Complotype affects the extent of down-regulation by Factor I of the C3b feedback cycle in vitro
Complotype affects the extent of down-regulation by Factor I of the C3b feedback cycle in vitro
复制标题
DOI：
10.1111/cei.12437
复制
发表时间：
2015-08-01
影响因子：
4.6
通讯作者：
Lachmann, P. J.
中科院分区：
文献类型：
--
作者：
Lay, E.;Nutland, S.;Lachmann, P. J.
对来自一大组正常受试者的血清进行了三种常见多态性的分型，一种在C3（R102 G）中，两种在因子H（V62 I和Y 402 H）中，这些多态性影响年龄相关性黄斑变性和某些形式的肾脏疾病的易感性。检测了三组血清：三种风险等位基因纯合的血清;三种风险等位基因杂合的血清;低风险等位基因纯合的血清。当旁路补体途径被酵母聚糖激活时，这些组对加入外源性因子I的反应不同。iC 3b形成的最大量的减少和iC 3b转化为C3 dg的速率都受到影响。对于这两种反应，有风险的补体型需要更高剂量的因子I来产生类似的下调。由于与补体受体CR 3反应的iC 3b是补体活化引起炎症的主要机制，因此可以看出iC 3b分解为C3 dg对于减少补体诱导的炎症具有重要意义。这些发现首次证明，来自具有不同补体等位基因的受试者的血清的行为与通过增加因子I的浓度而下调补体旁路途径的体外测定中预测的一样。这些结果支持这样的假设，即外源性因子I可能是下调C3 b反馈循环的过度活跃的有价值的治疗辅助物，从而为年龄相关性黄斑变性和晚年的其他炎性疾病提供治疗。
Sera from a large panel of normal subjects were typed for three common polymorphisms, one in C3 (R102G) and two in Factor H (V62I and Y402H), that influence predisposition to age-related macular degeneration and to some forms of kidney disease. Three groups of sera were tested; those that were homozygous for the three risk alleles; those that were heterozygous for all three; and those homozygous for the low-risk alleles. These groups vary in their response to the addition of exogenous Factor I when the alternative complement pathway is activated by zymosan. Both the reduction in the maximum amount of iC3b formed and the rate at which the iC3b is converted to C3dg are affected. For both reactions the at-risk complotype requires higher doses of Factor I to produce similar down-regulation. Because iC3b reacting with the complement receptor CR3 is a major mechanism by which complement activation gives rise to inflammation, the breakdown of iC3b to C3dg can be seen to have major significance for reducing complement-induced inflammation. These findings demonstrate for the first time that sera from subjects with different complement alleles behave as predicted in an in-vitro assay of the down-regulation of the alternative complement pathway by increasing the concentration of Factor I. These results support the hypothesis that exogenous Factor I may be a valuable therapeutic aid for down-regulating hyperactivity of the C3b feedback cycle, thereby providing a treatment for age-related macular degeneration and other inflammatory diseases of later life.