Infection Immunity Foetus
Discuss the vertical transmission of infection and immunity from the mother to her foetus and newborn
Vertical transmission refers to the mother-child transmission of immunity as well as infection such as HIV, hepatitis. It refers to the passage of a disease-causing agent vertically from mother directly to baby during the perinatal period, the period instantaneously before and after birth. This period starts at the 20th to 28th week of gestation and ends 1 to 4 weeks after birth. Transmission may occur across the placenta or via ingestion of breast milk,
Pregnancy is a state whereby a female carries a foetus for approximately a period of nine months, in her uterus. During fertilization, the male sperm carrying 23 chromosomes, penetrates the female's egg, which contains the same number of chromosomes, forming a zygote with 46 chromosomes. http://www.google.co.uk/search?hl=en. During pregnancy, it is the mother's major task to tolerate her foetus. For the foetus to survive in the womb, mechanisms exist which suppresses the maternal immune response to paternally inherited alloantigens. The mother and foetus have different Major Histocompatibility Complexes (MHC's), and this can cause an immune response to elicit, towards the baby. There is an absence of class I and class II MHC antigens on the placental villous trophoblast, which shields the foetus from allogeneic attack. These alterations in regulation of MHC genes, lead to the unique expression of the HLA-G proteins which is present on the extra-villous cytotrophoblasts. This serves the purpose of shielding the trophoblast from being destroyed by uterine endometrial natural killer cell subsets known as large granular lymphocytes, Roitt (1994). MHC class I also act as an inhibitor of a positive signal from a target, to the natural killer cells, Roitt (1994).
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An Inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), plays an imperative role in conferring fetomaternal tolerance. Studies have shown that blockade of PDL1 signaling during murine pregnancy resulted in amplified rejection rates of allogeneic but not syngeneic concepti. It was also noted that fetal rejection was dependant on T and not B- cell, as PDL1- specific antibody treatment caused fetal rejection in B cell deficient but not in Recombination Activating gene 1 (RAG-1) deficient females. Henceforth, PDL1 is involved majorly in fetomaternal tolerance, Guleria et al (2005).
Regulatory T cells are also accountable for feto-maternal tolerance. These cells act in an antigen specific manner during pregnancy. Interleukin 10 is involved in the regulatory T-cell-mediated protection for the foetus. An elevation in systemic regulatory T cell levels have been observed in pregnant females, therefore; confirming the generation of regulatory T cells specific for paternal antigens, Habicht et al (2007). Research has confirmed that the T regulatory cells; CD4+CD25+ play a chief role in fetomaternal tolerance, in conjunction with PDL1, as PDL1 is expressed on T-regulatory cells, Schumacher et al (2007). Although the exact mechanisms of fetomaternal tolerance have not been fully elucidated, it has been shown that Histocompatibility antigen-G (HLA-G) plays a role in the programmed-cell-death of maternal leukocytes during pregnancy, Habicht et al (2007). The expression of HLA-G occurs on the cytotrophoblasts and it permits migration in maternal circulation. HLA-G also infiltrates into the maternal tissue, hence creating a general state of tolerance. A Complement regulatory protein (crry), expressed in the placenta was seen to support tolerance. It was made known that Indoleamine 2,3 dioxygenase protects allogeneic concepti from maternal T cell-mediated immunity, Aluvihare et al (2006, cited in Habicht 2007). All these factors enable the foetus to survive in the maternal womb, and avoid eradication by the mother's immune system. Another likely explanation is that; foetal cells migrate across the maternal-foetal border and penetrate into the maternal circulation therefore inducing short-term tolerance to foetal antigens, Bonney (1997).
A newborn baby is highly susceptible to infections, especially after birth, he/she is exposed to various antigens. The baby's immune system is not fully established at this stage, therefore making it hard to fight off infections. HIV, as well as other viral infections can be transferred to the foetus and the newborn from the mother. During pregnancy and delivery, the foetus is at high risk of contracting the virus. Susceptibility increases towards birth, and this is characterized by viral particles passing through the placenta. Such viruses include; Hepatitis B and C, and cytomegaly virus. Anti-Rhesus antibodies are able to pass on from a Rh- mother to the Rh+ foetus, via the placenta, causing haemolytic disease of the newborn. Infections can also pass to the foetus during parturition (child birth), by the mixing of body fluids including blood, from the mother to the baby. Infections which can be transferred in this way include not only HIV but also Hepatitis (B and C), Syphilis, Chlamydia, Gonorrhea, genital herpes, cytomegaly virus and many more. Although it is possible that the infection could be passed on to the unborn baby, the main risk to the infant occurs when passing through the infected cervix during delivery. The infection rate is high, with up to 70% of babies born to mothers with chlamydial infection becoming infected. Between 30-40% will develop conjunctivitis or ‘sticky eye' and 10-20% tend to develop a characteristic pneumonia. These infections are contracted as there may be tearing from the mother's womb or uterus during delivery, therefore exposing the microbes to the newborn.
Passive immunity is the conveying of humoral immunity, administered as ready-made antibodies. This can be naturally occurring, such as the transfer of maternal antibodies to foetus, via the placental FcRn receptors. Passive immunity can also be conferred artificially through the administration of horse globulins, to individuals with poor immunity, Male (2004). This type is also known as temporarily-induced immunity. The innate immune system is compromised mainly by cells, components and mechanisms that defend the host from foreign organisms or microbes. Humoral immunity involves the activation of B lymphocytes which release antibodies from plasma cells. The antibodies are specific for the particular antigen, and this immunity type has the capability of forming memory against that antigen, henceforth eliciting a quicker response during a second attack by the same pathogen, Roitt (1994). Innate, also called natural immunity, relies on vast number of non-specific immunological effector mechanisms, which are imprecise and are not improved by repeated exposure to a particular pathogen. The principle elements involved include; the complement system, which aids in the control of inflammation, removal of immune complexes and lysis of antibody-sensitized cells and pathogens. Acute phase proteins play role in binding the pathogen, hence accommodating its uptake by phagocytes. On the other hand, interferons limit spread of viral infections, Male (2004). Cells of this system include; mast cells, leukocytes, phagocytes (macrophages, dentritic cells, neutrophils, and basophils), NKcells and T-cells, http://bioweb.wku.edu/courses/biol328.
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Specific (adaptive) immunity is acquired after birth and during pregnancy, as maternal immunoglobulins pass through the placenta to the foetus. A characteristic of the specific immunity is the ability to develop memory for the antigen it has encountered. The immune system is able to masters the appropriate way to attack the antigen and begins to develop memory cells, which proliferate during a second exposure to the same antigen, this making the response more effective and rapid. The characteristics of specific immunity are its ability to learn, adapt, and form memory.
Lymphocytes are the most imperative type of white blood cell involved in specific immunity. Dendritic cells, antibodies, cytokines, and the complement system (which enhances the effectiveness of antibodies) are also majorly involved. B lymphocytes have particular sites (epitope binding sites) on their surface where antigens can attach unambiguously. On encountering an antigen, B lymphocyte proliferation into plasma cells occurs. This is initiated by the antigen attaching onto to the B-cell receptor. Plasma cells possess the ability to produce antibodies, immunoglobulins (Ig) which are specific to the antigen that stimulated their production. Antibodies guard the body by aiding other immune cells ingest antigens, by inactivating toxic substances produced by bacteria, and also by directly attacking bacterial and viral particles. Antibodies activate the complement system which is forms a cascade of reactions, including serum proteins, in-order to eradicate pathogens from the host. Each antibody molecule has two chains, a heavy and a light chain. The molecule is further divided into two parts, one that varies and is responsible for attachment of an antigen and the other which contributes to the determination of the antibody class; IgG, IgD, IgE, IgA, or IgG, http://www.merck.com/
Research has shown that infants who are breast fed are at lower risk of contracting infections than those taking formula milk. Although some physicians argued that the only reason for this, was due to the fact that breast milk lacked bacteria as it had low risk of contamination, and this is not entirely correct. It has been confirmed that breast milk is particularly beneficial during the first few months of life, when the newborn's immune system is not well established. Even though breast milk can be very beneficial, the newborn also receives protection whilst still in the womb. The mother passes antibodies to the foetus through the placenta during pregnancy, and these circulate in the infant's blood for weeks after birth, Slade et al (1987). Humoral immunity transferred through the placenta is dominantly of immunoglobulin G (IgG). IgG is a multimeric immunoglobulin, built of two heavy chains γ and two light chains, with each complex containing two antigen binding sites. It is the most abundant immunoglobulin in the blood. IgG is mainly produced in a secondary response to an antigen, and is more capable of passing the placenta, than IgM, which is the primary immunoglobulin produced at first antigenic encounter, http://www.bindingsite.com/iggigasubclasses-10.asp.
The prenatal transfer of IgG from mother to foetus is promoted by the presence of an IgG receptor on the placenta. The presence of Fc receptors on placental syncytiotrophoblast (multinucleated cells found in the placenta), as well as the presence of maternal antibodies in amniotic fluid in early gestation offers suggestive evidence that IgG transfer occurs from the intestine to systemic circulation of the foetus, Brambell et al (1954, cited in Israel et al 1992), therefore offering immunization of the foetus against the antigen that is detected and bound by that particular IgG molecule. Studies have shown that the uptake of IgG from maternal milk is facilitated by the gastrointestinal tract (GIT) of endodermal origin. In support of this, animal research has proved that transfer of maternal antibodies occurs through a modified yolk sac, which is an organ of endodermal origin. A major route for the passive prenatal acquirement of immunoglobulins from the mother was noted to be Fc receptor present on the placental trophoblast, Brambell et al (1954, cited in Israel et al 1992). Trophoblasts are cells forming the outer layer of a blastocyst, which provides essential nutrients to the embryo, and also forms a large part of the placenta. At 22 weeks of gestation onwards, the IgG concentration in the foetal serum is almost equal with the maternal IgG, hence suggesting a process of active transport, protecting the foetus from infections before its own immune system develops, Pritchard et al (1985, cited in Israel et al 1992). However, for an unknown reason, research has revealed that passively transferred antibodies interfere with the active synthesis of neonate's own antibodies, Vahlquist et al (1948, cited in Miller 1966). IgG There has been evidence of the transfer of antibodies against diphtheria, herpes simplex, tetanus and incomplete Rhesus (Rh) antibodies, from mother to foetus.
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Figure 1: Structure of the IgG molecule, showing the heavy and light chains. Pooled from http://www.pasteur.fr/recherche/unites/ImmStr/images/igg-avectext-afterphotoshop.JPG
Having mentioned how a foetus gains immunity against antigens, there is a great significance in terms of autoimmunity. During a certain stage in embryogenesis, the foetus develops a recognition mechanism which enables the acknowledgement of self-antigens so that an immune response is not elicited against its own cells. Hence, any new antigens presented following this stage, are recognised as foreign, therefore eliciting a response, Nossal and Mitchell (1966, cited in Miller 1966). Although the maternal IgG can be beneficial, it can cause haemolytic disease of the newborn. This occurs when maternal IgG passes through the placenta and attacks the foetus' RBC, causing anaemia. This condition results in the build up of bilirubin, causing the foetus to be born with jaundice. Transfer of the IgG may occur due to fetal-maternal haemorrhage, which can be caused by a tear in the placenta, or may be due to the mother receiving a blood transfusion. Different sub-types of this disease are; ABO-haemolytic disease caused by differences in ABO blood groups between mother and foetus. A rhesus negative mother and Rhesus positive foetus can also cause this condition to occur, this due to the fact that the mother produces antibodies against the foetus as they are of different Rh nature. Usually the second pregnancy is the one mostly affected. Lastly, the anti-kell haemolytic disease also occurs during pregnancy, although quite rare, Geifman-Holzman (1997).
Breast milk has deemed very effective at passing on immunity to the newborn. Breast milk contains antibodies, other essential proteins and immune cells. These molecules prevent organisms from entering the body's tissues by binding to microbes in the lumen of the gastrointestinal tract. Breast milk contains an abundance of Immunoglobulin A (IgA), however other Ig types have also been identified but in lesser amounts. When a mother is exposed to particular antigens, she produces the antibodies against them, which are then gained by the baby during breastfeeding, which makes the baby immune to the infection caused by that particular antigen. Furthermore, IgA molecules are able to eliminate infections without causing inflammation, this being beneficial to the newborn, as their mucosal surfaces will be too delicate, Newman (1995).
Figure 2: The immune benefits of Breast milk, showing some of the components of breast milk and mode of action, pooled from Newman (1995).
In addition to the mentioned molecules, oligosaccharides contain sub-units which resemble normal bacterial binding sites, through which bacteria gain access into the host's intestinal tract cells. These oligosaccharide molecules can interrelate with the bacteria, forming harmless complexes that can be excreted by the baby, Wood (2001).
Colostrum, which is produced by the mother a few days after birth, has been noted to have strong anti-viral activity. Colostrum is high in antibodies, carbohydrates and proteins, yet being low in fat. As the newborn has a undersized digestive system, colostrum passes on high concentration of nutrients but in low volumes. It also aids in the excretion of meconium, aiding the clearance of excess bilirubin in the baby's body. All five immunoglobulins are contained in colostrum; IgM, IgE, IgG, IgD, IgA, as well as growth factors (IGF I and II), Korhonen et al (2000). Fibronectin which is present in large quantities in colostrum, can make phagocytes more hostile, therefore ingesting microbes rapidly, Newman (1995).
It is an amazing phenomenon how the immune system develops during pregnancy, and is able to offer protection for the foetus against the infections. Even after birth, immune system continues to develop, offering the baby protection against the possible antigens it may encounter within its environments. Vertical transmission of immunity, is therefore a very important process, and further research is still required as to the exact mechanisms of vertical immunity and infection.
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