Insights into deregulated TNF and IL-10 production in malaria: Implications for understanding severe malarial anaemia
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Date
2012
Journal Title
Journal ISSN
Volume Title
Publisher
Malaria Journal
Abstract
Abstract
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.
Description
Keywords
Malaria, Anaemia, Cerebral malaria, Severe malarial anaemia, Monocytes, T cells, CD69, HLA-DR, Monocyte de-activation, TNF, IL-10, Cytokines