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IFNG +874T/A polymorphism is not associated with American tegumentary leishmaniasis susceptibility but can influence Leishmania induced IFN-gamma production.

Matos GI, Covas Cde J, Bittar Rde C, Gomes-Silva A, Marques F, Maniero VC, Amato VS, Oliveira-Neto MP, Mattos Mda S, Pirmez C, Sampaio EP, Moraes MO, Da-Cruz AM - BMC Infect. Dis. (2007)

Bottom Line: Cutaneous leishmaniasis cases exhibiting AA genotype produced lower levels of IFN-gamma than TA/TT genotypes.In mucosal cases, high and low IFN-gamma producers were clearly demonstrated but no differences in the cytokine production was observed among the IFNG +874T or A carriers.On the other hand, it is possible that in ML cases, other potential polymorphic regulatory genes such as TNF-alpha and IL-10 are also involved thus interfering with IFN-gamma secretion.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratório de Hanseníase, Departamento de Micobacterioses, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil. gmatos@ioc.fiocruz.br <gmatos@ioc.fiocruz.br>

ABSTRACT

Background: Interferon-gamma is a key cytokine in the protective responses against intracellular pathogens. A single nucleotide polymorphism (SNP) located in the first intron of the human IFN-gamma gene can putatively influence the secretion of cytokine with an impact on infection outcome as demonstrated for tuberculosis and other complex diseases. Our aim was to investigate the putative association of IFNG+874T/A SNP with American tegumentary leishmaniasis (ATL) and also the influence of this SNP in the secretion of IFN-gamma in vitro.

Methods: Brazilian ATL patients (78 cutaneous, CL, and 58 mucosal leishmaniasis, ML) and 609 healthy volunteers were evaluated. The genotype of +874 region in the IFN-gamma gene was carried out by Amplification Refractory Mutational System (ARMS-PCR). Leishmania-induced IFN-gamma production on peripheral blood mononuclear cell (PBMC) culture supernatants was assessed by ELISA.

Results: There are no differences between +874T/A SNP frequency in cases and controls or in ML versus CL patients. Cutaneous leishmaniasis cases exhibiting AA genotype produced lower levels of IFN-gamma than TA/TT genotypes. In mucosal cases, high and low IFN-gamma producers were clearly demonstrated but no differences in the cytokine production was observed among the IFNG +874T or A carriers.

Conclusion: Our results suggest that +874T/A polymorphism was not associated with either susceptibility or severity to leishmaniasis. Despite this, IFNG +874T/A SNP could be involved in the pathogenesis of leishmaniasis by influencing the amount of cytokine released by CL patients, although it could not prevent disease development. On the other hand, it is possible that in ML cases, other potential polymorphic regulatory genes such as TNF-alpha and IL-10 are also involved thus interfering with IFN-gamma secretion.

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IFN-γ levels detected in Leishmania antigens stimulated peripheral blood mononuclear cell culture supernatants from patients with cutaneous and mucosal leishmaniasis divided according the genotype group. Each symbol represents one patient. Symbols refer to ■ AA, ● TA and ▲ TT genotypes, respectively. Bars represent the median values.
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Figure 1: IFN-γ levels detected in Leishmania antigens stimulated peripheral blood mononuclear cell culture supernatants from patients with cutaneous and mucosal leishmaniasis divided according the genotype group. Each symbol represents one patient. Symbols refer to ■ AA, ● TA and ▲ TT genotypes, respectively. Bars represent the median values.

Mentions: The analysis of IFN-γ production upon Leishmania antigens stimulation showed, as expected, that differences in the IFN-γ secretion between CL and ML were very significant (p < 0.001). In order to evaluate the functional influence of SNP +874 in the production of IFN-γ (mean ± SD) observed in these clinical forms of ATL, a comparison of leishmanial induced cytokine levels produced in each genotype was carried-out (Figure 1). In ML patients, similar levels of IFN-γ were produced independently of the IFNG +874 genotype (p = 0.09): AA = 9,504 ± 7,858 pg/mL (median = 11,740 pg/mL; n = 11), TA = 9,522 ± 8,995 pg/mL (median = 5,582 pg/mL; n = 11) and TT = 2,406 ± 2,883 pg/mL (median = 1,884 pg/mL, n = 5). In addition, ML patients can be clearly (p < 0.0001) separated into two groups according to the levels of IFN-γ production: high (>10.000 pg/ml; 15,700 ± 5,866 pg/ml, n = 12) and low (<10.000 pg/ml; 2,191 ± 2,192 pg/ml, n = 15). This profile of IFN-γ producers was observed indistinctively among AA and TA genotypes. On the other hand, CL patients presented significant differences when IFN-γ production was compared among patients from the three IFNG +874 genotypes (p = 0.01). The detectable IFN-γ values were lower for +874AA individuals (844 ± 1,099 pg/mL, median = 244 pg/mL, n = 10); moderate for +874TA (2,700 ± 1,818 pg/mL, median = 2,556 pg/mL, n = 08) and high in +874TT (4,162 ± 1,678 pg/mL, n = 2). Pos-test indicates that significant differences were observed between +874AA and +874TA (p < 0.05). In 11 CL and 2 ML the IFN-γ values were under the minimum detectable levels.


IFNG +874T/A polymorphism is not associated with American tegumentary leishmaniasis susceptibility but can influence Leishmania induced IFN-gamma production.

Matos GI, Covas Cde J, Bittar Rde C, Gomes-Silva A, Marques F, Maniero VC, Amato VS, Oliveira-Neto MP, Mattos Mda S, Pirmez C, Sampaio EP, Moraes MO, Da-Cruz AM - BMC Infect. Dis. (2007)

IFN-γ levels detected in Leishmania antigens stimulated peripheral blood mononuclear cell culture supernatants from patients with cutaneous and mucosal leishmaniasis divided according the genotype group. Each symbol represents one patient. Symbols refer to ■ AA, ● TA and ▲ TT genotypes, respectively. Bars represent the median values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1878480&req=5

Figure 1: IFN-γ levels detected in Leishmania antigens stimulated peripheral blood mononuclear cell culture supernatants from patients with cutaneous and mucosal leishmaniasis divided according the genotype group. Each symbol represents one patient. Symbols refer to ■ AA, ● TA and ▲ TT genotypes, respectively. Bars represent the median values.
Mentions: The analysis of IFN-γ production upon Leishmania antigens stimulation showed, as expected, that differences in the IFN-γ secretion between CL and ML were very significant (p < 0.001). In order to evaluate the functional influence of SNP +874 in the production of IFN-γ (mean ± SD) observed in these clinical forms of ATL, a comparison of leishmanial induced cytokine levels produced in each genotype was carried-out (Figure 1). In ML patients, similar levels of IFN-γ were produced independently of the IFNG +874 genotype (p = 0.09): AA = 9,504 ± 7,858 pg/mL (median = 11,740 pg/mL; n = 11), TA = 9,522 ± 8,995 pg/mL (median = 5,582 pg/mL; n = 11) and TT = 2,406 ± 2,883 pg/mL (median = 1,884 pg/mL, n = 5). In addition, ML patients can be clearly (p < 0.0001) separated into two groups according to the levels of IFN-γ production: high (>10.000 pg/ml; 15,700 ± 5,866 pg/ml, n = 12) and low (<10.000 pg/ml; 2,191 ± 2,192 pg/ml, n = 15). This profile of IFN-γ producers was observed indistinctively among AA and TA genotypes. On the other hand, CL patients presented significant differences when IFN-γ production was compared among patients from the three IFNG +874 genotypes (p = 0.01). The detectable IFN-γ values were lower for +874AA individuals (844 ± 1,099 pg/mL, median = 244 pg/mL, n = 10); moderate for +874TA (2,700 ± 1,818 pg/mL, median = 2,556 pg/mL, n = 08) and high in +874TT (4,162 ± 1,678 pg/mL, n = 2). Pos-test indicates that significant differences were observed between +874AA and +874TA (p < 0.05). In 11 CL and 2 ML the IFN-γ values were under the minimum detectable levels.

Bottom Line: Cutaneous leishmaniasis cases exhibiting AA genotype produced lower levels of IFN-gamma than TA/TT genotypes.In mucosal cases, high and low IFN-gamma producers were clearly demonstrated but no differences in the cytokine production was observed among the IFNG +874T or A carriers.On the other hand, it is possible that in ML cases, other potential polymorphic regulatory genes such as TNF-alpha and IL-10 are also involved thus interfering with IFN-gamma secretion.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratório de Hanseníase, Departamento de Micobacterioses, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil. gmatos@ioc.fiocruz.br <gmatos@ioc.fiocruz.br>

ABSTRACT

Background: Interferon-gamma is a key cytokine in the protective responses against intracellular pathogens. A single nucleotide polymorphism (SNP) located in the first intron of the human IFN-gamma gene can putatively influence the secretion of cytokine with an impact on infection outcome as demonstrated for tuberculosis and other complex diseases. Our aim was to investigate the putative association of IFNG+874T/A SNP with American tegumentary leishmaniasis (ATL) and also the influence of this SNP in the secretion of IFN-gamma in vitro.

Methods: Brazilian ATL patients (78 cutaneous, CL, and 58 mucosal leishmaniasis, ML) and 609 healthy volunteers were evaluated. The genotype of +874 region in the IFN-gamma gene was carried out by Amplification Refractory Mutational System (ARMS-PCR). Leishmania-induced IFN-gamma production on peripheral blood mononuclear cell (PBMC) culture supernatants was assessed by ELISA.

Results: There are no differences between +874T/A SNP frequency in cases and controls or in ML versus CL patients. Cutaneous leishmaniasis cases exhibiting AA genotype produced lower levels of IFN-gamma than TA/TT genotypes. In mucosal cases, high and low IFN-gamma producers were clearly demonstrated but no differences in the cytokine production was observed among the IFNG +874T or A carriers.

Conclusion: Our results suggest that +874T/A polymorphism was not associated with either susceptibility or severity to leishmaniasis. Despite this, IFNG +874T/A SNP could be involved in the pathogenesis of leishmaniasis by influencing the amount of cytokine released by CL patients, although it could not prevent disease development. On the other hand, it is possible that in ML cases, other potential polymorphic regulatory genes such as TNF-alpha and IL-10 are also involved thus interfering with IFN-gamma secretion.

Show MeSH
Related in: MedlinePlus