Unique alterations in infection-induced immune activation during pregnancy

Authors

  • SS Witkin,

    1. Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, USA
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  • IM Linhares,

    1. Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, USA
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  • AM Bongiovanni,

    1. Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, USA
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  • C Herway,

    1. Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, USA
    2. Department of Obstetrics and Gynecology, New York Hospital Queens Medical Center, New York, NY, USA
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  • D Skupski

    1. Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, USA
    2. Department of Obstetrics and Gynecology, New York Hospital Queens Medical Center, New York, NY, USA
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Dr SS Witkin, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, 525 East 68th Street, Box 35, New York, NY 10065, USA. Email switkin@med.cornell.edu

Abstract

Please cite this paper as: Witkin S, Linhares I, Bongiovanni A, Herway C, Skupski D. Unique alterations in infection-induced immune activation during pregnancy. BJOG 2011;118:145–153.

Background  Immune responses to infection are uniquely regulated during gestation to allow for antimicrobial defence and tissue repair, whilst preventing damage to developing fetal organs or the triggering of preterm labour.

Objective  A review and analysis of studies delineating gestation-specific immune modulation and intra-amniotic regulation of pro-inflammatory immunity.

Search strategy  Identification of the alterations between the fetus/neonate and adult with regard to the endogenous and infection-induced expression of molecules with immune regulatory properties, and the characterisation of intra-amniotic immune mediators that inhibit bacterial-induced pro-inflammatory cytokine production.

Selection criteria  English and non-English publications from 1985 to the present.

Data collection and analysis  An electronic literature search using MEDLINE, PubMed, articles cited in the primary sources, as well as pregnancy-related immunology research from our laboratory at Weill Medical College of Cornell University.

Main results  During fetal development, interleukin (IL)-23, IL-10 and IL-6, as well as T-helper-17 (Th17)-mediated immune responses, are upregulated, whereas tumour necrosis factor-α (TNF-α) and IL-1β- and Th1-mediated immune responses are downregulated in the intrauterine environment (both the fetal compartment and the amniotic compartment). Infection-related immunity during gestation is preferentially directed towards combating extracellular microbial pathogens. Amniotic fluid and the neonatal circulation contain multiple components that improve the ability of the developing neonate to tolerate microbial-induced immune activation.

Conclusions  The repertoire of immune mechanisms to control infection and inflammation differ between fetal and adult life. The dual mechanisms of resistance to infection and tolerance to infection-induced immune activation prevent damage to the developing fetus and the triggering of premature labour.

Introduction

Pregnancy constitutes a time of distinctive challenges for the human immune system. The growth and development of a semi-allogeneic fetus must be tolerated by the mother, whilst both maternal and fetal protection against infection, as well as immunological processes crucial for tissue growth, remodelling and differentiation, must be maintained. It is becoming increasingly apparent that the expression and regulation of immune components during gestation are unique, especially during early and mid-gestation when the development of organ systems is sensitive to alterations in the immune milieu. The intrusion of a microorganism into the amniotic cavity, or the presence at this site of soluble microbial components, can trigger the induction of excessive pro-inflammatory immunity in the fetal compartment with potentially deleterious consequences. Intra-amniotic infection or inflammation is recognised as a major cause of preterm birth,1 as well as neonatal organ damage.2 Recent studies, however, have demonstrated that the amniotic fluid3–6 and maternal–fetal membranes7,8 are not always sterile. In addition, bacteria have been shown to be capable of traversing intact maternal–fetal membranes.9 Despite this potentially not infrequent exposure to microorganisms, the majority of women deliver healthy neonates at term. Mechanisms must be operative, therefore, to prevent or limit microbial proliferation and/or its pathological consequences at the maternal–fetal interface.

Resistance and tolerance

Protection against infection-related inflammation, tissue damage and cellular injury requires the function of two distinct, but complementary, processes. Resistance is defined as the capacity to recognise and neutralise the invading microorganism, thereby preventing the initiation of an adverse event. Tolerance is defined as the response mechanisms that negate or minimise the consequences of a given infectious event.10

The fetus develops the capacity to recognise and respond immunologically to invading microorganisms through the activation of Toll-like receptor-initiated pathways11 and the production of proteins, such as antimicrobial peptides12 and lipopolysaccharide (LPS)-binding protein.13 This latter protein amplifies the immune responses to bacterial LPS. However, it is the development of tolerance mechanisms, specifically the downmodulation of the extent and/or duration of a pro-inflammatory immune response to minimise fetal damage or premature expulsion from the uterus, that is the predominant and unique aspect of intra-amniotic immunity. The relationship between the induction of an exaggerated fetal intrauterine immune response and the occurrence of fetal morbidities, such as retinopathy of prematurity, cystic periventricular leucomalasia and cerebral palsy, as well as premature delivery, was first proposed by Leviton.14

This review focuses on the distinctive immune parameters that become altered during human gestation, the identity and function of the immune modulators that have been best characterised to date, as well as a comprehensive evaluation of the pregnancy-associated mechanisms that downmodulate pro-inflammatory immunity to a level sufficient to prevent the triggering of premature myometrial contractions and damage to developing organs.

Differences between fetal/neonatal and adult immunity

Qualitative differences exist in the repertoire of innate immune responses expressed by fetal and adult immune cells.15–18 In response to bacterial LPS, neonatal mononuclear cells from cord blood produce greater amounts of interleukin (IL)-6, IL-10 and IL-23, but smaller quantities of IL-1β, IL-12 and tumour necrosis factor-α (TNF-α), when compared with the corresponding cells from adults.16,17,19–21 The value of decreasing TNF-α and IL-1β production can be appreciated by the analysis of a murine double knockout model, where inactivation of the genes coding for TNF-α and IL-1β receptors prevents the induction of LPS-induced preterm labour and delivery.22 Thus, the downmodulation of the production of these two pro-inflammatory cytokines serves to limit their likelihood to prematurely trigger parturition.

IL-23

IL-23 is a member of the IL-12 cytokine family. Both IL-12 and IL-23 share a common subunit: p40. Each also has a unique subunit: p35 for IL-12 and p19 for IL-23.23 The decreased production of IL-12 by neonatal cells appears to be at least partially caused by a specific defect in transcription of the gene coding for the p35 subunit. This deficiency may be related to decreased production of interferon regulatory factor (IRF)-3 by human newborns and the requirement of IRF-3 for p35 synthesis.17 In contrast, p19 production is independent of IRF-3. The highly elevated concentration of cyclic adenosine monophosphate (cAMP) present in cord blood also enhances neonatal IL-23 production.24 IL-6, which is produced in elevated levels during pregnancy, also facilitates the activity of IL-23 by promoting the expression of the IL-23 receptor.25 Thus, the innate immune response during gestation is uniquely programmed towards IL-23-directed immunity over that of IL-12. IL-12 induces interferon (IFN)-γ production by CD4+ T lymphocytes and natural killer cells, and the differentiation of CD4+ T cells into T-helper-1 (Th1) effectors. It also acts on B lymphocytes to inhibit the synthesis of immunoglobulin G1 (IgG1) antibodies.26 The production of IFN-γ activates macrophages to respond primarily to intracellular microbial pathogens.27 In contrast, IL-23 promotes the development of the newly recognised Th17 CD4+ subset.28 Th17 cells are essential for the recruitment, activation and migration of neutrophils.29 The predominance of IL-23 during prenatal development indicates that the neonatal antimicrobial immune defence system is preferentially directed against extracellular pathogens and the preservation of antibody production. In addition, cytokines released by Th17 cells induce production by epithelial cells of antimicrobial peptides at cell surfaces.16 The bacteria that have been most commonly identified in amniotic fluid—Mycoplasma species, vaginal flora bacteria and oral bacteria—are extracellular microbes. IL-23-mediated immunity effectively mobilises a neutrophil defence against the small numbers of these and other microorganisms that successfully traverse the maternal and fetal amniotic membrane barriers. A more concentrated influx of bacteria, or the presence of microorganisms relatively resistant to neutrophil inactivation, will lead to profound induction of the pro-inflammatory cytokines TNF-α and IL-1β and the triggering of infection-related preterm labour and delivery.30,31

Although IL-23-initiated neutrophil activation is undoubtedly beneficial to fetal survival as an antimicrobial surveillance mechanism, excessive neutrophil production and the release of reactive oxygen species, proteases and other toxic molecules are deleterious to fetal cells. A mechanism to limit IL-23 activity within the amniotic cavity has been identified,32 and is discussed below.

The activation and function(s) during gestation of the other members of the IL-12 family, IL-27 and IL-35, remain to be determined.

IL-23-binding protein

Fetal and neonatal cells upregulate the production of IL-23 and downregulate the production of IL-12.16 This selective mechanism facilitates a neutrophil-mediated defence against extracellular pathogens. Although this function is undoubtedly essential to combat microbial invasion within the amniotic cavity, a too vigorous neutrophil response will be detrimental to fetal well-being. Neutrophil influx and activation within the amniotic cavity are well-known major contributors to preterm premature rupture of membranes and preterm birth.33,34 Recently, mid-trimester amniotic fluid has been found to contain a protein that selectively binds to IL-23, but not to IL-10, IL-12 or TNF-α.32 The identity of this protein remains to be determined. Regardless of whether it is a soluble IL-23 receptor, an anti-IL-23 antibody or some other protein, the presence of this activity provides a potential mechanism to limit the extent of neutrophil access and activation within the amniotic cavity. Currently, it is not known whether this IL-23-binding activity varies with ethnicity or environmental factors, or is reduced in cases that culminate in preterm labour and delivery, or preterm premature rupture of membranes.

IL-6

It is a well-recognised observation that the detection of an elevated concentration of IL-6 in the amniotic fluid of women in preterm labour is one of the most sensitive indicators of tocolytic-resistant impending premature delivery.30,35 This has led to wide acceptance of the assumption that IL-6 functions as a pro-inflammatory cytokine and a trigger of myometrial contractions. However, this may not be true. In contrast with the consequences of TNF-α and IL-1β administration, infusion of IL-6 into the amniotic fluid of pregnant monkeys did not result in the induction of preterm labour and delivery.36 Furthermore, although amniotic fluid IL-6 levels at mid-trimester were equivalent in women who subsequently delivered preterm or at term, endogenous IL-6 release by ex vivo-cultured whole mid-trimester amniotic fluid was found to be significantly higher in women with a term birth.37 IL-6 has anti-inflammatory properties and, indeed, the induction of high concentrations of IL-6 by TNF-α and IL-1β functions to facilitate the balance between pro- and anti-inflammatory outcomes.38 Thus, IL-6 may facilitate the downregulation of infection-induced and endogenous inflammation.

Similar to IL-23, the production of IL-6 in response to microbial antigens is higher in neonatal than in adult monocytes,19 and this may also be related to neonatal elevations of cAMP and adenosine.18 In addition, IL-6 production by neonatal cells exceeds TNF-α production in response to Toll-like receptor agonists, whereas the reverse is true for adult cells.19,39 This enhanced induced IL-6 production may provide distinct benefits in fetal antimicrobial defence. IL-6 inhibits the migration of neutrophils to inflammatory sites,38 thereby downmodulating the extent of fetal exposure to reactive oxygen species and other toxic components. Furthermore, IL-6 has been shown to enhance fetal lung branching morphogenesis,40 a desirable function in response to an infection that can lead to the induction of preterm labour. IL-6 also stimulates hepatocytes to synthesise and release soluble components of the antimicrobial innate immune system, mannose-binding lectin, C-reactive protein and soluble CD14.

IL-6 activity is mediated by two pathways. In the classical pathway, IL-6 binds to the membrane-bound IL-6 receptor (IL-6r). This results in activation of the signal-transducing glycoprotein gp130 and the induction of gene transcription. Alternatively, IL-6 can bind to a soluble form of IL-6r (sIL-6r), and this complex can also react with cell surface gp130. Thus, cells that lack membrane-bound IL-6r can also be triggered to respond to IL-6. The activation of this second pathway can be blocked by the binding of the sIL-6r–IL-6 complex to a soluble form of gp130 (sgp130).38 In studies yet to be published, we have identified sgp130 and sIL-6r in mid-trimester amniotic fluids, and observed that the sIL-6r to sgp130 ratio is elevated significantly in women who subsequently develop preterm premature rupture of membranes. Thus, the IL-6–sIL-6r–sgp130 pathway may contribute to the modulation of the extent of pro- and anti-inflammatory immune activity in the amniotic cavity.

IL-10

IL-10 is the prototypic Th2-derived anti-inflammatory cytokine.41 It blocks cell-mediated immune responses by inhibiting the production of the pro-inflammatory Th1 cytokines, TNF-α, IL-1β and IL-12 and, concomitantly, promoting the initiation of humoral immunity (antibody formation). Th1 lymphocytes also release IL-10 as a self-regulatory mechanism to prevent excessive pro-inflammatory cytokine production.42 Fetal and neonatal IL-10 production greatly exceeds that of comparable adult cells.16 This provides another mechanism to prevent the development of pro-inflammatory immunity from reaching a detrimental level during fetal development. In a nonhuman primate model, intra-amniotic administration of IL-10 has been shown to inhibit the development of IL-1β-induced myometrial contractions and preterm labour.43

TNF-α

TNF-α is a primary cytokine inducer of pro-inflammatory immunity and the initial trigger for the sequence of events culminating in infection-related preterm birth.36,44,45 The immunological consequences of exposure to bacterial LPS primarily involves the induction and release of TNF-α.46 TNF-α also induces the apoptosis of cells in the placenta.15 As mentioned above, neonatal cells, on exposure to bacteria or bacterial LPS, release higher levels of IL-6 than TNF-α into the culture medium, the converse of that observed in adult cells.15,16 This might be a function, at least in part, of the concomitant presence of soluble factors that modulate the extent of production of individual cytokines in response to activating stimuli. The elevated extracellular adenosine level in neonatal plasma is a prominent example of one such factor that impedes TNF-α production.18 Other mechanisms, discussed below, inhibit the activity of TNF-α that has already been released in response to Toll-like receptor activation.

TNF receptors

The biological activity of TNF-α is initiated by its binding to one of two receptors on cell membranes. When activated, TNF receptor 1 triggers apoptosis and the production of matrix metalloproteinases; TNF receptor 2 activation initiates a pro-inflammatory immune response.47,48 Truncated soluble forms of both receptors, that compete for binding to TNF-α and inhibit its bioactivity, can also be produced.49,50 In a study utilising amniotic fluid collected during preterm or term labour, it was observed that 96–99% of all samples were positive for soluble TNF receptor 1, and 99% of all samples were positive for soluble TNF receptor 2.51 There were no associations between the intra-amniotic concentration of either receptor and preterm birth. However, on the basis of ethnic differences in TNF-α levels between preterm cases from white and black subjects, the authors speculated that the soluble receptor to TNF-α molar ratio might explain, at least in part, the differences in the rate of spontaneous preterm birth between these two ethnic groups.

Histones

Histones are typically characterised as nuclear proteins that associate with chromosomal DNA. More recent investigations have revealed that several histones, most prominently histone H2B, can also be found in the cytoplasm and in extracellular fluids where they are potent antimicrobial agents.52 In a preliminary study presented in abstract form, it was shown that the ability of exogenous LPS to induce TNF-α production by amniocytes was inversely proportional to the amniotic fluid histone H2B concentration.53 Histone H2A and H2B bind to both the core region and lipid A moiety of LPS, with histone H2B exhibiting five- to six-fold times stronger binding capability.52 Amniotic fluid obtained from 20 women at term and not in labour was found to contain 250 ± 67 ng/ml histone H2B, whereas amniotic fluid obtained from women at 15–19 weeks of gestation was shown to contain a median histone H2B concentration of 341 ng/ml.53,54 By virtue of their antimicrobial and LPS-neutralising functions, histones may form a barrier to prevent bacteria from crossing the placental membranes and gaining access to the amniotic cavity.52 The additional presence of histone H2B in amniotic fluid would provide a second back-up level of protection against penetration by small numbers of bacteria or their release of LPS.

Several other recent studies have focused on mechanisms by which LPS-induced pro-inflammatory immunity within the amniotic cavity is downmodulated.

Gelsolin

Gelsolin is a cytoplasmic and extracellular protein that cleaves actin filaments to aid in chemotaxis and prevents the formation of capillary plugs by actin released from injured tissues.55 In addition, gelsolin binds with high affinity to the LPS component of various bacteria and is a competitive inhibitor of LPS-binding protein.56 The presence of gelsolin was recently identified in mid-trimester amniotic fluid from 40 women that reacted with LPS from Escherichia coli.57 Of potentially greater significance was the observation that TNF-α production by whole fresh amniotic fluid incubated ex vivo in the presence of LPS was inversely proportional to the amniotic fluid gelsolin concentration. Furthermore, preincubation of amniotic fluid with an anti-gelsolin monoclonal antibody led to increased LPS-induced TNF-α release. In contrast, LPS-induced IL-10 production was independent of the intra-amniotic level of gelsolin.

Hyaluronan

Hyaluronan is a complex carbohydrate composed of repeated disaccharide units of d-glucuronic acid and N-acetyl-d-glucosamine linked by β(1–3) and β(1–4) glycoside linkages. It interferes with the activation of the Toll-like receptor 4–CD44 complex,58 and LPS-induced pro-inflammatory cytokine production is inhibited by hyaluronan.59,60 Hyaluronan is present in the amniotic cavity,61,62and depresses the magnitude of LPS-induced TNF-α production by ex vivo amniotic fluid cultures.62 The median hyaluronan concentration in mid-trimester amniotic fluid was increased in women who conceived following in vitro fertilisation (4.0 μg/mg total protein) relative to women who conceived spontaneously (3.1 μg/mg total protein) (P = 0.01). In addition, the median intra-amniotic hyaluronan concentration was 4.5 μg/mg protein in women with two or more spontaneous abortions, 2.7 μg/mg protein in those with one abortion and 3.2 μg/mg protein in women with no previous spontaneous abortions (P = 0.01). There were no associations between hyaluronan concentration and parity, spontaneous or indicated preterm birth or preterm premature rupture of membranes.62 These observations suggest that hyaluronan levels in amniotic fluid may fluctuate depending on the need for immune downregulation.

Adenosine

The release of adenosine nucleotides at sites of infection leads to their conversion by ectonucleases to extracellular adenosine. Concomitantly, intracellular adenosine triphosphate is dephosphorylated, leading to the release of free adenosine. The adenosine binds to adenosine receptors on the surface of neutrophils, monocytes/macrophages and T lymphocytes, increases intracellular cAMP levels and strongly inhibits Toll-like receptor-mediated pro-inflammatory cytokine release.63,64 As mentioned above, adenosine concentrations in neonatal plasma were shown to be nearly 20 times higher than those present in adult plasma.17 Furthermore, the ability of neonatal plasma to inhibit Toll-like receptor-mediated production of TNF-α by neonatal peripheral blood mononuclear cells was severely compromised by the addition of adenosine deaminase, the enzyme that irreversibly degrades adenosine, to neonatal plasma. Similar observations have been reported recently for mid-trimester amniotic fluid.65 The capacity of amniocytes in ex vivo-cultured whole amniotic fluid to release TNF-α was increased from a median of 0.9 to 7.3 pg/ml (P = 0.001) if adenosine deaminase was included in the culture medium. This finding, consistent with studies on neonatal plasma, strongly suggests that adenosine is also a component of mid-trimester amniotic fluid. Furthermore, the extent of adenosine deaminase-mediated intra-amniotic TNF-α production was found to be proportional to the number of deliveries. As labour has recently been shown to result in the migration of bacteria into the amniotic cavity,66 it is possible that increased endogenous TNF-α production with successive deliveries may be the result of the persistence of microorganisms in the uterine cavity following delivery.

Receptor for advanced glycation end-products (RAGE)

Another immune pathway leading to the stimulation of pro-inflammatory cytokine production is composed of the ligand S100A12 protein and RAGE. S100A12 binding to RAGE results in activation of the transcription factor nuclear factor kappa B and the initiation of transcription of genes encoding TNF-α and other pro-inflammatory cytokines.67 A soluble form of RAGE, sRAGE, has also been identified.68 Similar to the soluble TNF receptors, sRAGE competes with membrane-bound RAGE for S100A12, as well as other ligands, and abrogates RAGE-mediated signalling. Amniotic fluid from healthy women not in labour has been found to be positive for sRAGE.69 Intra-amniotic sRAGE levels were low in mid-trimester and increased about 100-fold by gestational week 30. The mean sRAGE concentration in term amniotic fluid was 16.5 ng/ml. In contrast, S100A12 was identified only in amniotic fluid obtained from women in preterm labour or with preterm premature rupture of membranes.

Neutrophils

Neutrophils and neutrophil-derived products appear to be double-edged swords in human pregnancy. In addition to IL-23, amniotic fluid and fetal membranes are also positive for epithelial cell-derived neutrophil-activating peptide-78 (ENA-78).70 ENA-78 is a ligand for a chemokine receptor that is expressed on the neutrophil surface, CXCR2. Thus, neutrophils may also be recruited to the fetal membranes and amniotic cavity by this mechanism. Although the concentration of intra-amniotic ENA-78 is elevated during intrauterine infection, its presence in the apparently uninfected uterus suggests that it might also have a role in uncomplicated gestations. This might involve the production of several neutrophil-derived components present in amniotic fluid that actively participate in antimicrobial defence—neutrophil defensins 1–3, calprotectin and bacterial/permeability-increasing protein (BPI).71

Exosomes

Evidence is increasing that exosomes are also involved in the modulation of intra-amniotic pro-inflammatory immunity. Exosomes are multivesicular bodies that are formed by inverse membrane budding into the lumen of an endocytic compartment. The multivesicular bodies fuse with the plasma membrane, facilitating the release of exosomes into the extracellular milieu.72 The observation that exosomes isolated from a bone marrow donor prior to transplantation prolonged survival of the allograft in a recipient,73 together with studies demonstrating the immunosuppressive properties of exosomes in diverse situations,74,75 provides supportive evidence that exosomes downregulate immune responses. Two studies have reported the detection of exosomes in mid-trimester amniotic fluid.76,77 They complement earlier findings that identified exosomes in sera obtained from pregnant women at 28–30 weeks of gestation,78 and the release of exosome-like microvesicles from first-trimester trophoblast cells.79,80 In each of these three studies, the exosomes were shown to be capable of modulating T-lymphocyte immune responses and/or inducing T-cell apoptosis. Thus, exosomes appear to have one or more gestation-related immune functions.

The exosomes in mid-trimester amniotic fluid were shown to be positive for both the inducible (hsp72) and constitutive (hsc73) form of the 70-kDa heat shock protein.76 Hsp72-containing exosomes have been shown previously to be released by cells in response to infection or inflammation and to down-modulate immune activity.81 Similarly, the addition of a synthetic mimic of a Gram-positive bacterial cell wall component to ex vivo-cultured mid-trimester amniotic fluid induced the release of hsp72 into the culture supernatant.82 The binding of hsp72 to Toll-like receptor 4 and the inhibition of LPS-induced TNF-α production have also been reported.83 Whether hsp72 is a component of exosomes present in pregnancy sera or is released by trophoblasts, as well as more direct evidence of their immune function at mid-trimester, remains to be uncovered. The observation that exosome levels were reduced in the circulation of pregnant women who subsequently underwent a preterm delivery, as opposed to women who delivered at term,78 suggests that alterations in the concentration and/or composition of exosomes may influence immune regulatory mechanisms during gestation.

Other potential immune modulators

Other proteins with immune functions, such as Clara cell protein 16,84 ubiquitin,85 C-reactive protein86 and triggering receptors of myeloid cells (TREM-1),87,88 have also been reported to be present in amniotic fluid. A more recent study has identified truncated soluble TLR2 in amniotic fluid.89 This might similarly modulate intra-amniotic pro-inflammatory immunity. Investigations using proteomics also show promise in identifying novel combinations of biomarkers predictive of intra-amniotic infection.90–92 A study in mice has identified increased production of interleukin receptor-associated kinase (IRAK)-1, IRAK-3 and Fas-associated protein with death domain (FADD) messenger RNA in the uterine cavity of pregnant mice.93 IRAK-1 and FADD function synergistically to downregulate LPS-induced Toll-like receptor activation and pro-inflammatory cytokine production. IRAK-3 is required to prevent enhanced neutrophil recruitment and an exaggerated immune response in IRAK knockout mice. Whether these activities also function in human gestation remains to be determined.

Conclusions

A recent study has demonstrated that tolerance mechanisms in response to infection and microbial components vary strikingly in extent between individual mammalian species.94 Furthermore, these differences appear to be caused by variations in the presence and/or concentration of soluble serum factors that inhibit the production of pro-inflammatory cytokines. As discussed by the authors, this indicates that various species have evolved significantly diverse set points, that is cytokine concentrations, at which the induction of downmodulation becomes necessary to maximise survival. We propose that pregnancy is another situation in which mammals have evolved a unique and diverse set of mechanisms to downmodulate the pro-inflammatory milieu relative to the nonpregnant state. This appears to be true for both the intra-amniotic cavity and the neonatal circulation. A consequence of this development to effectively deal with microbial-induced inflammation is that a given microbial presence will have a neutral influence on pregnancy outcome. The ability to tolerate infection may be beneficial, both in terms of reducing fetal secondary exposure to toxic immune products that are needed for effective microbial resistance, as well as reducing or eliminating pressure on the invading microorganism to evolve new antiresistance mechanisms.

Furthermore, it may be that individual variations in these tolerance mechanisms influence a woman’s likelihood to deliver prematurely. The identification of differences in the presence and/or concentration of novel mediators between women may allow an assessment of susceptibility to inflammation-mediated preterm birth. Furthermore, protocols to exogenously provide the missing factors may prove to be of value in modifying a negative outcome.

Disclosure of interest

None of the authors report any conflict of interest or financial interest.

Contribution to authorship

SSW conceived the idea for the manuscript and, with IML, composed the original draft. AMB conducted searches and identified relevant articles. DS, CH and AMB amended the original manuscript and contributed new ideas and insights.

Details of ethics approval

Experiments performed in Dr Witkin’s laboratory were approved by the Institutional Review Boards of Weill Cornell Medical Center-New York Presbyterian Hospital and New York Hospital Queens Medical Center. Written informed consent was obtained from each participant.

Funding

None.

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