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NK cell activity differs between patients with localized and diffuse cutaneous leishmaniasis infected with Leishmania mexicana: a comparative study of TLRs and cytokines.

Cañeda-Guzmán IC, Salaiza-Suazo N, Fernández-Figueroa EA, Carrada-Figueroa G, Aguirre-García M, Becker I - PLoS ONE (2014)

Bottom Line: The altered protein expression found in NK cells of DCL patients correlated with their down-regulation of IFN-γ gene expression in LPG-stimulated and non-stimulated cells as compared to LCL patients.We conclude that in DCL patients the reduced NK-cell numbers and their diminished activity, evidenced by low TLR expression and low cytokine production, are possibly involved in the severity of the disease.Our results provide new information on the contribution of NK cells in Leishmania infections of the human host.

View Article: PubMed Central - PubMed

Affiliation: Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Hospital General de México, México, D.F., México.

ABSTRACT
Leishmania mexicana causes localized (LCL) or diffuse cutaneous leishmaniasis (DCL). The cause of dissemination in DCL remains unknown, yet NK cells possibly play a role in activating leishmanicidal mechanisms during innate and adaptive immune responses. We had previously shown that Leishmania lipophosphoglycan (LPG) is a ligand for TLR2, activating human NK cells. We have now analyzed NK cells in LCL and DCL patients. NK numbers and effector mechanisms differed drastically between both groups of patients: DCL patients showed reduced NK cell numbers; diminished IFN-γ and TNF-α production; and lower TLR2, TLR1, and TLR6 expression as compared to LCL patients. The altered protein expression found in NK cells of DCL patients correlated with their down-regulation of IFN-γ gene expression in LPG-stimulated and non-stimulated cells as compared to LCL patients. NK cell response was further analyzed according to gender, age, and disease evolution in LCL patients showing that female patients produced higher IFN-γ levels throughout the disease progression, whereas TLR2 expression diminished in both genders with prolonged disease evolution and age. We furthermore show the activation pathway of LPG binding to TLR2 and demonstrated that TLR2 forms immunocomplexes with TLR1 and TLR6. In addition to the reduced NK cell numbers in peripheral blood, DCL patients also showed reduced NK cell numbers in the lesions. They were randomly scattered within the lesions, showing diminished cytokine production, which contrasts with those of LCL lesions, where NK cells produced IFN-γ and TNF-α and were found within organized granulomas. We conclude that in DCL patients the reduced NK-cell numbers and their diminished activity, evidenced by low TLR expression and low cytokine production, are possibly involved in the severity of the disease. Our results provide new information on the contribution of NK cells in Leishmania infections of the human host.

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Related in: MedlinePlus

TLR2 expression in NK cells in LCL patients (n = 28).Analysis according to: (A) gender, (B) disease evolution (≤3 or ≥4 months) or (C) age (≤25 or ≥26 years). □ Non-stimulated NK cells, ▪ LPG-stimulated NK cells. Cell surface expression is indicated by MFI. These results are the mean ± SEM. *p≤0.05 was considered significant.
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pone-0112410-g004: TLR2 expression in NK cells in LCL patients (n = 28).Analysis according to: (A) gender, (B) disease evolution (≤3 or ≥4 months) or (C) age (≤25 or ≥26 years). □ Non-stimulated NK cells, ▪ LPG-stimulated NK cells. Cell surface expression is indicated by MFI. These results are the mean ± SEM. *p≤0.05 was considered significant.

Mentions: To ascertain whether the increased TLR2 expression found in LCL patients was related to gender, disease duration or age, we subdivided the 28 patients according to these parameters. Thus, we analyzed the TLR2 expression in 11 females and 17 males. We found that NK cells of male LCL patients expressed significantly higher levels of TLR2, as compared to females, both in non-stimulated as in LPG-stimulated cells (Fig. 4A). When analyzing TLR2 expression in NK cells according to disease progression, we found that both in males and females the expression of TLR2 diminishes significantly after four months of disease duration (Fig. 4B). The analysis of TLR2 expression according to age revealed that males ≥26 years always express higher levels of TLR2, as compared to female LCL patients of the same age group, both in non-stimulated as well as in LPG-stimulated cells (Fig. 4C).


NK cell activity differs between patients with localized and diffuse cutaneous leishmaniasis infected with Leishmania mexicana: a comparative study of TLRs and cytokines.

Cañeda-Guzmán IC, Salaiza-Suazo N, Fernández-Figueroa EA, Carrada-Figueroa G, Aguirre-García M, Becker I - PLoS ONE (2014)

TLR2 expression in NK cells in LCL patients (n = 28).Analysis according to: (A) gender, (B) disease evolution (≤3 or ≥4 months) or (C) age (≤25 or ≥26 years). □ Non-stimulated NK cells, ▪ LPG-stimulated NK cells. Cell surface expression is indicated by MFI. These results are the mean ± SEM. *p≤0.05 was considered significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232367&req=5

pone-0112410-g004: TLR2 expression in NK cells in LCL patients (n = 28).Analysis according to: (A) gender, (B) disease evolution (≤3 or ≥4 months) or (C) age (≤25 or ≥26 years). □ Non-stimulated NK cells, ▪ LPG-stimulated NK cells. Cell surface expression is indicated by MFI. These results are the mean ± SEM. *p≤0.05 was considered significant.
Mentions: To ascertain whether the increased TLR2 expression found in LCL patients was related to gender, disease duration or age, we subdivided the 28 patients according to these parameters. Thus, we analyzed the TLR2 expression in 11 females and 17 males. We found that NK cells of male LCL patients expressed significantly higher levels of TLR2, as compared to females, both in non-stimulated as in LPG-stimulated cells (Fig. 4A). When analyzing TLR2 expression in NK cells according to disease progression, we found that both in males and females the expression of TLR2 diminishes significantly after four months of disease duration (Fig. 4B). The analysis of TLR2 expression according to age revealed that males ≥26 years always express higher levels of TLR2, as compared to female LCL patients of the same age group, both in non-stimulated as well as in LPG-stimulated cells (Fig. 4C).

Bottom Line: The altered protein expression found in NK cells of DCL patients correlated with their down-regulation of IFN-γ gene expression in LPG-stimulated and non-stimulated cells as compared to LCL patients.We conclude that in DCL patients the reduced NK-cell numbers and their diminished activity, evidenced by low TLR expression and low cytokine production, are possibly involved in the severity of the disease.Our results provide new information on the contribution of NK cells in Leishmania infections of the human host.

View Article: PubMed Central - PubMed

Affiliation: Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Hospital General de México, México, D.F., México.

ABSTRACT
Leishmania mexicana causes localized (LCL) or diffuse cutaneous leishmaniasis (DCL). The cause of dissemination in DCL remains unknown, yet NK cells possibly play a role in activating leishmanicidal mechanisms during innate and adaptive immune responses. We had previously shown that Leishmania lipophosphoglycan (LPG) is a ligand for TLR2, activating human NK cells. We have now analyzed NK cells in LCL and DCL patients. NK numbers and effector mechanisms differed drastically between both groups of patients: DCL patients showed reduced NK cell numbers; diminished IFN-γ and TNF-α production; and lower TLR2, TLR1, and TLR6 expression as compared to LCL patients. The altered protein expression found in NK cells of DCL patients correlated with their down-regulation of IFN-γ gene expression in LPG-stimulated and non-stimulated cells as compared to LCL patients. NK cell response was further analyzed according to gender, age, and disease evolution in LCL patients showing that female patients produced higher IFN-γ levels throughout the disease progression, whereas TLR2 expression diminished in both genders with prolonged disease evolution and age. We furthermore show the activation pathway of LPG binding to TLR2 and demonstrated that TLR2 forms immunocomplexes with TLR1 and TLR6. In addition to the reduced NK cell numbers in peripheral blood, DCL patients also showed reduced NK cell numbers in the lesions. They were randomly scattered within the lesions, showing diminished cytokine production, which contrasts with those of LCL lesions, where NK cells produced IFN-γ and TNF-α and were found within organized granulomas. We conclude that in DCL patients the reduced NK-cell numbers and their diminished activity, evidenced by low TLR expression and low cytokine production, are possibly involved in the severity of the disease. Our results provide new information on the contribution of NK cells in Leishmania infections of the human host.

Show MeSH
Related in: MedlinePlus