ReviewPlacental Plasmodium falciparum infection: Causes and consequences of in utero sensitization to parasite antigens
Section snippets
Foreword
Several aspects of the immunology and pathogenesis of pregnancy-associated Plasmodium falciparum (Pf) malaria (PAM), including maternal antibody- and cell-mediated responses to placental infection, have been reviewed recently and will not be addressed in detail here [1], [2], [3]. This review deals specifically with PAM-associated cellular immunological activity from the maternal but particularly from the foetal perspective. The choice of focus on the latter relates to its relative neglect as a
Neonatal immunity: APC and T cell interactions in the absence of PAM
Neonates have comparatively poor immune responses. One of the explanations could be that neonatal T cells are not yet fully developed, but, since mammals with a gestational period longer than 60 days already have mature immune systems before birth (reviewed in [22]), this is unlikely. Lymphocytes are present in the human foetal circulation between 7 and 8 weeks. T cells develop subsequently in the thymus and by week 12 they express a T cell receptor (TCR). By mid-gestation alloreactive T cells
Materno-foetal transfer across the syncytiotrophoblast & PAM
Reliable reports of the presence of Pf-infected erythrocytes (Pf-iE) in cord blood i.e. those studies where appropriate precautions were taken to exclude the possibility of contamination with maternal blood from the placental compartment, indicate that traversal of the placental barrier by Pf-iE occurs in a proportion of cases, seemingly dependent on geographical location. This is best illustrated by the fact that the same group of researchers has consistently observed 1–3% of cord blood
Dendritic cells
There are no published studies dealing specifically with neonatal dendritic cells and possible PAM-induced functional changes. At the purely descriptive level, absolute numbers of both myeloid and plasmacytoid DC are increased in cord blood of those whose mothers experienced Pf infection during gestation [88], but any functional implication of this observation remains to be determined. Interestingly, in the same study, a significant inverse association, independent of the presence or absence of
Neonatal acquired immunity: T cells & PAM
A handful of cross-sectional studies performed in the last decade have assessed the capacity of neonatal (cord blood) T cells to respond to in vitro stimulation with Pf antigens (Table 1). Cameroonian neonates’ cord blood mononuclear cells (CBMC) produced less IFN-γ than adults’ cells but similar amounts of other cytokines (IL-2, IL-4), although the overall levels of lymphoproliferative and cytokine responses were low and PAM was found to be associated only with elevated Pf asexual stage
Cytokines, chemokines & PAM
PAM skews the placental environment from the normal Th2-type [66] to a Th1-type cytokine milieu, with a majority of the relevant studies revealing increased levels of TNF-α in the placental compartment [62], [67], [68], [69], [70], [71], [72]. Semi-mature DC can develop when immature DC are exposed to TNF-α in the absence of a pathogenic motif, and the impaired capacity of such DC to stimulate T cells leads to generation of regulatory T cells (Treg) [73], [74]. Immature foetal DC may thus be
Immunology meets epidemiology and public health
The results of two recent studies, although still requiring confirmation by others, seem set to alter our thinking about placental Pf infection and its influence on encounter with the parasite in early life. Firstly, the epidemiological observation that offspring of Pf-infected primigravid mothers are at significantly lower risk of parasitaemia during infancy than those born either to Pf-infected multigravid or to uninfected primigravid mothers challenges the expectation that PAM must always
Acknowledgements
The invaluable contributions of our many friends and colleagues cannot be overstated. In particular we recognize the pivotal support and advice of Urszula Krzych and Peter G. Kremsner. Our own work relied heavily on the willing participation of mothers and their babies, for which we are grateful, and on the help of a multitude of staff at the Albert Schweitzer Hospital in Lambaréné and the Medical Research Unit thereof, to all of whom we are thankful.
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