率惊人。完全的纯合子缺乏很少见，仅占系统性LE患者的一小部分。然而，这些成分的部分杂合子缺乏则更为常见，并且也会增加患这些疾病的易感性。文中给出了这种关联的一种解释。在补体系统功能正常的情况下，免疫复合物保持可溶且尺寸相对较小。据推测，这是由于C4和C3掺入抗原 - 抗体晶格导致抗原和抗体的有效价降低的结果。戈德堡免疫沉淀理论预测，价的降低会抑制沉淀和大复合物的形成。在缺乏足够补体功能的情况下，该机制将失效，会形成带有少量C4和C3的大的、潜在不溶性复合物。这些没有足够C4和C3结合在其上的大免疫复合物也不会正常地与红细胞CR1结合，因此将在（外周）血浆流中运输，而不是在（中央）红细胞流中运输。据推测，这将导致免疫复合物在外周小血管中沉积，而不是在肝脏和脾脏的血窦中沉积；并且这种外周沉积会引发炎症，释放自身抗原并形成更多自身抗体。在这些疾病的活动期，CR1数量的减少强调了CR1与这些疾病的相关性。这似乎是由于在免疫复合物携带的红细胞被隔离在网状内皮系统时，受体发生了蛋白水解作用。
