IgA肾病和紫癜性肾炎患者白细胞介素-1受体拮抗剂基因多态性的功能研究

Functional significance of IL1 receptor antagonist gene polymorphism in IgA nephropathy and HenochSchonlein nephritis

目的阐明白细胞介素１受体拮抗剂（ＩＬ１ｒａ）基因多态性对其功能的影响，论证ＩＬ１ｒａ基因型与ＩｇＡ肾病（ＩｇＡＮ）及紫癜性肾炎（ＨＳＰＮ）临床表型之间联系的机理。方法用ＰＣＲ方法对ＩｇＡＮ和ＨＳＰＮ患者ＩＬ１ｒａ基因型进行分析，从ＩＬ１ｒａ不同基因型患者获取外周血单核细胞，观察单核细胞经单核巨噬细胞集落刺激因子（ＧＭＣＳＦ）刺激后，ＩＬ１ｒａ、ＩＬ１α和ＩＬ１β的产生能力。结果无论是ＩｇＡＮ，还是ＨＳＰＮ患者，携带ＩＬ１ｒａ基因ＩＬ１ＲＮ＊２等位基因者其单核细胞ＩＬ１ｒａ的产生能力明显低于不携带该等位基因的个体，而ＩＬ１α和ＩＬ１β的产生能力与是否携带ＩＬ１ＲＮ＊２等位基因无关。结论ＩＬ１ｒａ基因多态性能对其功能产生影响。携带ＩＬ１ＲＮ＊２等位基因者其体内ＩＬ１ｒａ的产生能力存在缺陷。该结果为临床上根据ＩＬ１ｒａ基因型有针对地采取干预治疗奠定了基础。

Objective To further explore the underlying mechanism of the association between IL1 receptor antagonist(IL1ra) gene polymorphism and disease phenotype,the functional significance of IL1ra gene polymorphism was studied. Methods The genotype of IL1ra was detected by PCR.Peripheral monocytes obtained from patients with IgA nephropathy ,HenochSchonlein nephritisN*2(-),n=6;IL1RN*2(+),n=6] and normal controls]were cultured and stimulated by GMCSF(10ng/ml).IL1ra,IL1 and IL1 contents in the supernatant were measured by ELISA method. ResultsGMCSF was found to be able to stimulate the production of IL1ra,IL1 and IL1 by monocytes in general,but the amount of production of IL1ra varied in individuals of different genotypes.The amount of IL1ra production was significantly lower in individuals with the IL1RN*2 allele as compared to those without this allele both in IgA nephropathy and HonochScgonlein nephritis,while there were no differences in the production of IL1 and IL1 in patient with or without the IL1RN*2 allele. Conclusion The individuals carrying the IL1RN*2 allele have a lower circulating level of IL1ra in response to inflammation thereby inducing an increased activity of IL1 which could be responsible for trigging the development of clinical manifestation in IgA nephropathy and HenochSchonlein nephritis.Administration of rhIL1ra might attenuate the cytokin response and improve the clinical manifestation in these patients,particularly to those with the IL1RN*2 allele.