Wilkinson R J, Patel P, Llewelyn M, Hirsch C S, Pasvol G, Snounou G, Davidson R N, Toossi Z
Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio 44106-4984, USA.
J Exp Med. 1999 Jun 21;189(12):1863-74. doi: 10.1084/jem.189.12.1863.
Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. The proinflammatory cytokine interleukin (IL)-1beta and its antagonist, IL-1Ra (IL-1 receptor agonist), are strongly induced by M. tuberculosis and are encoded by polymorphic genes. The induction of both IL-1Ra mRNA and secreted protein by M. tuberculosis in IL-1Ra allele A2-positive (IL-1Ra A2(+)) healthy subjects was 1.9-fold higher than in IL-1Ra A2(-) subjects. The M. tuberculosis-induced expression of mRNA for IL-1beta was higher in subjects of the IL-1beta (+3953) A1(+) haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1beta induced by M. tuberculosis was markedly higher in IL-1Ra A2(+) individuals (P < 0.05), with minor overlap between the groups, reflecting linkage between the IL-1Ra A2 and IL-1beta (+3953) A2 alleles. In M. tuberculosis-stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon gamma increased and IL-10 decreased IL-1beta production, indicative of a differential influence on the IL-1Ra/IL-1beta ratio by cytokines. In a study of 114 healthy purified protein derivative-reactive subjects and 89 patients with tuberculosis, the frequency of allelic variants at two positions (-511 and +3953) in the IL-1beta and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2(-)/IL-1beta (+3953) A1(+) haplotype was unevenly distributed, being more common in patients with tuberculous pleurisy (92%) in comparison with healthy M. tuberculosis-sensitized control subjects or patients with other disease forms (57%, P = 0.028 and 56%, P = 0. 024, respectively). Furthermore, the IL-1Ra A2(+) haplotype was associated with a reduced Mantoux response to purified protein derivative of M. tuberculosis: 60% of tuberculin-nonreactive patients were of this type. Thus, the polymorphism at the IL-1 locus influences the cytokine response and may be a determinant of delayed-type hypersensitivity and disease expression in human tuberculosis.
多条证据表明，控制免疫反应的宿主遗传因素会影响结核分枝杆菌感染。促炎细胞因子白细胞介素（IL）-1β及其拮抗剂IL-1Ra（IL-1受体激动剂）受结核分枝杆菌强烈诱导，且由多态性基因编码。在IL-1Ra等位基因A2阳性（IL-1Ra A2(+)）的健康受试者中，结核分枝杆菌诱导的IL-1Ra mRNA和分泌蛋白水平比IL-1Ra A2(-)受试者高1.9倍。在IL-1β（+3953）A1(+)单倍型的受试者中，结核分枝杆菌诱导的IL-1β mRNA表达更高（P = 0.04）。结核分枝杆菌诱导的IL-1Ra/IL-1β摩尔比在IL-1Ra A2(+)个体中明显更高（P < 0.05），两组之间有少量重叠，反映了IL-1Ra A2和IL-1β（+3953）A2等位基因之间的连锁关系。在结核分枝杆菌刺激的外周血单核细胞中，添加IL-4会增加IL-1Ra分泌，而干扰素γ会增加、IL-10会减少IL-1β产生，这表明细胞因子对IL-1Ra/IL-1β比值有不同影响。在一项针对114名健康的纯化蛋白衍生物反应性受试者和89名结核病患者的研究中，两组之间IL-1β和IL-1Ra基因两个位置（-511和+3953）的等位基因变异频率没有差异。然而，促炎的IL-1Ra A2(-)/IL-1β（+3953）A1(+)单倍型分布不均，与健康的结核分枝杆菌致敏对照受试者或其他疾病形式的患者相比，在结核性胸膜炎患者中更常见（分别为92%、57%，P = 0.028和56%，P = 0.024）。此外，IL-1Ra A2(+)单倍型与对结核分枝杆菌纯化蛋白衍生物的结核菌素反应降低有关：60%的结核菌素无反应患者属于这种类型。因此，IL-1基因座的多态性会影响细胞因子反应，可能是人类结核病中迟发型超敏反应和疾病表现的一个决定因素。
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