The immune response to malaria in utero

Abstract

Malaria causes tremendous early childhood morbidity and mortality, providing an urgent impetus for the development of a vaccine that is effective in neonates. However, the infant immune response to malaria may be influenced by events that occur well before birth. Placental malaria infection complicates one quarter of all pregnancies in Africa and frequently results in exposure of the fetus to malaria antigens in utero, while the immune system is still developing. Some data suggest that in utero exposure to malaria may induce immunologic tolerance that interferes with the development of protective immunity during childhood. More recently, however, a growing body of evidence suggests that fetal malaria exposure can prime highly functional malaria-specific T- and B-cells, which may contribute to postnatal protection from malaria. In utero exposure to malaria also impacts the activation and maturation of fetal antigen presenting cells and innate lymphocytes, which could have implications for global immunity in the infant. Here, we review recent advances in our understanding of how various components of the fetal immune system are altered by in utero exposure to malaria, discuss factors that may tilt the critical balance between tolerance and adaptive immunity, and consider the implications of these findings for malaria prevention strategies.

Keywords: T-cells; fetal; immune development; placental malaria; pregnancy; tolerance.

Figure 1.. Developmental changes in the placenta and fetal immune system during gestation.

Maternal blood first enters the intervillous space at 8–9 weeks gestation, enabling P. falciparum-infected red blood cells to contact the placenta. This is followed by progressive loss of the cytotrophoblast (CTB) layer beginning at week 14, leaving the fused syncytiotrophoblast (STB) layer as the sole barrier between maternal and fetal blood. At 13–16 weeks gestation, STB cells begin expressing FcRn, which transports IgG and immune complexed antigens across the placenta. Transplacental transfer of IgG increases exponentially until term. Meanwhile, T cells are evident in the fetus as early as week 10 of gestation, thymic architecture is mature at week 14, and the splenic T zone is evident at week 18. Fetal Foxp3+ CD4 Tregs and γδ T cells are most abundant in the fetus at mid-gestation, but decline progressively between weeks 20–40.

Figure 2.. The maternal fetal interface and potential routes of antigen transfer.

A. Anatomically, the human placenta is comprised of tree-like chorionic villi (CV) that directly contact maternal blood in the intervillous space (IVS). B. Chorionic villi are lined by a single layer of multinucleated syncytiotrophoblast (STB) cells. P. falciparum-infected red blood cells (iRBCs) adhere to syncytiotrophoblasts, and attract inflammatory mediators which may lead to focal STB denudement (dotted line). This disruption of the STB barrier may cause free malaria antigens to contact the villous stroma, which is patrolled by fetal Hofbauer cells (Hof). C. FcRn mediates transfer of IgG, and possibly immune complexes, across the STB layer to the fetus. FcγRIII may also contribute to antigen internalization.