The active metabolite of vitamin D, 1,25 dihydroxyvitamin D3, is an important immunoregulatory hormone [1]. Its effects are exerted by interaction with the vitamin D receptor, which is present on human monocytes and activated T and B lymphocytes. Variation in the vitamin D receptor gene was typed in 2015 subjects from large case-control studies of three major infectious diseases: tuberculosis, malaria, and hepatitis B virus. Homozygotes for a polymorphism at codon 352 (genotype tt) were significantly underrepresented among those with tuberculosis (X 2 = 6.22, 1 df, P =.01) and persistent hepatitis B infection (X 2 = 6.25, 1 df, P =.01) but not in subjects with clinical malaria compared with the other genotypes. Therefore, this genetic variant, which predisposes to low bone mineral density in many populations, may confer resistance to certain infectious diseases.

Tuberculosis and Chronic Hepatitis B Virus Infection in Africans and Variation in the Vitamin D Receptor Gene

The role of IL-10 in immune regulation during M. tuberculosis infection.

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.

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Influence of Polymorphism in the Genes for the Interleukin (IL)-1 Receptor Antagonist and IL-1β on Tuberculosis

Role of innate cytokines in mycobacterial infection

�untranslated region, were associated with TB susceptibility and resistance, respectively. Other polymorphisms associated with differential susceptibility to TB were not associated with susceptibility or resistance to TB in Cambodians. The novel pattern of genetic associations with susceptibility and resistance to TB detected in Cambodia is consistent with the conclusion that unique environmental and natural selective factors have resulted in the development of ethnic-specific host genetic factors associated with TB susceptibility and resistance worldwide. Approximately one-third of the world’s population is infected with the bacteria that causes tuberculosis (TB), Mycobacterium tuberculosis. One in 10 of those infected are estimated to progress to active TB disease. Thus, TB is a significant cause of morbidity and mortality and causes ∼2 million deaths annually [1–3]. As early as 1949, Haldane [4] proposed that the maintenance of multiple genes that confer relative susceptibilities on the host to infectious diseases would be favored by evolution. In support of this hypothesis, certain populations appear to be at risk for both increased susceptibility to infection [5] and progressive clinical disease due to mycobacteria [6–9], and several case-control studies have identified associations between TB disease and candidate genes potentially involved in the immune response to TB [10, 11].

C. Ruwende

Papers

Assessment of the interleukin 1 gene cluster and other candidate gene polymorphisms in host susceptibility to tuberculosis.