title: Insights into deregulated TNF and IL-10 production in malaria: implications for understanding severe malarial anaemia.
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.
authors.affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites URA CNRS 2581, Paris, France.
authors.forename: Philippe S
authors.initials: PS
authors.lastname: Boeuf
authors.forename: Séverine
authors.initials: S
authors.lastname: Loizon
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Awandare
authors.forename: John K A
authors.initials: JK
authors.lastname: Tetteh
authors.forename: Michael M
authors.initials: MM
authors.lastname: Addae
authors.forename: George O
authors.initials: GO
authors.lastname: Adjei
authors.forename: Bamenla
authors.initials: B
authors.lastname: Goka
authors.forename: Jørgen A L
authors.initials: JA
authors.lastname: Kurtzhals
authors.forename: Odile
authors.initials: O
authors.lastname: Puijalon
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
authors.forename: Bartholomew D
authors.initials: BD
authors.lastname: Akanmori
authors.forename: Charlotte
authors.initials: C
authors.lastname: Behr
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007223:Infant; D016753:Interleukin-10 / Q000378:metabolism*; D037181:Lectins, C-Type / Q000032:analysis; D008213:Lymphocyte Activation; D008288:Malaria / Q000276:immunology* / Q000473:pathology*; D008297:Male; D009000:Monocytes / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D006684:HLA-DR Antigens; D016753:Interleukin-10; D037181:Lectins, C-Type; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens; C508609:IL10 protein, human; C439524:TNF protein, human