Taking the brakes off NK cells. (Top) The activity of NK cells is determined by the integration of signals coming from activating receptors and inhibitory receptors such as KIR2DL. (Middle) The three interactions between HLA-C1 and HLA-C2 and KIR2DL receptors that inhibit NK cells. The weak interaction between KIR2DL3 and HLA-C1 can be easily overcome such that individuals with this genotype more readily resolve infection with hepatitis C virus than infected individuals of other genotypes (5). (Bottom) The two common chromosomal arrangements of KIR2DL genes.
正如Peter Parham在一篇研究评述中指出的，大约20%的感染丙肝病毒的人能够靠自己的免疫系统清除掉这些病毒，而世界上另外的1.8亿被丙肝病毒感染的人则患慢性肝炎，并可能会因此得肝癌或肝功能衰竭。本期一篇报告说，一个基因的组合帮助释放出一组免疫细胞，这些细胞也许帮助了那20%的人的免疫系统来清除丙肝病毒。现在还没有针对丙肝病毒的疫苗，但对研究疫苗的人来说，如果能知道是什么原因使一些人有成功的免疫反应，而另一些人的免疫系统不起作用，这将是一个帮助。为此，Salim I. Khakoo和同事研究了“自然杀手细胞”的基因多样性，自然杀手细胞一旦被激活能杀死受感染的细胞。这些英国和美国的研究人员的研究了一组自身免疫系统清除了丙肝病毒感染的人群，以及一组慢性丙肝病毒感染的人群。他们发现，第一组人的某些免疫细胞受体上携带有一个基因标记的可能性更高，这些人的自然杀手细胞能更有效地被激活。这个基因型只帮助那些通过针头感染少量丙肝病毒的人，不能帮助那些通过输血感染大量病毒的人。
NK Cells Lose Their Inhibition
Hepatitis C virus (HCV) infects more than 180 million people worldwide and can lead to liver failure or liver cancer later in life. As Parham discusses in his thought-provoking Perspective, a step toward understanding how the human immune system resolves HCV infection and to developing a vaccine has been made with the finding that infected individuals of a particular genotype more readily resolve HCV infection than infected individuals of other genotypes (Khakoo et al.).
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HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection
Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV.
Fig. 1. Progressive effect of KIR2DL3-HLA-C1 on the outcome of HCV infection in nontransfused individuals. Individuals were divided according to KIR2DL3 and HLA-C genotype. 2DL3-C1 homozygous individuals have the genotype KIR2DL3/KIR2DL3-HLA-C1C1; 2DL3-C1 heterozygous have the genotypes 2DL3/2DL3-C1C2, 2DL3/2DL2-C1C1, or 2DL3/2DL2-C1C2; 2DL3-C1 null comprise the remainder and are missing KIR2DL3, HLA-C1, or both. The odds ratios, the 95% confidence intervals for resolution of HCV as calculated from two-by-two contingency tables, and the results of a chi-square test for trend based on the number of these interactions are shown.
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