32 Responses

  1. Raeesa
    Raeesa at | | Reply

    The article above discussing the immune clock and human pregnancy seems to me, to be strikingly similar to how the endocrine system works during human pregnancy. Therefore I am prompted to ask, what is the relationship between the endocrine system, the immune system and human pregnancy? The endocrine system during pregnancy maintains tight control over hormone levels, such as estrogen, progesterone, cortisol and even leptin. This allows the pregnant mother to have behavior alternate to what would be defined as “normal”. In a study performed on pregnant rats, it was found that corticosterone levels had immunosuppressive properties. Increasing corticosterone levels, as pregnancy progressed, correlated with inhibition of lymphocyte proliferation and stimulation of macrophage colony stimulating factor -1. Correspondingly, blood samples taken from the pregnant rats showed an increase in macrophages when compared to blood taken from rats that were not pregnant. This increase in macrophages is proposed to result in increased levels of nitric oxide (NO) in pregnant rats. The presence of NO during pregnancy is suggested to help mediate immunity (1). It would be interesting to see more research regarding direct connections between the hormones of the endocrine system during pregnancy and the immune system pregnancy clock.

    1) Endocrine and Immune System Interactions during Pregnancy (https://www.ncbi.nlm.nih.gov/pubmed/25257860)

    1. SauceTargaryen
      SauceTargaryen at | | Reply

      Interesting. What about the level of neutrophils in pregnant rats? And how does (NO) mediate immunity?

      1. Robert Taylor IV
        Robert Taylor IV at | | Reply

        Nitric oxide mediates immunity because the critical enzymes in mitochondrial respiration are also inhibited by RNOS, and this leads to a depletion of ATP and cellular energy. These interactions mediate the regulation of immune and inflammatory cells. Nitric oxide is synthesized by many cell types involved in immunity and inflammation. NO is vital as a toxic defense molecule against infectious organisms. It also regulates macrophages, T lymphocytes, antigen-presenting cells, mast cells, neutrophils and natural killer cells.

    2. Raven Gougis
      Raven Gougis at | | Reply

      Raeesa, I like your comment and the connection you made with the endocrine and immune system during pregnancy. The endocrine system and immune system actually work closely together to support a successful pregnancy. The pregnant woman’s immune system experiences a shift that prevents inflammatory responses that cause an inflammatory response that will reject the fetus(1). The key players in this process surprisingly are hormones that help to shift immune functions in all three trimesters of pregnancy.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376705/

    3. Seshata
      Seshata at | | Reply

      This was an amazing finding! The correlation between hormone production and immune response is certainly worth looking into. This article discusses how hormones relate the immune system. Anti-inflammatory responses are pivotal during pregnancy, because antibodies from the mother need to be transferred to the fetus. Anti-inflammatory responses increases are trimesters progress. Estrogen levels increase throughout pregnancy and regulate inflammatory responses. Infections that require inflammation to clear a pathogen proves themselves more difficult to combat in pregnant women.

      1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376705/

  2. Orezime Uyeh
    Orezime Uyeh at | | Reply

    According to this paper, IL-2-dependent STAT5ab activity is essential for the development of the T-regulatory cells, specifically CD25+FoxP3+ Tregs , that maintain the feto-maternal tolerance during pregnancy (Aghaeepour et al. 2017). This study does open the door to determining when alterations or mutations associated with gestational pathologies occur in the series of immunological events. After reading this blog post, I wanted to know specifically which gestational pathologies could be tracked prior to clinical manifestations. For example, one gestational pathology that I am familiar with is hemolytic disease of the newborn (HDFN, or erythroblastosis fetalis), which is an “alloimmune” condition or a Type-II hypersensitivity reaction. Unfortunately, I could not find any research discussing the levels of immune cells during the pregnancy of a mother with this pathology. Since this paper discussed the important role regulatory T cells play in pregnancy, I researched on some autoimmune diseases that are characterized to occur based on the levels of regulatory T (Treg) cells, and one study proposed that pre-eclampsia and preterm labor were associated with a significant reduction of the suppressive activity of the total Treg pool (Steinborn et al. 2012). Another study also suggested gestational diabetes melitus (GDM) was associated with significant reduction of the Treg suppression activity due to alterations in the homeostatic parameters (Schober et al. 2014). These pathologies can potentially be pinpointed if a future study was done on when would these alterations of the T-regulatory cells pool occur for each pathology in the immune clock of a women’s pregnancy.
    https://www.ncbi.nlm.nih.gov/pubmed/22132888/
    https://www.ncbi.nlm.nih.gov/pubmed/24547967

  3. Mallory Coody
    Mallory Coody at | | Reply

    The study below involved a group of fifty-four pregnant women, with a history of immunological reproductive failure. All had their peripheral blood Treg cells monitored and quantified to determine the miscarriage risk rate in newly pregnant women. It was proposed that the combination of CD4+, CD25+, FOXp3+ T regulatory cells could asses the risk rate of miscarriage. While NK, NKT, TNFα⁄IL-10, and IFNγ ⁄IL-10 were not predictive of miscarriage. Patients with Treg values of 1.0% or more are not at risk of miscarriage while values below 0.7% are at risk of miscarriage.

    https://www.ncbi.nlm.nih.gov/pubmed/21314851

    1. Zach M
      Zach M at | | Reply

      It is interesting that this study shows NK cells as an insignificant marker in miscarriages because I have found an article seeming to counter this argument. Krechetova et al proved that observing increased CD69 expression in blood draws in gestation weeks 1-6 corresponded to a significantly higher number of women with miscarriages. CD69 is found on the surface of T-cells and NK cells. I am curious to see if the study you are referencing observes these findings in a different time period of the pregnancy than the one to which I am referring because Krechetova et al also discussed that no difference was seen in these levels after gestation week 6 to correspond with any significance to miscarriage.

      Source: https://link.springer.com/article/10.1007%2Fs10517-016-3453-8

    2. Justin
      Justin at | | Reply

      According to the article below pregnancy shows a significant increase in the number of monocytes as well as granulocytes. On the other hand, dendritic cells, natural killer cells, and natural killer cell production of IFN gamma is decreased. Furthermore, no live infants were born when NK levels reached 18% (1). However, the term miscarriage was never used. Instead I believe they were referring to a stillbirth. Although these numbers do not correspond to miscarriages, I believe they could be markers for testing health within the development of the fetus. I do find it interesting though that the one article mentions NK cells were not predictive of miscarriage but the other shows that a certain level of NK cells results in stillborn. I wonder why NK cells are not markers for miscarriage but are a result in stillborn infants.
      https://www.medscape.com/viewarticle/734891_2

  4. SauceTargaryen
    SauceTargaryen at | | Reply

    The article above discusses briefly how the immune system changes or modifies itself during pregnancy to where ere is believed to be a “biological clock” that goes off where everything is on a timed schedule of when and what is going to happen. The immune system has to modify in order for immunosuppression to take place, if not the mothers immune system will look at the fetus as foreign and do what the immune system does best, kill it. This change is interesting and another article published by Dionne P Robinson and Sabra L. Klein go in detail about the different changes that take place, some mentioned in the above article, some not. The one that interested me the most was “The severity of diseases caused by inflammatory responses (e.g., multiple sclerosis) is reduced and the severity of diseases that are mitigated by inflammatory responses (e.g., influenza and malaria) is increased during pregnancy.” So with this biological clock finding everything has to be on schedule and everything has to line up because e hormones have to prepare the immune system for whats to come and if not then it can end up with the immune system attacking the fetus.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376705/

    1. Orezime Uyeh
      Orezime Uyeh at | | Reply

      You mentioned that, during pregnancy, there is an increase in the severity of the diseases (e.g. influenza and malaria) that are normally mitigated by inflammatory responses. At first, I was surprised by this, because it appears that immune clock during pregnancy strengthens the immune system’s response to pathogens or foreign bodies. However, after researching a little bit more on this, I found one article that explained how the parasite involved in malaria (Plasmodium falciparum) causes an upregulation of the CD4+CD25+FOXP3+ regulatory T cells which in turn increases the growth of the parasite. This is because the parasite induces regulatory T cells that regulate the response of effector cells to P. falciparum. However, at the same time, malaria can possibly make the regulatory T cells defective and therefore make the infection even more severe. I can only assume that this information potentially plays a factor in the increase in the severity of disease, like malaria, in pregnant women.
      http://www.cell.com/immunity/fulltext/S1074-7613(05)00245-1

    2. Seshata
      Seshata at | | Reply

      This study highlights the detrimental effects of the mother’s immune response isn’t regulated.
      When the mother’s antibodies recognize the fetal beta-3 integrin on platelets. This recognition inadvertently leads to heavy bleeding. The researchers are tying this to miscarriage cause, even though there isn’t ample data on the number of miscarriage caused specifically by this problem.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204841/

    3. Mallory Coody
      Mallory Coody at | | Reply

      Interesting how the immune system lines up to assure the survival of both the mother and fetus. In the study below they show that regulatory T cells are to expand during pregnancy, allowing for tolerance of the immune cell responses at the fetal-maternal interface. Progesterone plays an important role in the reproductive tract during pregnancy, with reference to spontaneous abortion and preterm labor. Progesterone is able to prevent the maternal immune system from activating effector T cells capable of attacking fetal cells. This study finds the existence of membrane progesterone receptor α which may be the regulation pathway by which progesterone regulates Treg cells and lead to better understanding of progesterone usage in preterm birth.

      https://www.ncbi.nlm.nih.gov/pubmed/25639501

    4. A. Ferrell
      A. Ferrell at | | Reply

      The immune system is readily available to attack foreign bodies. Unfortunately, the immune system is not easily regulated to benefit the host. Pregnancy is desired among specific individuals so when the immune response is activated against a growing fetus or foreign body the immune response is performing its duty. Which cannot be manipulated without the consequence of disrupting the normal flora or increasing the possibility of opportunistic infections. However, it is great that immune cells can be reprogrammed to rectify an attack on desirable foreign bodies with time. Studies show that genes alteration must occur to develop tolerance against foreign bodies (1). Being able to determine how immune cells respond to desirable foreign bodies helps with understanding why some women pregnancies are rejected, and others proceed. Further, immune tolerance can be useful for autoimmune diseases like cancer, rheumatoid arthritis, or lupus. If, the immune system could be reprogrammed or genetically modified to build a tolerance to harmless antigens. Future, prevention methods could be developed to control the effects of innate immune cells and T-cells that cannot recognize self or harmless antigens (fetus, pollen, or peanuts). As a result, T-cells and innate immune cells would be more enhanced to recognize disease-causing, self, and harmless antigens.

      Reference:

      1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070970/

    5. Casey
      Casey at | | Reply

      Sauce, your comment makes me think about other inflammatory responses that are prevented in pregnancy to protect a fetus. I am specifically thinking about the Rhogam shot that suppresses the immune response when given to mothers who are Rh negative that are found to have Rh positive babies. Without this shot, the fetus and mother are at risk for extreme inflammation subsequent hemolysis (1).

      1. Casey
        Casey at | | Reply

        Sorry, the link to the related article did not post!
        http://www.ajhp.org/content/72/4/267.long?sso-checked=true

  5. Kingsley Nwaobasi
    Kingsley Nwaobasi at | | Reply

    For a successful reproduction, the role of immunometabolism with regards to molecular and cellular mechanisms is necessary. Immunometabolism have the potential for a therapeutic approach to alter the course of immune diseases(1). In addition, nutritional maternal aspects can trigger metabolic reprogramming of immune cells and since the maternal immune system is able to adapt by suppression of anti-fetal effector T cell response and generation of regulatory T cells, in the presence of fetal antigens, I believe this should help investigators find solutions to complications experienced during pregnancies.

    (1). https://www.ncbi.nlm.nih.gov/pubmed/29071391

  6. Seshata
    Seshata at | | Reply

    In this study, researcher tracked the changes that occurring in the immune system over time via mass cytometry. This technique provides a concise view of what is happening during pregnancy. The hope is using this to study between healthy full-term pregnancies to those that are problematic and premature. In short, they found that adaptive immune response was suppressed, while innate immune response was accelerating. This makes sense. During pregnancy that adaptive immune response would need to be hinder, in order to avoid perceiving the child as a pathogen. Specially the interleukin-2-dependent STAT5ab signaling pathways regulation of T-Cells (1). The innate immune response would need to be hyperactive, to protect the mother and child through the term. The I concur with their inference that disruptions in that sequence is more than likely the root cause of pathological births.

    1. http://immunology.sciencemag.org/content/2/15/eaan2946/tab-pdf

    1. SauceTargaryen
      SauceTargaryen at | | Reply

      If the adaptive immune response is hindered does it still allow for memory cells to adapt to the perceived pathogen at this point? I’m interested in the fact that the innate immunity is hyperactive. I would think certain parts are ramped up and other relaxed, macrophages vs. dendritic cells for instance since the adaptive immune response is suppressed. Why this specific pathway? Are there any other signaling pathways that are hindered?

      1. Seshata
        Seshata at | | Reply

        My understanding is memory cells would be unaffected. The body would respond and defeat pathogens its already encountered. The adaptive immune suppression is make sure the child isn’t received as a pathogen and foreign. Similar to how transplant recipients reject organs. You do make me raise some questions. Like, is there a selective process eliminating the B&T cells that recognize the child as a pathogen. The article did mention antibodies being transferred from the mother. I wonder how that transfer protects the child from pathogens and the mother’s immune system.

  7. Owlette
    Owlette at | | Reply

    The levels of inflammatory cytokines and chemokines were measured by Gillespie, et al. They found that as the pregnancy progresses, levels of inflammatory cytokines, such as IL-6, TNF-alpha, and IL-1beta, would increase during the inflammatory response to LPS. During post-partum periods, these levels would return to “normal”. The application for these findings, coupled with the discovery of the “immunologic clock during pregnancy” is valuable in establishing a “Norm” for early detection of common problems that arise during pregnancy. The maternal-fetal immune system relationship is very important to identify and characterize for a clinical standpoint. Future research can reveal potential causes for a variety of conditions such as reoccurring miscarriages, stillbirth, etc.

    Source: http://www.sciencedirect.com/science/article/pii/S0165037815300887?

    1. Kelly Freeman
      Kelly Freeman at | | Reply

      I like the fact that you discussed that the different phases of pregnancy exhibit different levels of inflammatory cytokines that could affect the progress of the pregnancy. In a study by Mor and Cardenas, the discussion of the different levels of macrophages, natural killer cells and regulatory T cells varies and changes through the different trimesters of the pregnancy. Because of these levels of changes and the fact that pregnant women seem to be more susceptible to bacteria and/or viral infections, the complexity of how to treat the mother and fetus comes into the play (1). Therefore, not only does the mother’s body deal with immune suppression with the pregnancy but also has to deal with how to fight infections that may attack the immune system while the mother is pregnant. The body will have to adjust the levels of cells and inflammatory cytokines to fight the infections, while not seeing the fetus as a foreign pathogen.

      1-https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025805/

  8. Kelly Freeman
    Kelly Freeman at | | Reply

    The role of NK cells, macrophages and dendritic cells is very important for the functionality of pregnancy. The depletion or absence of certain cells can affect the placental development, implantation and/ or decidual formation. The study I found discussed how the immune system deals with the regulation of the immune cells at the site of implantation and the response that is seen by trophoblast cell. These cells induce monocyte –like THP-1 cells that secrete certain cytokines. The immunology of the pregnancy is the result of a combination of signals and responses. The signals originated from the maternal immune system and fetal-placental immune system.

    https://www.ncbi.nlm.nih.gov/pubmed/21401634

    1. Byron P. Lee
      Byron P. Lee at | | Reply

      A successful pregnancy is dependent on the immune system and endocrine cross-talk. In a paper by Rohini R. Nair et al., they suggest that human chronic gonadotropin (hCG) plays an important role modulating immune cells at the maternal-fetal interface. hCG and luteinizing hormone (LH) was found to induce T regulatory cells and prevent semiallogeneic fetus rejection. hCG also helps with fetal survival by increasing the regulatory function of human B regulatory cells. For IVF treatment, intrauterine injection of hCG before embryo transfer improves implantation rate. With just hCG as an example, the interaction between the endocrine and immune system is valuable for the survival of a fetus in the womb. More immunological therapies could treat unexplained infertility, implantation failure, and recurring pregnancy losses.

      Rohini R. Nair et al. 2016
      https://doi.org/10.1016/j.ygcen.2016.03.003

    2. Anthony Kram
      Anthony Kram at | | Reply

      Kelly, I find your comment very interesting as this article has definitely informed me a great deal on the impact the immune system overall has on a mother’s pregnancy journey which we typically just take at face value, but Is very complex. I find it equally interesting the role NK cells, macrophages, and dendritic cells play in the journey of pregnancy, and how without them, the journey can become less than pleasant for a mother-to-be. With this, I located an article that also outlined how maternal-fetal interface evolves allowing the newly formed fetus to mature and develop while still inside of the mother (1). The literary work also explains, as you have done as well, how decidual natural killer cells and antigen presenting cells, inclusive of macrophages and dendritic cells, account for a considerable amount of decidual leukocyte populations which are vital for the modulation of trophoblast invasions, vascular remodeling, as well as angiogenesis (1). This all was very new material to me and I am very intrigued to do further research on how it impacts the pregnancy if any of these key elements do not function correctly as is typical for any other parts of the body which is so complex.

      Citation: https://www-ncbi-nlm-nih-gov.ezproxy.gsu.edu/pubmed/29055791

    3. Philip S.
      Philip S. at | | Reply

      As you mentioned, macrophages, NK, and dendritic cells are important immunological components of a pregnancy. One of the articles cited by the author of your paper indicated the importance of toll-like receptors (TLR) in pregnancy (1). Koga Et. Al., mentioned in their article that pathogens are recognized by toll-like receptors and give rise to cytokine release and the recruitment of various immune cells. In pregnancy, cells from the placenta express TLR 2-6, and 9. The researchers believe that TLRs take part in signaling because of the expression of some TLRs during the first-trimester and then the expression of others, such as TLR6 being expressed in the third trimester (1). The presence and absence of these toll-like receptors at various times in pregnancy suggest the general susceptibility of a fetus to certain pathogens during pregnancy. This demonstrates a role of the maternal immune system in protecting a fetus.

      http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0897.2010.00848.x/full

    4. Rouzbeh Teimouri
      Rouzbeh Teimouri at | | Reply

      Kelly,
      It is good that you mention how intricate functions of immune cells play a major role in proper fetal development, along with the major transformations that occur in both the fetus and the female body during pregnancy, the immunity of both the mother and the fetus have to cooperate for successful fetal growth and delivery.
      During investigations into the root causes of infertility, it was found that natural killer cells, if modified for any reason, can play a role in setting up an immune response against the fetus; this is called reproductive autoimmune failure syndrome. [1]
      It would be a fruitful research topic to attempt to find out how the fetus’ immune system can attack the mother; I would not be surprised if the mother’s sensitivity to developing allergies decreases after each pregnancy.

      [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534451/

  9. Robert Taylor IV
    Robert Taylor IV at | | Reply

    More research into finding out how Zika and other virus attack and effect pregnant women could give us more answers about pregnancy and immune response. Researchers have also tied the Zika virus into the suppression of the immune system. They found that the Zika targets macrophages. Thus hindering the engulfing and clear out cell debris and damage. The Asian Zika virus strain caused the macrophages to signal that the body is healing and turn off immune system activation. Zika then tricks the immune system into thinking that the infection is healing, while the Zika virus is allowed to continue spreading and replicating.

    http://time.com/4908546/zika-pregnant-women-immune-system/

    1. Seshata
      Seshata at | | Reply

      The power of immune response during pregnancy is significant. To the point where the “boost” immune system activity can give the illusion that a diseases or symptoms have disappeared but they return three months after pregnancy. This is the case for rheumatoid arthritis (RA). Changes in gene expression impact immune system cells. Women with RA showed the same gene expression in the third trimester as healthy women. These “healthy” gene expressions are specifically related to increasing phagocytes and decreasing lymphocytes. This shows that the innate immune response plays a role in delaying the effects of RA and innate immune response has increased activity during pregnancy.

      https://www.medscape.com/viewarticle/585506

    2. Mallory Coody
      Mallory Coody at | | Reply

      Zika is able to attack and infect pregnant women more easily due to the reduced CD4+ levels. I was curious as to how susceptible HIV positive patients would be to the prospects of Zika. In the study linked below it was found that CD4+ varied based on pregnancy term. HIV positive pregnant women recorded lower CD4+ T cell count at all the gestational ages when compared with the HIV negative pregnant women. Making HIV positive women more susceptible to viruses such as Zika.

      https://www.ncbi.nlm.nih.gov/pubmed/17464809

    3. Casey
      Casey at | | Reply

      Great comment Robert!

  10. Sarah Leeann Smart
    Sarah Leeann Smart at | | Reply

    While transplantation can be comparable to implantation, it is not good model for pregnancy. A transplanted organ would still have significantly different DNA to be recognized as foreign and subject to attack. The zygote formed is made partially of the maternal DNA, and therefore should have some self antigen recognition. Maternal morphogens, transcription factors, and RNA are slowly “turned off” as the forming organism develops, which could also attribute to the altered immune response. It should be stated that development starts in a state of inflammation, as the blastocyst must break through the uterine lining and attach to the uterine wall, causing damage. Cytokine levels are elevated at the beginning of pregnancy, and the state of inflammation causes the physiological stressors such as morning sickness. A tolerance to the growing fetus is developed, until gestational development is complete, where a new state of inflammation is introduced. This leads to contractions and the pushing of the baby out of the birth canal. It could be stated that pregnancy begins and ends in an inflamed state, necessary for success. It is possible that a small portion of miscarriages could be attributed to an overly heightened inflamed state.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025805/

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