Insights into deregulated TNF and IL-10 production in malaria: implications for understanding severe malarial anaemia

TY - JOUR

T1 - Insights into deregulated TNF and IL-10 production in malaria

T2 - implications for understanding severe malarial anaemia

AU - Boeuf, Philippe S

AU - Loizon, Séverine

AU - Awandare, Gordon A

AU - Tetteh, John Ka

AU - Addae, Michael M

AU - Adjei, George O

AU - Goka, Bamenla

AU - Kurtzhals, Jørgen Al

AU - Puijalon, Odile

AU - Hviid, Lars

AU - Akanmori, Bartholomew D

AU - Behr, Charlotte

PY - 2012

Y1 - 2012

N2 - Background: Severe malarial anaemia (SMA) is a major life-threatening complication of paediatric malaria. Protracted production of pro-inflammatory cytokines promoting erythrophagocytosis and depressing erythropoiesis is thought to play an important role in SMA, which is characterized by a high TNF/IL-10 ratio. Whether this TNF/IL-10 imbalance results from an intrinsic incapacity of SMA patients to produce IL-10 or from an IL-10 unresponsiveness to infection is unknown. Monocytes and T cells are recognized as the main sources of TNF and IL-10 in vivo, but little is known about the activation status of those cells in SMA patients. Methods. The IL-10 and TNF production capacity and the activation phenotype of monocytes and T cells were compared in samples collected from 332 Ghanaian children with non-overlapping SMA (n=108), cerebral malaria (CM) (n=144) or uncomplicated malaria (UM) (n=80) syndromes. Activation status of monocytes and T cells was ascertained by measuring HLA-DR+ and/or CD69+ surface expression by flow cytometry. The TNF and IL-10 production was assessed in a whole-blood assay after or not stimulation with lipopolysaccharide (LPS) or phytohaemaglutinin (PHA) used as surrogate of unspecific monocyte and T cell stimulant. The number of circulating pigmented monocytes was also determined. Results: Monocytes and T cells from SMA and CM patients showed similar activation profiles with a comparable decreased HLA-DR expression on monocytes and increased frequency of CD69+ and HLA-DR+ T cells. In contrast, the acute-phase IL-10 production was markedly decreased in SMA compared to CM (P=.003) and UM (P=.004). Although in SMA the IL-10 response to LPS-stimulation was larger in amplitude than in CM (P=.0082), the absolute levels of IL-10 reached were lower (P=.013). Both the amplitude and levels of TNF produced in response to LPS-stimulation were larger in SMA than CM (P=.019). In response to PHA-stimulation, absolute levels of IL-10 produced in SMA were lower than in CM (P=.005) contrasting with TNF levels, which were higher (P=.001). Conclusions: These data reveal that SMA patients have the potential to mount efficient IL-10 responses and that the TNF/IL-10 imbalance may reflect a specific monocyte and T cell programming/polarization pattern in response to infection.

AB - Background: Severe malarial anaemia (SMA) is a major life-threatening complication of paediatric malaria. Protracted production of pro-inflammatory cytokines promoting erythrophagocytosis and depressing erythropoiesis is thought to play an important role in SMA, which is characterized by a high TNF/IL-10 ratio. Whether this TNF/IL-10 imbalance results from an intrinsic incapacity of SMA patients to produce IL-10 or from an IL-10 unresponsiveness to infection is unknown. Monocytes and T cells are recognized as the main sources of TNF and IL-10 in vivo, but little is known about the activation status of those cells in SMA patients. Methods. The IL-10 and TNF production capacity and the activation phenotype of monocytes and T cells were compared in samples collected from 332 Ghanaian children with non-overlapping SMA (n=108), cerebral malaria (CM) (n=144) or uncomplicated malaria (UM) (n=80) syndromes. Activation status of monocytes and T cells was ascertained by measuring HLA-DR+ and/or CD69+ surface expression by flow cytometry. The TNF and IL-10 production was assessed in a whole-blood assay after or not stimulation with lipopolysaccharide (LPS) or phytohaemaglutinin (PHA) used as surrogate of unspecific monocyte and T cell stimulant. The number of circulating pigmented monocytes was also determined. Results: Monocytes and T cells from SMA and CM patients showed similar activation profiles with a comparable decreased HLA-DR expression on monocytes and increased frequency of CD69+ and HLA-DR+ T cells. In contrast, the acute-phase IL-10 production was markedly decreased in SMA compared to CM (P=.003) and UM (P=.004). Although in SMA the IL-10 response to LPS-stimulation was larger in amplitude than in CM (P=.0082), the absolute levels of IL-10 reached were lower (P=.013). Both the amplitude and levels of TNF produced in response to LPS-stimulation were larger in SMA than CM (P=.019). In response to PHA-stimulation, absolute levels of IL-10 produced in SMA were lower than in CM (P=.005) contrasting with TNF levels, which were higher (P=.001). Conclusions: These data reveal that SMA patients have the potential to mount efficient IL-10 responses and that the TNF/IL-10 imbalance may reflect a specific monocyte and T cell programming/polarization pattern in response to infection.

U2 - 10.1186/1475-2875-11-253

DO - 10.1186/1475-2875-11-253

M3 - Journal article

C2 - 22853732

SN - 1475-2875

VL - 11

SP - 253

JO - Malaria Journal

JF - Malaria Journal

IS - 1

ER -