A perfect storm: fetal inflammation and the developing immune system

Abstract

Histologic chorioamnionitis is an inflammatory disorder of the placenta that commonly precedes preterm delivery. Preterm birth related to chorioamnionitis and fetal inflammation has been associated with a risk for serious inflammatory complications in infancy. In addition, preterm infants exposed to chorioamnionitis may be more susceptible to infection in the neonatal intensive care unit and possibly later in life. A significant body of work has established an association between chorioamnionitis and inflammatory processes. However, the potential consequences of this inflammation on postnatal immunity are less understood. In this review, we will discuss current knowledge regarding the effects of fetal exposure to inflammation on postnatal immune responses.

Figure 1.. Potential effects of HCA on neonatal inflammatory and immune responses.

Studies in humans and in animal models have linked HCA, a neutrophil (PMN)-driven placental disorder associated with increased Th17 responses, with exaggerated inflammatory responses of both innate and adaptive immune cells. Neutrophil (PMN) production and activation may be increased, along with the release of inflammatory cytokines and chemokines that promote PMN infiltration and injury to major organs. Experimental fetal inflammation can induce functional maturation and activation of monocytes (Mono) and macrophages (Macs) that can also heighten inflammatory responses. Fetal inflammation enhances the generation of inflammatory Th17 cells and IL-17+ Treg cells; while IL-17 is important to host protection, high levels can induce organ injury, particularly in the brain. Exaggerated inflammatory responses may lead to suppression of protective immune responses, which increase risk for infection. Neonatal infection in the context of HCA exposure has also been shown to increase risk for organ injury and has been linked to bronchopulmonary dysplasia.

Figure 2.. Potential mechanisms of suppressed protective immunity in neonates exposed to fetal inflammation associated with HCA.

Experimental HCA has been associated with ‘immune paralysis’ as suggested by decreased LPS responsiveness in fetal sheep monocytes. HCA has been variably associated with quantitative and qualitative defects in T cells. Conversely, increases in Th17 and inflammatory Treg cells promote IL-17 release. While IL-17 provides immune protective function, it can also promote the generation of myeloid-derived suppressor cells (MDSCs), which adversely affect protective immunity. The increased expression of S100 proteins, particularly S100A8 and S100A9, may promote host protection; however, high levels can increase MDSC generation. Recent evidence also indicates an immunosuppressive role of CD71+ erythroid cells, which could potentially be increased with HCA.