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Associations between hepcidin and immune response in individuals with hyperbilirubinaemia and severe malaria due to Plasmodium vivax infection.

Mendonça VR, Souza LC, Garcia GC, Magalhães BM, Gonçalves MS, Lacerda MV, Barral-Netto M - Malar. J. (2015)

Bottom Line: The polymorphism 744 G > T in the ferroportin gene was identified by restriction fragment-length polymorphism analysis and the restriction enzyme PvuII.The polymorphism at position 744 G > T in the ferroportin gene was typed and no differences in the distributions of genotypes or alleles were observed between the study groups.Hepcidin levels are positively associated with immune markers in vivax malaria outcomes.

View Article: PubMed Central - PubMed

Affiliation: Laboratório Integrado de Microbiogia e Imunoregulação (LIMI), Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil. vitorrosaramos@hotmail.com.

ABSTRACT

Background: Hyperbilirubinaemia (bilirubin >51.3 μmol/L) alone is not indicative of severe malaria, and the immune response underlying hyperbilirubinaemia remains largely unexplored. Liver damage associated with hyperbilirubinaemia may alter the expression of hepcidin, which regulates systemic iron by degrading ferroportin. For this study, the association between hepcidin and the levels of cytokines and chemokines in the serum of individuals with mild and severe vivax malaria and subjects with malaria with isolated hyperbilirubinaemia was evaluated.

Methods: Cytokines/chemokines and hepcidin were measured in individuals with mild (n = 72) and severe (n = 17) vivax malaria, as well as in the serum of subjects with vivax malaria with isolated hyperbilirubinaemia (n = 14) from the Brazilian Amazon between 2009 and 2013 by multiplex assay and ELISA, respectively. The polymorphism 744 G > T in the ferroportin gene was identified by restriction fragment-length polymorphism analysis and the restriction enzyme PvuII.

Results: The polymorphism at position 744 G > T in the ferroportin gene was typed and no differences in the distributions of genotypes or alleles were observed between the study groups. Subjects with severe malaria had higher levels of interleukin (IL)-2 and IL-13 than subjects with hyperbilirubinaemia. No differences in the expression of immune markers were observed between subjects with mild malaria and those with hyperbilirubinaemia. However, hepcidin levels were higher in individuals with severe malaria and hyperbilirubinaemia than those with mild malaria (p = 0.0002 and p = 0.0004, respectively) and cut-off values of hepcidin differentiated these groups from subjects with mild malaria. Hepcidin was positively associated with IL-6 and IL-10 levels and with parasitaemia in subjects with mild malaria and with IFN-γ in subjects with severe malaria.

Conclusions: Malaria in the presence of hyperbilirubinaemia produces a less robust inflammatory response compared to severe cases of malaria. Hepcidin levels are positively associated with immune markers in vivax malaria outcomes.

No MeSH data available.


Related in: MedlinePlus

Concentration of cytokines and chemokines according to study groups. A heat map was designed to depict the overall pattern of expression of immune markers in the different study groups according to the median value of each parameter (a). A two-way hierarchical cluster analysis (Ward’s method) of immune molecules by clinical group was performed (a). Biomarkers that had the same median in the three groups were excluded from the heat map and cluster analysis. The colours shown for each symbol represent the fold variation from the median values calculated for each marker (a). Differentiation between mild malaria and hyperbilirubinaemia, hyperbilirubinaemia and severe malaria, and mild malaria and severe malaria were noted by cytokine and chemokine levels using a multinominal regression analysis adjusted for age and gender that calculated odds ratios (ORs) and 95 % confidence intervals (CI), represented by the icons and bars, respectively (b). Red icons represent a statistically significant difference. A p-value <0.05 was considered statistically significant
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Fig2: Concentration of cytokines and chemokines according to study groups. A heat map was designed to depict the overall pattern of expression of immune markers in the different study groups according to the median value of each parameter (a). A two-way hierarchical cluster analysis (Ward’s method) of immune molecules by clinical group was performed (a). Biomarkers that had the same median in the three groups were excluded from the heat map and cluster analysis. The colours shown for each symbol represent the fold variation from the median values calculated for each marker (a). Differentiation between mild malaria and hyperbilirubinaemia, hyperbilirubinaemia and severe malaria, and mild malaria and severe malaria were noted by cytokine and chemokine levels using a multinominal regression analysis adjusted for age and gender that calculated odds ratios (ORs) and 95 % confidence intervals (CI), represented by the icons and bars, respectively (b). Red icons represent a statistically significant difference. A p-value <0.05 was considered statistically significant

Mentions: A panel of 17 cytokines and chemokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17, IFN-γ, TNF, CCL2, CCL4, GCSF, GMCSF) and inflammatory ratios (TNF/IL-10, IFN-γ/IL-10 and (TNF + IFN-γ)/IL-10) were used to build a heat map to identify unique signatures that could highlight differences between the study groups in a hierarchical cluster analysis (Fig. 2a). Among the clinical groups evaluated, individuals with severe malaria exhibited the highest median concentrations of the majority of the immune markers (GCSF, IFN-γ, IL-7, IL-2, IL-12p70, IL-13, IL-17, TNF, IL-4, IL-8, IL-6, IFN-γ/IL-10, TNF/IL-10, CCL2, and (TNF + IFN-γ)/IL-10; Fig. 2a). Subjects with mild malaria exhibited the highest plasma levels of IL-10 (Fig. 2a).Fig. 2


Associations between hepcidin and immune response in individuals with hyperbilirubinaemia and severe malaria due to Plasmodium vivax infection.

Mendonça VR, Souza LC, Garcia GC, Magalhães BM, Gonçalves MS, Lacerda MV, Barral-Netto M - Malar. J. (2015)

Concentration of cytokines and chemokines according to study groups. A heat map was designed to depict the overall pattern of expression of immune markers in the different study groups according to the median value of each parameter (a). A two-way hierarchical cluster analysis (Ward’s method) of immune molecules by clinical group was performed (a). Biomarkers that had the same median in the three groups were excluded from the heat map and cluster analysis. The colours shown for each symbol represent the fold variation from the median values calculated for each marker (a). Differentiation between mild malaria and hyperbilirubinaemia, hyperbilirubinaemia and severe malaria, and mild malaria and severe malaria were noted by cytokine and chemokine levels using a multinominal regression analysis adjusted for age and gender that calculated odds ratios (ORs) and 95 % confidence intervals (CI), represented by the icons and bars, respectively (b). Red icons represent a statistically significant difference. A p-value <0.05 was considered statistically significant
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4607001&req=5

Fig2: Concentration of cytokines and chemokines according to study groups. A heat map was designed to depict the overall pattern of expression of immune markers in the different study groups according to the median value of each parameter (a). A two-way hierarchical cluster analysis (Ward’s method) of immune molecules by clinical group was performed (a). Biomarkers that had the same median in the three groups were excluded from the heat map and cluster analysis. The colours shown for each symbol represent the fold variation from the median values calculated for each marker (a). Differentiation between mild malaria and hyperbilirubinaemia, hyperbilirubinaemia and severe malaria, and mild malaria and severe malaria were noted by cytokine and chemokine levels using a multinominal regression analysis adjusted for age and gender that calculated odds ratios (ORs) and 95 % confidence intervals (CI), represented by the icons and bars, respectively (b). Red icons represent a statistically significant difference. A p-value <0.05 was considered statistically significant
Mentions: A panel of 17 cytokines and chemokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17, IFN-γ, TNF, CCL2, CCL4, GCSF, GMCSF) and inflammatory ratios (TNF/IL-10, IFN-γ/IL-10 and (TNF + IFN-γ)/IL-10) were used to build a heat map to identify unique signatures that could highlight differences between the study groups in a hierarchical cluster analysis (Fig. 2a). Among the clinical groups evaluated, individuals with severe malaria exhibited the highest median concentrations of the majority of the immune markers (GCSF, IFN-γ, IL-7, IL-2, IL-12p70, IL-13, IL-17, TNF, IL-4, IL-8, IL-6, IFN-γ/IL-10, TNF/IL-10, CCL2, and (TNF + IFN-γ)/IL-10; Fig. 2a). Subjects with mild malaria exhibited the highest plasma levels of IL-10 (Fig. 2a).Fig. 2

Bottom Line: The polymorphism 744 G > T in the ferroportin gene was identified by restriction fragment-length polymorphism analysis and the restriction enzyme PvuII.The polymorphism at position 744 G > T in the ferroportin gene was typed and no differences in the distributions of genotypes or alleles were observed between the study groups.Hepcidin levels are positively associated with immune markers in vivax malaria outcomes.

View Article: PubMed Central - PubMed

Affiliation: Laboratório Integrado de Microbiogia e Imunoregulação (LIMI), Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil. vitorrosaramos@hotmail.com.

ABSTRACT

Background: Hyperbilirubinaemia (bilirubin >51.3 μmol/L) alone is not indicative of severe malaria, and the immune response underlying hyperbilirubinaemia remains largely unexplored. Liver damage associated with hyperbilirubinaemia may alter the expression of hepcidin, which regulates systemic iron by degrading ferroportin. For this study, the association between hepcidin and the levels of cytokines and chemokines in the serum of individuals with mild and severe vivax malaria and subjects with malaria with isolated hyperbilirubinaemia was evaluated.

Methods: Cytokines/chemokines and hepcidin were measured in individuals with mild (n = 72) and severe (n = 17) vivax malaria, as well as in the serum of subjects with vivax malaria with isolated hyperbilirubinaemia (n = 14) from the Brazilian Amazon between 2009 and 2013 by multiplex assay and ELISA, respectively. The polymorphism 744 G > T in the ferroportin gene was identified by restriction fragment-length polymorphism analysis and the restriction enzyme PvuII.

Results: The polymorphism at position 744 G > T in the ferroportin gene was typed and no differences in the distributions of genotypes or alleles were observed between the study groups. Subjects with severe malaria had higher levels of interleukin (IL)-2 and IL-13 than subjects with hyperbilirubinaemia. No differences in the expression of immune markers were observed between subjects with mild malaria and those with hyperbilirubinaemia. However, hepcidin levels were higher in individuals with severe malaria and hyperbilirubinaemia than those with mild malaria (p = 0.0002 and p = 0.0004, respectively) and cut-off values of hepcidin differentiated these groups from subjects with mild malaria. Hepcidin was positively associated with IL-6 and IL-10 levels and with parasitaemia in subjects with mild malaria and with IFN-γ in subjects with severe malaria.

Conclusions: Malaria in the presence of hyperbilirubinaemia produces a less robust inflammatory response compared to severe cases of malaria. Hepcidin levels are positively associated with immune markers in vivax malaria outcomes.

No MeSH data available.


Related in: MedlinePlus