Lucisano Valim Y M, Lachmann P J
Molecular Immunopathology Unit, Medical Research Council Centre, Cambridge, England.
Clin Exp Immunol. 1991 Apr;84(1):1-8. doi: 10.1111/j.1365-2249.1991.tb08115.x.
A systematic study has been carried out to investigate the role of immunoglobulin isotype, epitope density, and antigen/antibody ratio on the capacity of immune complexes to activate the classical and alternative pathways of human complement and for the complexes subsequently to bind to erythrocyte C3b-C4b receptors (CRI). For this purpose, a series of chimaeric monoclonal anti-NIP antibodies was used, which all shared the same combining site but had different human constant domains. Antigen epitope density was varied by coupling different numbers of NIP hapten molecules to bovine serum albumin. All three parameters affect complement fixation. In general, complement activation is better in antibody excess and at equivalence than it is in antigen excess, and better at high epitope density than at low epitope density, although the effects are variable for different immunoglobulin isotypes and for the two pathways. It has been confirmed that IgG1 and IgG3 are good activators of the classical pathway and are tolerant to variations in both epitope density and antigen/antibody ratio. IgG4 and IgA do not activate the classical pathway in any circumstances. IgG2 activates the classical pathway only at high epitope density and at equivalence or antibody excess. IgM activates the classical pathway well only at the higher epitope densities and at equivalence or antibody excess but, in addition, shows an interesting and unexpected prozone phenomenon where immune complex in antibody excess inhibits complement activation by the classical pathway. The results of the alternative pathway activation are strikingly different. IgA is by far the best activator of the alternative pathway and is relatively tolerant to epitope density and to antigen/antibody ratio. IgM, IgG1 and IgG3 do not significantly activate the alternative pathway in any circumstances. IgG2 is the best IgG subclass for alternative pathway activation but requires high epitope density and equivalence or antibody excess. Binding to CR1 in general parallels the amount of complement fixed independent to the pathway by which it is fixed. However, IgG1 and IgG3 complexes in antigen excess activate complement well but bind poorly to CR1. Nascently formed complexes seem to bind complement in a way that is similar to that bound by preformed complexes, but are then less able to bind to red cell CR1. These observations help to explain the pathogenesis of complement activation in various autoimmune and immune complex diseases such as systemic lupus erythematosus, autoimmune thyroiditis and others.
已开展一项系统性研究，以调查免疫球蛋白同种型、表位密度以及抗原/抗体比率对免疫复合物激活人类补体经典途径和替代途径的能力，以及对这些复合物随后与红细胞C3b - C4b受体（CR1）结合能力的作用。为此，使用了一系列嵌合型抗NIP单克隆抗体，它们都具有相同的结合位点，但有不同的人恒定区。通过将不同数量的NIP半抗原分子偶联到牛血清白蛋白上，改变抗原表位密度。所有这三个参数均影响补体固定。一般来说，在抗体过量和等价时补体激活比在抗原过量时更好，在高表位密度时比在低表位密度时更好，尽管不同免疫球蛋白同种型和两条途径的影响有所不同。已证实，IgG1和IgG3是经典途径的良好激活剂，并且耐受表位密度和抗原/抗体比率的变化。IgG4和IgA在任何情况下都不激活经典途径。IgG2仅在高表位密度以及等价或抗体过量时激活经典途径。IgM仅在较高表位密度以及等价或抗体过量时能很好地激活经典途径，但此外，还表现出一种有趣且意想不到的前带现象，即抗体过量时的免疫复合物会抑制经典途径的补体激活。替代途径激活的结果显著不同。IgA是替代途径迄今为止最好的激活剂，并且相对耐受表位密度和抗原/抗体比率。IgM、IgG1和IgG3在任何情况下都不会显著激活替代途径。IgG2是替代途径激活的最佳IgG亚类，但需要高表位密度以及等价或抗体过量。与CR1的结合一般与补体固定量平行，与补体固定的途径无关。然而，抗原过量时的IgG1和IgG3复合物能很好地激活补体，但与CR1的结合较差。新形成的复合物似乎以与预先形成的复合物相似的方式结合补体，但随后与红细胞CR1的结合能力较弱。这些观察结果有助于解释各种自身免疫性疾病和免疫复合物疾病（如系统性红斑狼疮、自身免疫性甲状腺炎等）中补体激活的发病机制。
