Tumor necrosis factor-alpha promoter polymorphism TNF2 is associated with a stronger delayed-type hypersensitivity reaction in the skin of borderline tuberculoid leprosy patients

Tropical Medicine Department, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil.
Immunogenetics (Impact Factor: 2.23). 03/2001; 53(1):45-7.
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Available from: Alexandre Silva de Almeida, May 02, 2014
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    • "The only haplotype carrying both alleles associated with a more stable mRNA or less mRNA decay is UTR-1, that is, all these patients were homozygous for the UTR-1 haplotype, and UTR-1/ UTR-1 homozygous has been implicated in high soluble HLA-G expression (Cristofaro et al. 2012). It was reported that T-cell activation induces HLA-G+ Treg cells to produce high levels of IL-10, which are responsible for T responder cell shift in cytokine expression from IFN-c to IL-10-producing cells (Moraes et al. 2001; Walker and Lockwood 2006; Huang et al. 2009). It was also reported that a sustained leprosy antigen stimulus due to the deficient cell-mediated immunity in LL is responsible for the imbalance between T-effector and T reg cells and the consequent Th2 immune phenotype observed in LL patients (Attia et al. 2010; Sampaio et al. 2012). "
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    ABSTRACT: Considering that variability in immune response genes has been associated with susceptibility to leprosy and with disease severity, leprosy presents clinicopathological variants that are highly associated with the immune response, HLA-G has a well-recognized role in the modulation of the immune response, and polymorphisms at the 3' untranslated region (UTR) of the HLA-G gene may influence HLA-G production, we studied the polymorphic sites at the 3' UTR of the HLA-G gene in leprosy and their association with disease severity. We evaluated by sequencing analysis the allele, genotype, and haplotype frequencies of the 3' UTR HLA-G polymorphic sites (14-bpINDEL/+3003C-T/+3010C-G/+3027A-C/+3035C-T/+3142C-G/+3187A-G/+3196C-G) in 146 individuals presenting reactive leprosy from a highly endemic area, and associated with bacillary load and the type of reactive leprosy. A total of 128 healthy subjects were also studied. Allele, genotype, and haplotype frequencies for the 3' UTR HLA-G polymorphisms in leprosy patients did not differ from those observed in healthy donors. The +3187A allele was responsible for protection against the development of multibacillary leprosy in a dominant model (AA + AG)/GG, OR = 0.11, P = 0.018), and the +3187A allele and +3187A-A genotype were overrepresented in type II reactive leprosy reaction. The effect of genetic factors on leprosy susceptibility may be hidden by environmental components in highly endemic areas. The HLA-G + 3187A polymorphic site, which is related to unstable mRNA production, was associated with the development of polar forms of leprosy and reactive leprosy reaction.
    Full-text · Article · Sep 2013
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    • "Studies conducted in Brazil by Santos et al. [43], Moraes et al. [44], Santos et al. [45], Franceschi et al. [46], and Cardoso et al. [47] indicated the association of TNF-308A (rs1800629) allele with a protective effect against the development of the disease. Vanderborght et al. [101], in a study in Rio de Janeiro, observed that patients possessing an A allele in the promoter region of TNF-308 had a lower bacteriological index (BI), whereas the carriers of the A allele in the promoter region of TNF-238 (rs361525) had higher BI. "
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    ABSTRACT: Many genes including HLA, KIR, and MICA genes, as well as polymorphisms in cytokines have been investigated for their role in infectious disease. HLA alleles may influence not only susceptibility or resistance to leprosy, but also the course of the disease. Some combinations of HLA and KIR may result in negative as well as positive interactions between NK cells and infected host cells with M. leprae, resulting in activation or inhibition of NK cells and, consequently, in death of bacillus. In addition, studies have demonstrated the influence of MICA genes in the pathogenesis of leprosy. Specifically, they may play a role in the interaction between NK cells and infected cells. Finally, pro- and anti-inflammatory cytokines have been influencing the clinical course of leprosy. Data from a wide variety of sources support the existence of genetic factors influencing the leprosy pathogenesis. These sources include twin studies, segregation analyses, family-based linkage and association studies, candidate gene association studies, and, most recently, genome-wide association studies (GWAS). The purpose of this brief review was to highlight the importance of some immune response genes and their correlation with the clinical forms of leprosy, as well as their implications for disease resistance and susceptibility.
    Full-text · Article · Jul 2013
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    • "The Mitsuda response measures the granulomatous response to intradermally injected heat-killed leprosy bacilli (lepromin) and reflects the ability to develop an immune-inflammatory response against M. leprae antigens. Results of family-based studies have linked the quantitative Mitsuda response to polymorphisms in the NRAMP1 gene (Alcais et al. 2000), while population studies have reported a role for TNF SNPs (Moraes et al. 2001). Here, no differences were found when the quantitative Mitsuda response was compared in ?874T carriers and non-carriers even after the stratification of the patients according to the covariates, BCG vaccination and reversal reaction. "
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    ABSTRACT: Leprosy is a chronic infectious disease caused by Mycobacterium leprae, a low virulence mycobacterium, and the outcome of disease is dependent on the host genetics for either susceptibility per se or severity. The IFNG gene codes for interferon-γ (IFN-γ), a cytokine that plays a key role in host defense against intracellular pathogens. Indeed, single nucleotide polymorphisms (SNPs) in IFNG have been evaluated in several genetic epidemiological studies, and the SNP +874T>A, the +874T allele, more specifically, has been associated with protection against infectious diseases, especially tuberculosis. Here, we evaluated the association of the IFNG locus with leprosy enrolling 2,125 Brazilian subjects. First, we conducted a case-control study with subjects recruited from the state of São Paulo, using the +874 T>A (rs2430561), +2109 A>G (rs1861494) and rs2069727 SNPs. Then, a second study including 1,370 individuals from Rio de Janeiro was conducted. Results of the case-control studies have shown a protective effect for +874T carriers (OR(adjusted) = 0.75; p = 0.005 for both studies combined), which was corroborated when these studies were compared with literature data. No association was found between the SNP +874T>A and the quantitative Mitsuda response. Nevertheless, the spontaneous IFN-γ release by peripheral blood mononuclear cells was higher among +874T carriers. The results shown here along with a previously reported meta-analysis of tuberculosis studies indicate that the SNP +874T>A plays a role in resistance to mycobacterial diseases.
    Full-text · Article · Nov 2010 · Human Genetics
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