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,
,
* Immunobiology Unit and
Centre for International Health and Development, Institute of Child Health, London, United Kingdom; and
Department of Paediatrics and Child Health and
Virology Laboratory, University Teaching Hospital, Lusaka, Zambia
Malnutrition predicts an increased risk of morbidity and mortality from infection. Defects in cell-mediated immunity, such as thymic atrophy, impaired cutaneous tuberculin responses, and reduced T cell mitogenesis in vitro, are well characterized. There has been no convincing mechanism proposed for these T cell defects. However, as T cell responses rely on signals received from APCs, this study evaluates dendritic cell (DC) function in children with severe malnutrition. Repeated sampling of peripheral blood from 81 severely malnourished children at the University Teaching Hospital, Lusaka, Zambia, demonstrated for the first time a defect in DC numbers in children with malnutrition (28 per microliter) and a recovery in cell number (48 per microliter; p < 0.01) with standard treatment. We describe normal DC maturation in the majority of malnourished children. However, in 17% of our study patients, in association with endotoxemia we describe the novel finding of DC maturation failure (down-regulation rather than up-regulation of HLA-DR). There was a strong correlation between the strength of HLA-DR up or down-regulation and the generation of IL-10 (r = –0.481; p = 0.003). These "anergic" DCs failed to support T cell proliferation. Defects in DC number and the immunosuppressive phenotype of DCs from severely malnourished children with endotoxemia provide a rational basis for the anergy found in severe malnutrition.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Wellcome Trust through a Clinical Tropical Medicine Training Fellowship (to S.M.H.).
2 Address correspondence and reprint requests to Dr. Stephen Hughes at the current address: Consultant Paediatric Immunologist, Royal Manchester Children’s Hospital, Oxford Road, Manchester M13 9WL, U.K. E-mail address: stephen.hughes{at}cmft.nhs.uk
3 Abbreviations used in this paper: SM, severe malnutrition/severely malnourished; ART, antiretroviral therapy; CI, confidence interval; CMI, cell-mediated immunity; CRP, C-reactive protein; DC, dendritic cell; iDC, immature DC; mDC, mature DC; MFI, mean fluorescence intensity; pDC, plasmacytoid DC; PPD, tuberculin purified protein derivative; TB, tuberculosis; W/H, weight for height (Z score).
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