In vivo immune signatures of healthy human pregnancy: Inherently inflammatory or anti-inflammatory?

Abstract

Changes in maternal innate immunity during healthy human pregnancy are not well understood. Whether basal immune status in vivo is largely unaffected by pregnancy, is constitutively biased towards an inflammatory phenotype (transiently enhancing host defense) or exhibits anti-inflammatory bias (reducing potential responsiveness to the fetus) is unclear. Here, in a longitudinal study of healthy women who gave birth to healthy infants following uncomplicated pregnancies within the Canadian Healthy Infant Longitudinal Development (CHILD) cohort, we test the hypothesis that a progressively altered bias in resting innate immune status develops. Women were examined during pregnancy and again, one and/or three years postpartum. Most pro-inflammatory cytokine expression, including CCL2, CXCL10, IL-18 and TNFα, was reduced in vivo during pregnancy (20–57%, p<0.0001). Anti-inflammatory biomarkers (sTNF-RI, sTNF-RII, and IL-1Ra) were elevated by ~50–100% (p<0.0001). Systemic IL-10 levels were unaltered during vs. post-pregnancy. Kinetic studies demonstrate that while decreased pro-inflammatory biomarker expression (CCL2, CXCL10, IL-18, and TNFα) was constant, anti-inflammatory expression increased progressively with increasing gestational age (p<0.0001). We conclude that healthy resting maternal immune status is characterized by an increasingly pronounced bias towards a systemic anti-inflammatory innate phenotype during the last two trimesters of pregnancy. This is resolved by one year postpartum in the absence of repeat pregnancy. The findings provide enhanced understanding of immunological changes that occur in vivo during healthy human pregnancy.

Innate Immune Responses to Acute Viral Infection During Pregnancy

“…With the advent of technologies including microscopy, advanced cytometry and single-cell sequencing, these models have been superseded by new data that suggest a tightly regulated balance between inflammatory and tolerogenic states during the "immune chronology" of normal pregnancy (4)(5)(6)(7)(8). Longitudinal studies of peripheral, decidual, and amniotic fluid cytokine profiles and immune cell subsets demonstrate that a pro-inflammatory environment predominates during early trophoblast invasion and at parturition, while the second and third trimesters require an anti-inflammatory bias to facilitate fetal growth (5,(8)(9)(10)(11). The balance between innate and adaptive immunity shifts in favor of innate mechanisms, particularly in the first trimester; as pregnancy progresses, silencing of chemokine genes inhibits accumulation of effector T cells in the decidua, peripheral B cells are depleted and pregnancyspecific hormones skew B cell polarization toward a tolerogenic IL-10-producing phenotype (12)(13)(14).…”

The association between selected mid-trimester amniotic fluid candidate proteins and spontaneous preterm delivery

“…Changes in the immune system must occur to prevent immune-mediated rejection of the semi-allogenic fetus while it must also be maintained, to prevent external pathogens that can affect the mother or fetus. A strong expression of anti-inflammatory mediators and reduced expression of many, but not all, cytokines linked to host defense and inflammatory immune capacity are found already in the second trimester of healthy pregnancy [36], leading to an inflammatory response deployed by the fetus [35]. The anti-inflammatory phenotype intensifies with increasing gestational age and is self-resolving by one year post-partum in the absence of repeat pregnancy [36].…”

Uveitis causes according to immune status of patients

“…Immune responses during pregnancy are shifted towards an anti‐inflammatory status, which is advantageous for the outcome of pregnancy but might influence the course of immune‐mediated disorders and infections (Robinson & Klein ; Graham et al. ). Though not immunosuppressed, pregnant females might show a different spectrum of uveitis and therefore are specified separately as well as patients with DM and HIV infections and CD4+ T cell counts above 300 cells/mm 3 .…”