The immunobiology of preterm labor and birth: intra-amniotic inflammation or breakdown of maternal-fetal homeostasis

Abstract

In brief: The syndrome of preterm labor comprises multiple established and novel etiologies. This review summarizes the distinct immune mechanisms implicated in preterm labor and birth and highlights potential strategies for its prevention.

Abstract: Preterm birth, the leading cause of neonatal morbidity and mortality worldwide, results from preterm labor, a syndrome that includes multiple etiologies. In this review, we have summarized the immune mechanisms implicated in intra-amniotic inflammation, the best-characterized cause of preterm labor and birth, as well as novel etiologies non-associated with intra-amniotic inflammation (i.e. formally known as idiopathic). While the intra-amniotic inflammatory responses driven by microbes (infection) or alarmins (sterile) have some overlap in the participating cellular and molecular processes, the distinct natures of these two conditions necessitate the implementation of specific approaches to prevent adverse pregnancy and neonatal outcomes. Intra-amniotic infection can be treated with the correct antibiotics, whereas sterile intra-amniotic inflammation could potentially be treated by administering a combination of anti-inflammatory drugs (e.g. betamethasone, inflammasome inhibitors, etc.). Recent evidence also supports the role of fetal T-cell activation as a newly described trigger for preterm labor and birth in a subset of cases diagnosed as idiopathic. Moreover, herein we also provide evidence of two maternally-driven immune mechanisms responsible for preterm births formerly considered to be idiopathic. First, the impairment of maternal Tregs can lead to preterm birth, likely due to the loss of immunosuppressive activity resulting in unleashed effector T-cell responses. Secondly, homeostatic macrophages were shown to be essential for maintaining pregnancy and promoting fetal development, and the adoptive transfer of homeostatic M2-polarized macrophages shows great promise for preventing inflammation-induced preterm birth. Collectively, in this review, we discuss the established and novel immune mechanisms responsible for preterm birth and highlight the potential targets for novel strategies aimed at preventing the multi-etiological syndrome of preterm labor leading to preterm birth.

Fig. 1.. Distinct immune responses in the amniotic cavity of women with preterm labor.

Representative diagrams of the fetus and amniotic cavity showing the causative agents and responding immune cells associated with distinct immune responses leading to preterm labor. (A) Intra-amniotic infection is typically triggered by the ascending invasion of bacteria from lower genital tract and is characterized by a massive local immune response including elevated concentrations of inflammatory mediators such as interleukin (IL)-6 and abundant neutrophils, monocytes/macrophages, and T cells. (B) Sterile intra-amniotic inflammation can be triggered by endogenous alarmins and involves elevated concentrations of inflammatory mediators such as IL-6 and a mild infiltration of immune cells such as neutrophils, monocytes/macrophages, and T cells. (C) A subset of cases of preterm labor and birth, formerly considered to be idiopathic, can be driven by the fetal immune system, as indicated by the activation and increased presence of fetal T cells and their mediators in the amniotic cavity. This immune response may also include the activation of amniotic fluid resident innate immune cells such as neutrophils and monocytes/macrophages.

Fig. 2.. Regulatory T cells and homeostatic macrophages: two potential mechanisms of ‘idiopathic’ preterm labor.

(A) Regulatory T cells serve to suppress effector T cells, thereby preventing a maternal anti-fetal immune response. When the balance between regulatory and effector T cells is disrupted, the activation and infiltration of effector T cells at the maternal-fetal interface can occur, leading to preterm labor and birth. (B) Homeostatic macrophages are important sentinels of the maternal-fetal interface that act as non-antigen specific mediators of maternal-fetal homeostasis and promote fetal development. The inadequate function of these cells can permit the acquisition of a pro-inflammatory phenotype by decidual macrophages as a consequence of preterm labor, emphasizing the importance of homeostatic macrophages in late pregnancy. Importantly, homeostatic macrophages may represent a therapeutic approach to prevent preterm labor and birth.