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An innate view of human pregnancy

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Abstract

Our understanding of the immunology of pregnancy has been dominated by the fetal allograft model and by changes in the maternal-specific immune system. Here, Gavin Sacks and colleagues draw attention to substantial and contrasting changes in the maternal innate system and hypothesize that its function and that of monocytes in particular, has a central role in the maternal–fetal relationship.

Section snippets

Immune system overview

There are two arms of the immune system: the innate (non-specific) and adaptive (specific) systems, both of which have cellular and humoral components (Table 1). The adaptive system has been studied most because of its specificity, effectiveness at eliminating infection and exclusive presence in higher multicellular organisms. The innate system is more primitive, thought to be ‘unsophisticated, unintelligent, indiscreet, and obsolescent’5. However, this might not be the case: the innate system

Special considerations in the maternal–fetal relationship

The fetal allograft model compares pregnancy with tissue transplantation but, clearly, they are not the same. An allograft usually requires surgical trauma, delivers an acute and large antigen exposure and is most likely to be rejected after its antigens are presented by antigen-presenting cells (APCs) belonging to the engrafted tissue itself. None of these factors apply to the fetal allograft. In addition, it has been difficult to account for the fact that the placenta is neither an inert nor

The maternal innate immune system is stimulated in pregnancy

The key evidence, sometimes overlooked, is that components of the maternal innate immune system are activated systemically (Table 2). There are increased numbers of monocytes and granulocytes from the first trimester onwards. It has also been found that, in normal pregnancy, circulating monocytes and granulocytes in whole blood have activated phenotypes, in some ways comparable with changes observed in systemic sepsis14. Others have shown increased monocyte phagocytosis and respiratory burst

The monocyte model

We hypothesize that particulate or soluble placental products, or both, have opposing modulatory effects on maternal innate and adaptive immune systems. The adaptive response is either avoided or suppressed9. We argue that, in contrast to this suppression, components of the innate system are activated, presumably driven by pregnancy-specific factors. We speculate that monocytes are the likely target and are stimulated to release soluble factors such as cytokines, enzymes, lipids and free

The signal P hypothesis

We hypothesize that placental particulate or soluble products, or both, can act as adjuvants, stimulating signal 2 of classical immune responses. Monocytes, for instance, can be stimulated to produce proinflammatory cytokines such as IL-12 and to express costimulatory surface molecules such as CD80 (Ref. 6). However, a relative absence of specific antigen presentation (signal 1) prevents a T-cell mediated rejection response. The immune response to pregnancy is thus signal 2 in the absence of

Significance of innate activation in pregnancy

Although activation of the maternal innate system might be merely an epiphenomenon, we hypothesize that it has a central role in the maternal adaptation to pregnancy, perhaps to help protect the mother against infection16. However, most infections are eliminated by the combined efforts of the innate and adaptive systems. Although phagocytosis and the production of IL-12 are essential parts in the response to extracellular bacterial infections, viruses and other intracellular pathogens (e.g.

Conclusions

Maternal–fetal immunological interactions need to be redefined. The maternal innate immune system is activated in pregnancy and, because adaptive immunity is relatively suppressed, might assume a particularly important role in overall maternal immune defence. Excessive innate activation can lead to more severe clinical presentations of some infections and to the pregnancy-specific disorder of pre-eclampsia. Our hypothesis gives a framework for further investigation.

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