Anatomy & Physiology for Midwives 3: Third Edition

Chapter 10. Overview of immunology

Learning objectives

• To review the immune system, identifying the roles of innate and specific immunity.

• To recognize how pregnancy affects the maternal immune system.

• To discuss the reasons why the fetus is not rejected.

• To appreciate the importance of placental transfer of immunoglobulins.

• To demonstrate an understanding of Rhesus incompatibility and how it is prophylactically treated.

• To appreciate the immunological immaturity of the neonate and why this is relevant to midwifery practice.

• To describe the principles of neonatal immunization.

• To outline the effects of human immunodeficiency virus (HIV) infection on the functioning of the immune system.

Introduction

Knowledge of the immune system is important in midwifery for several reasons. First, implantation and the nurture of an immunologically foreign fetus presents some interesting questions as to the functioning of the immune system in pregnancy. Second, some causes of infertility may be related to the immunological rejection of the sperm or fetus. During pregnancy, the maternal immune system is modified so the fetus is not attacked, but maternal defences against infection still function. Pregnant women have enhanced immunological responses to bacterial infections. However, they seem to develop increased susceptibility to viral infections such as seasonal influenza, and human immunodeficiency virus (HIV)-related problems may increase during pregnancy. Pregnancy affects immune-related conditions in a variety of ways: some may temporarily improve during pregnancy, such as asthma (Bohacs et al., 2010), whilst others may worsen and cause serious complications such as systemic lupus erythematosus (SLE) which can increase the risk of maternal death of 20 times or more (Day et al., 2009). Maternal immune adaptations in pregnancy also seem to prepare for possible pathogenic contamination of the placental wound site, during the vulnerable period of the puerperium. Blood group incompatibility and the resulting immune response can compromise the well-being of the developing fetus. The neonate is born immunologically immature but receives some passive immunity, both during pregnancy and neonatally in breast milk.

Chapter case study

Zara and James try and live a healthy lifestyle; they both have never smoked and have not drunk any alcohol for many years. They follow a vegetarian diet and prefer to have organic, fresh products that are unprocessed and rely on milk products, nuts and pulses as the main source of protein in their diet. What precautions do Zara and Steve need to take and what particular types of food do they need to avoid and what are the reasons for this?

As part of their preparation to work in Africa, both Zara and James underwent in-depth medical screening to ensure that they were fit enough to undertake this work. Zara has the blood group O Rhesus negative and James has the blood group AB negative.

• As they are both Rhesus negative, then Rhesus incompatibility is not going to occur, but what possible complications could arise in the pregnancy as a result of these different blood groups, how could they be recognized and what are the possible treatments that may be required?

• What advice would women need before, during and after pregnancy in regard to travelling to or from tropical countries?

The immune system is a complex network of specialized cells and chemical signals, which interact to provide a defence against infectious organisms. A number of microorganisms are associated with the body. Some, described as commensal organisms, exist within or on their host without causing any harm. Others are beneficial, or symbiotic, like those inhabiting the skin and the gut. However, some organisms, including microbes (bacteria, viruses, fungi, etc.), and larger organisms like tapeworms, are potentially damaging and are described as pathogens because they cause disease. The immune system of man has evolved to detect and eradicate these pathogenic organisms. Pathogens are diverse and numerous and have a rapid rate of replication and therefore are constantly evolving their own mechanisms to combat the host's defence.

The role of the immune system becomes clearly evident when it is compromised such as in acquired immune deficiency syndrome (AIDS) when HIV causes breakdown of the immune system (Fig. 10.1). However, under less extreme conditions, both infections and poor nutrition can overwhelm the immune system. To some extent, both the pregnant woman and the neonate are immunocompromised, but the concept that pregnancy is a state of immunosuppression which increases susceptibility to infectious diseases is controversial. It does not make evolutionary sense for pregnancy to be dangerous from an immunological perspective. Reproduction is crucial for survival of the species; a paramount aspect of this is that the immune system, and therefore the survival of the mother and fetus, is strengthened by enhanced recognition, cell communication, trafficking and repair mechanisms (Mor and Cardenas, 2010). It is preferable to describe pregnancy as a state of immunomodulation. An alternative explanation to the apparent increased risk of infection in pregnancy is that the mother is more readily sensitized by the changes that occur in her immune system.

The evolution of the immune system

The detection of the presence of pathogens initiates the immune response in the host, stimulating a cascade of interactions, which culminates in a counter-attack on the pathogen. There are two types of immunity: innate immunity and adaptive immunity.

Innate (natural) immunity pre-exists in an organism before any contact with pathogens; it is a collection of genetically encoded responses to foreign pathogens which does not change throughout the lifespan. Innate immunity occurs throughout the plant and animal kingdom, occurring in mammals, birds, sponges and worms. It evolved early and is particularly effective against bacteria, probably the earliest form of life on earth. It mounts an immediate non-specific response to an invading microorganism.

The second type of immunity, adaptive or acquired immunity, is facilitated by mechanisms that adapt to the presence of pathogens and becomes more effective with each exposure. As organisms became more complex and colonized new habitats, they were vulnerable to a broader range of more recently evolved pathogens such as viruses. Adaptive immunity occurs exclusively in higher multicellular organisms that have evolved relatively recently, such as mammals, birds and some fish (jawed vertebrates). It has evolved in response to increased pressure on survival and augments innate immunity; it is specific and effective at eliminating infection. The adaptive immune system ensures that, if an animal survives an initial infection by a pathogen, it is usually immune to further illness caused by the same pathogen; this response is exploited in medical vaccination programmes. Although the innate and adaptive systems operate differently, there are many common mechanisms and components. It has been hypothesized that the innate system, though more ‘primitive’, plays a critical role in viviparity and toleration of the fetal allograft (Sacks et al., 1999).

Overview of the immune system

Innate immunity is inherent and does not require contact with a pathogen for responses to occur. The defence is non-specific but not long-lasting. The responses are mobilized quickly and activated by receptors that generically respond to a broad range of pathogens. The first line of defence can be considered to be the physical and chemical barriers of the respiratory, reproductive and gastrointestinal systems and skin (Brostoff et al., 1991; Fig. 10.2). The skin is an impermeable barrier which is naturally acidic and undergoes continual desquamation. The gastrointestinal and respiratory tracts utilize peristalsis and cilia, respectively, to keep potentially infectious moieties moving. Commensal organisms on the skin or the epithelium of the respiratory and gastrointestinal systems create an environment which is hostile to pathogens. In addition, various secretions such as sweat, tears and secretions in the respiratory and gastrointestinal systems contain antimicrobial substances. The chemical protective mechanisms of the innate immune system include that provided by lysozyme, the complement system, interferons and phagocytotic activity of the white blood cells (Table 10.1). The responses of the innate immune system, such as inflammation, generate cytokines (chemical signals) which recruit immune cells to the site of infection, resulting in identification and removal of dead cells and foreign substances and also communicate with the adaptive immune system via presentation of antigens.

Cells of the innate immune system express pattern recognition receptors (PRRs) which recognize pathogen-associated molecular patterns (PAMPs) which are unique molecular sequences expressed on the surface of pathogenic microorganisms (Koga et al., 2009). When PRRs of the immune cells bind to PAMPs on the pathogen, an inflammatory response is generated against the pathogen. One of the main families of PRRs is the Toll-like receptors (TLRs). Eleven types of TLRs have been identified in humans. TLRs are very specific to particular PAMPs that are molecules which are evolutionary conserved and critical to the pathogen's function (Koga and Mor, 2010). For instance, TLR4 recognizes gram-negative bacterial lipopolysaccharide and TLR2 recognizes bacterial lipoproteins, gram-positive bacterial peptidoglycans and fungal zymosan. TLRs also act with host cells which display ‘danger signals’, for instance, express different molecules on their surface when they are apoptotic or stressed or damaged, for instance, by reactive oxygen species.

Lysozyme, which is sometimes described as ‘the body's own antibiotic’, is an enzyme that attacks the unique polysaccharide structure of bacterial cell walls. It is an abundant component of body secretions such as blood, sweat, tears, nasal secretion, breast milk and the mucous secretions of the reproductive tract.

The complement system involves over 30 interacting proteins, mostly synthesized by the liver, and receptors which form an amplification cascade of defence, leading to cytolysis of bacteria, chemotaxis, opsonization and inflammation. As in the blood coagulation cascade, the components of the complement cascade exist in an inactive precursor form that can be triggered and activated. There are three pathways of activation: the classic pathway, which involves antibodies (or immunoglobulins), the alternative pathway, where the complement cascade is activated by the unique composition of an organism's cell wall (activator surfaces), and the mannan-binding lectin pathway. The outcome of complement activation is the formation of a membrane attack complex, cylindrical assembly of proteins that form a tube that perforates the plasma membrane of target cells. This perforation allows ions to enter cells so that fluid follows by osmosis and the bacterial cells swell and burst. The complement cascade stimulates the release of histamine and kinins from mast cells, recruits macrophages and neutrophils to the site and enhances phagocytosis by opsonization. The complement system may be a factor in a number of diseases such as multiple sclerosis, asthma, Alzheimer's disease, type 1 diabetes (Hewagama and Richardson, 2009) and autoimmune diseases such as SLE (Chen et al., 2010).

Interferons are cytokines secreted by virally infected cells that carry out a non-specific defence which prevents viral replication. Viruses replicate by ‘hijacking’ protein synthesis in the host cells they have infected. Therefore, the cell is diverted to make viral mRNA, which is translated into viral proteins and assembled as viral particles. Interferons interfere with this production of new viral proteins; they damage the viral mRNA and inhibit protein translation, not just in the infected cells but in neighbouring uninfected cells as well, subsequently creating a barrier around the viral infection, which prevents the viral replication. Interferons also stimulate macrophages and natural killer (NK) cells; they can also up-regulate major histocompatibility complexes (MHCs). Interferons produced by genetic engineering are used therapeutically.

The cells of the immune system are leukocytes and lymphocytes. Although they are described as white blood cells, some of the cells spend very little time in the circulation, whereas others never enter the vascular system at all and remain in the lymphatic system, spleen or other tissues. Blood cells are derived from a single population of haemopoietic stem cells (HSCs) in the bone marrow. These precursor cells have the potential to divide into progenitor cells which can differentiate into all the cell types present in blood. After radiation for cancer treatment, the destroyed stem cells have to be replaced by a bone marrow transplant; very few cells need to be transplanted for regeneration of a mature population of cells.

Neutrophils and macrophages are phagocytic white blood cells that can engulf and digest foreign cells and unwanted matter, such as the body's own dead and dying cells, through the processes of phagocytosis, cytotoxicity and the generation of an inflammatory response. The cells that mediate innate immunity are the granulocytes: neutrophils, monocytes, eosinophils and basophils. Neutrophils, also known as polymorphonuclear leukocytes, are the most numerous, forming about 40–70% of the circulating white blood cells. On entering the circulation, neutrophils, which have a lifespan of a few days, cease cell division. Neutrophils are motile and exhibit chemotactic behaviour, moving through a concentration gradient towards chemical messengers, such as those released from dividing bacteria, activated platelets or other phagocytotic cells, towards the site of infection. Neutrophils have multilobed nuclei which aid diapedesis (the amoeboid movement of the cells through the gaps between the capillary endothelial cells). Neutrophil phagocytosis is fast. Neutrophils usually reach the site of infection and begin phagocytosis within about 90 min of the initial stimulation; they surround the unwanted material and engulf it in a phagosome which merges with a lysosome containing substances that kill the engulfed bacterium or neutrophil granules to form a phagolysosome. The neutrophil can generate a vigorous and lethal respiratory burst releasing lethal reactive oxygen species or produce nitric oxide which kills both the phagocyte itself and the engulfed pathogen. Alternately, the bacterium is killed by myeloperoxidase from neutrophil granules which can generate hypochlorite (bleach) which is very toxic to bacteria; the green haem pigment of myeloperoxidase gives the greenish colour of bacterially infected mucous and ‘pus’.

Adherence of the phagocyte to the target cell can be increased by opsonization. Opsonins include antibodies which bind specifically to an antigen on the pathogen surface and are then recognized by Fc receptors on phagocytes so that the pathogen is more efficiently recognized and phagocytosed. The complement component, C3, also binds to pathogens and is recognized by the complement receptor on phagocytes, thus increasing the efficiency of recognition and adherence of the phagocyte. Effectively, the opsonin acts as a bridge between the pathogen and the phagocyte, so promoting phagocytosis. Monocytes circulate for a short time in the bloodstream and then migrate to tissues and organs where they differentiate into macrophages and exhibit characteristics specific to their host tissue. Less than 7% of circulating white blood cells are monocytes, but ‘resident macrophages’ are abundantly distributed in the body tissues and are particularly dense around blood vessels, the gut walls, the genital tract and lungs. Macrophages are oestrogen-sensitive. Monocytes are the largest white blood cell and have a characteristic horse-shaped nucleus. They are also phagocytes and have a longer lifespan than neutrophils. Circulating monocytes respond more slowly than neutrophils, reaching the site of infection within about 48 h, but they have a greater capacity for phagocytosis, engulfing more material than neutrophils.

Many pathogens have evolved mechanisms to evade phagocyte activity; these include inhabiting niches like the skin where phagocytes cannot reach, suppressing inflammatory responses, interfering with the phagocyte recognition of pathogens or interfering with chemotaxis. In addition, some bacteria can block phagocytosis or survive within phagocytes or in the phagolysomes.

NK cells are cytotoxic lymphocytes which attack compromised host cells such as virally infected and cancerous cells. Although NK cells are lymphocytes, they are part of the innate immune system. NK cells kill cells which express low levels of MHC proteins, which is a common characteristic of both virally infected cell and some cancer cells. NK cells alter the target cell's plasma membrane by releasing proteases and perforins from their cytoplasmic granules so water and ions diffuse in; consequently, the virus-infected cell swells and lyses or dies by apoptosis. To recognize the body's own cells which are infected or behaving abnormally, NK cells have to be able to distinguish between self and altered-self state. Apoptotic cells are tagged by the phophatidylserine phospholipids of the cell membrane, which are usually orientated on the internal cytosolic face of the membrane, ‘scrambling’ to the exterior of the membrane which alerts phagocytotic cells.

Lymphocytes, which constitute about 20–40% of the circulating white blood cells, coordinate the adaptive immune responses. These small cells have relatively little cytoplasm, few organelles and no granules. T lymphocytes (or T cells) have secretory vesicles containing perforins and granzymes. B lymphocytes are dominant in humoral responses, mediated by immunoglobulins (antibodies) which attack bacteria and viruses in body fluids. T lymphocytes are dominant in cell-mediated immunity (see Chapter 1). Small lymphocytes also circulate in the lymphoid system and spend much of the time resident in the organs of the lymphoid system. The lymphoid system is the main site of the adaptive immune responses. Fluid leaks out of the blood capillaries into the intercellular spaces. Some of the fluid re-enters the blood capillary (see Chapter 1) but some enters the lymphatic capillaries. This lymph fluid, therefore, has a similar composition to plasma, except that the protein component of plasma is retained within the blood vessels so lymph fluid has low protein content. Ultimately, the lymph fluid is transported through lymph vessels to the thoracic duct and back into the bloodstream. The small lymphocytes ‘burrow out’ of the small veins as they pass through the lymph nodes and so enter the lymphoid tissue. Each lymphocyte spends minutes in the bloodstream compared with hours residing in the lymphoid system. Lymphocytes have different levels of maturity; naïve lymphocytes which are mature but have not encountered the antigen they will recognize, effector cells which have been activated by an antigen and memory cells which have survived from past exposure to the antigen and could rapidly divide in response to subsequent exposure to the antigen.

The classical view is that cells of the immune system differentiate between self (body) and non-self (foreign) cells (and changed self in host cells which are infected by a virus), identifying foreign cells and pathogens which have evaded the innate immune system and attack them. It has been hypothesized that the immune system differentiates between dangerous and non-dangerous rather than between self and non-self or infectious or non-infectious (Gallucci and Matzinger, 2001). The surface of a pathogen displays a unique combination of antigenic determinants that can be recognized by the immune cells as ‘foreign’ or non-self. The whole cell that engenders an immune response is described as an antigen, although the cluster of antigenic determinants itself is called the epitope. Each antigen can be displayed by the pathogenic cell itself, or can be secreted by a pathogen, for instance, bacterial toxins, or substances from non-pathogenic sources, such as plant pollens, resulting in allergic responses, or chemicals such as synthetic vaccines. Only certain parts of the entire antigen are immunogenic; these parts bind antibodies and activated lymphocytes. Most naturally occurring antigens have numerous antigenic determinants that can mobilize several different lymphocyte populations. Large chemically simple molecules (such as plastics) have little or no immunogenicity. Antigenicity depends on the ability of the host to identify the substance as an antigen; there are variations in individual responses.

Lymphocytes have high-affinity surface receptors that recognize antigens with very high specificity. Each lymphocyte has a single type of specific antigen receptor, unlike the cells of the innate (non-specific) immune system, which have many different types of receptor on each cell. These receptors differ between T lymphocytes (T-cell receptors) and B lymphocytes, the latter displaying on its cell surface copies of the specific antibody that each cell can secrete. Infective pathogens will normally display multiple antigens which are recognized as foreign by many different lymphocytes in the infected host. There are over 100 million pathogenic epitopes. Each person has, at birth, a population of lymphocytes consisting of clones, each of a few cells. A clone has a few identical lymphocytes, each of which has many copies of the same antigen receptor on its surface. The population of lymphocytes has the capability, described as its repertoire of receptors, to respond to a vast number of antigens, most of which are unlikely to be encountered in a lifetime. Initially, the number of cells expressing receptors for any particular antigen is small and this clone will remain small unless the antigen reacts. So, one of the first steps in mounting an effective immune response is to expand the clone by increasing the number of cells expressing the same antigen, a response termed ‘clonal selection’.

There are far more antigen receptors than there are human genes encoded for by DNA (about 100 million epitopes and only approximately 25000 different human genes). It is hypothesized, therefore, that each antigen receptor site is coded for by a few randomly selected genes. As there are several hundred possible genes involved, the random selection of a few genes that can be cut and spliced (somatic recombination) can produce enough combinations of antigen receptor gene segments to make all the 100 million epitope-binding sites. So, an individual can develop a huge number of diverse types of lymphocytes, each expressing a unique receptor for an antigen from a small family of genes. The gene segments recombine to form unique genes. This process is known as combinatorial diversification or V(D)J (variable, diverse and joining gene segment) recombination.

However, in the random production of antigen receptors, some lymphocytes will possess receptors for the body's own antigens. In the fetal thymus, clonal deletion takes place, which results in the destruction or deletion of self- or autoreactive T lymphocytes by apoptosis. This process is called central tolerance. Any T lymphocyte binding to specialized cells presenting self-epitopes on the surface will be stimulated to undergo apoptosis. Self-reactive B lymphocytes do not need to be destroyed because they require a signal from a T lymphocyte (helper T cell) before they can function. It seems that some of the self-reactive T cells escape central tolerance in all individuals (Weetman, 2010). These are prevented from causing autoimmune disease in healthy people by a range of peripheral tolerance mechanisms (Mueller, 2010). It is important that the immune system has self-tolerance and does not harm cells or molecules of the host that are recognized as antigenic; otherwise, the host would be damaged (as happens in autoimmune diseases).

The immune response to a second and subsequent exposure to the antigen is faster and more effective than the first exposure (Fig. 10.3). The primary adaptive response, on the first exposure, is slow to develop, perhaps taking 7–14 days, and then builds slowly to a peak about 2 weeks later. The time for the response to become evident is termed the ‘incubation period’. Then, symptoms become apparent until the immune response has become effective. The secondary adaptive response, when the host subsequently encounters the same antigen, develops sooner, lasts longer and is more effective so signs of infection or symptoms may be prevented. On first exposure, the small numbers of lymphocytes binding the antigen are stimulated to undergo rapid cell division. A single lymphocyte can divide fast enough to produce 64000 daughter cells in 4 days. As the new cells, also bearing receptor sites specific to the stimulating antigen, are produced, they mature and differentiate. If B lymphocytes are activated, some members of the new population of lymphocytes are active in attacking the cells bearing the antigen. Most clone cells become antibody-secreting plasma cells. Others become memory cells, which have a long life and continue to circulate as a permanently enlarged clone of lymphocytes capable of recognizing specific antigens and mounting an immediate response. Effectively, the initial immune response is boosted by repeated exposure.

Individuals have immunity to an antigen if their immune system can mount a fast and effective specific response to that antigen. The role of a vaccine is to deliberately stimulate the immune response and increase the clonal size without causing the illness. Effective vaccines can be in the form of killed whole organisms, harmless organisms, organisms that have been modified or attenuated (as in most viral vaccines), fragments of organisms (as in many bacterial vaccines), substances with similar epitopes, synthetic epitopes or inactivated toxins (Table 10.2). Some antigens are more effective at triggering clonal expansion, such as rubella (German measles) virus, which is highly antigenic; thus, after primary exposure, the host rarely acquires the infection again. Other pathogens, such as Neisseria gonococcus (causing gonorrhoea) and Treponema pallidum (causing syphilis), are only weakly antigenic; therefore, there are no effective vaccines available.

Resistance to a specific pathogen, acquired by previous exposure or deliberate immunization resulting in clonal expansion, is active immunity. However, sometimes, the effect of infection can be disastrous before the immune system has time to mount a response. Passive immunization can overcome this by providing temporary resistance in the form of products from a donor source. Passive immunization causes destruction of the pathogenic cells without creating clonal expansion or making memory cells so its effects are not permanent. An individual who has no prior immunity but is exposed to antigens or a potentially dangerous disease is given preformed antibodies. Examples include treatment following a bite from a rabid dog or anti-D immunization following potential exposure to Rhesus-incompatible antigens (see below). The transfer of placental antibodies (IgG) to the fetus and consumption of antibodies (IgA) in colostrum and breast milk by the neonate are also examples of passive immunity.

Case study 10.1 looks at an example of exposure to German measles.

Case study 10.1

Melanie is expecting her first baby. She attends the midwives' clinic at 11 weeks' gestation concerned over the welfare of her unborn baby. Her 3-year-old nephew, Michael, whom she sees regularly, has German measles.

• What factors would the midwife need to consider in advising Melanie over her concerns?

• Would there be any specific investigations to carry out?

If Melanie was susceptible to Rubella infection, how would this be recognized and what subsequent management and care be planned?

There are three types of lymphocytes: those that mature in the bone marrow, called B lymphocytes, those that mature in the thymus, called T lymphocytes and NK cells (see above).

B lymphocytes secrete antibodies which are responsible for the humoral immune response. On binding to an antigen, B lymphocytes undergo clonal expansion producing two types of daughter cells: memory B cells and plasma cells. The plasma cells are short-lived cells which synthesize and secrete large amounts of antibodies (immunoglobulins), which are specialized glycoproteins that bind specifically to the antigen that was recognized by the B lymphocyte. These antibodies bind to their target antigens and enable other components of the immune system, such as phagocytes and complement proteins, to attack the precise organism bearing the antigen rapidly and effectively. There are five classes of antibody (Table 10.3); these differ in the structure of the ‘Y’-shape of the tail, which affects whether the antibodies bind in groups or singly (Fig. 10.4). The antigen receptor on B lymphocytes is a surface immunoglobulin (sIg) closely resembling the structure of the antibody-binding site that will bind to the same antigen. The binding of the B cell to the epitope is relatively straightforward in that the antigen is intact or native, whereas T lymphocytes bind only to processed antigens. However, antigen binding by a B lymphocyte usually requires helper T-cell activity before clonal expansion can take place.

There are three subsets of T lymphocytes: helper T cells, regulatory T (Treg) cells (formerly called suppressor cells) and cytotoxic T cells. Unique glycoproteins on the cell surface, which are involved in mediating cell function, can be identified using monoclonal antibodies and used to distinguish different subpopulations of T lymphocytes. The system of nomenclature is based on the cluster of differentiation (CD) system. Cytotoxic T cells express CD8 protein markers in the plasma membrane and recognize and destroy cells that have become infected or cancerous. Some regulatory T cells also express CD8 but express other markers as well, including CD4 and CD25, which distinguish them from other T-cell types.

T helper cells express CD4 proteins, and are sometimes called CD4 + cells. Helper T cells interact with macrophages and produce cytokines, which activate and regulate other components of the immune system. Cytokines are soluble polypeptides with a short range and lifespan that are also synthesized by lymphocytes and macrophages. They can induce fever, stimulate lymphocytes, stimulate antigen expression and potentiate the destruction of tumour cells. Cytokines include interleukins, interferons, tumour necrosis factor (TNF) and some colony-stimulating factors (CSF). Helper T cells induce proliferation of lymphocytes, stimulate antibody production by B lymphocytes and enhance the activity of cytotoxic T lymphocytes.

The receptor for HIV is the CD4 protein expressed not only by T cells but also by macrophages and possibly other cells. HIV reduces the number of helper T cells by inducing apoptosis so none of the immune mechanisms work effectively. Infection of macrophages shifts the profile of cytokines produced, which contributes to wasting and acute respiratory distress syndrome. Macrophages can act as a reservoir of the virus.

T lymphocytes have antigen receptors on their surface, formed of two peptide chains that contain the binding site for a specific epitope. However, the T lymphocyte cannot bind to an epitope unless it is has been processed and presented to the T lymphocyte by one of the host's own cells. Although most nucleated cells have the capability of presenting an antigen and activating T lymphocytes, some cells generate a more efficient immunostimulatory response. These ‘professional’ antigen-presenting cells (APCs) are dendritic cells, B lymphocytes and macrophages that bind the antigen and phagocytose it, degrading its protein and then migrating to the lymph nodes. The resulting epitope fragments are displayed in the cleft of the MHC molecule (Box 10.1) on the surface of the APC (Fig. 10.5). Helper and Treg lymphocytes bind only to epitopes processed in this manner. Cytotoxic T cells recognize the epitopes of intercellular pathogens, such as viruses, that are incorporated into the cell membrane during cell replication of an infected cell harbouring the virus.

Box 10.1

The major histocompatibility complex

Each person has a unique configuration of MHC antigens or molecules on the surface of their cells (except monozygous twins who have identical MHC). MHC molecules are a marker of ‘self’ and are synonymous with human leukocyte antigen (HLA). MHC molecules present the antigens to T cells. There are different classes of MHC molecules, which present antigens with different effectiveness. MHC molecules restrict helper T cells to interact with immune cells that have already bound to the epitope for which the T cell also has an antigen receptor. It is these cells that are involved in rejection of transplanted tissue, as all MHC molecules are different. Tissue grafts have increased survival if there is some similarity in MHC structure between the donor and the recipient (hence the need for tissue typing) and if drugs are used to suppress the immune response.

There are at least three forms of T helper cells: Th0, Th1 and Th2 cells, which are classified on the basis of their cytokine secretion. The dendritic cells present the antigen to T helper cells and direct them to differentiate into either Th1 or Th2 cells. When the resting T helper cells are initially activated, they become Th0 cells which have characteristics of both Th1 and Th2 cells; Th0 cells are then further activated and differentiate into either Th1 or Th2 cells depending on the type of threat. This pathway of differentiation is controlled by the cytokine secretion of the dendritic cell. Secretion of interleukins IL-12 and IL-10 by the dendritic cell drives the differentiation of Th1 and Th2 cells, respectively (Fig. 10.6).

The Th1 response tends to be initiated by viruses, cancer, yeasts and intracellular bacteria (e.g. Mycoplasma pneumoniae or Chlamydia). The outcome of the Th1 response is activation of cell-mediated immunity and the secretion of gamma-interferon (INF-γ), IL-2, lymphotoxin and granulocyte–macrophage colony-stimulating factor (GM-CSF). This activates cytotoxic T cells and NK cells to respond to target cells carrying intracellular pathogens or mutated proteins since these would not be responsive to circulating antibodies. Body cells continuously turn over their protein and some of these protein fragments or peptides are displayed on the cell surface in association with MHC proteins which the cells of the immune system monitor. Virally infected or cancerous cells display peptides from viral or mutated proteins which are recognized as foreign by the immune cells and displayed by APCs to provoke an immune response. Following clonal expansion of the T lymphocyte that recognizes the non-self peptide, cytotoxic T cells seek out the virally infected or mutated cells and, on contact, produce toxic and perforating substances that induce apoptosis and then turn the immune response off when the antigen-expressing cells have been eliminated When the infection has resolved, most of the cytotoxic T cells die and are removed by phagocytosis; a small percentage of the T cells remain as memory cells.

Other bacteria, parasites, toxins and allergens predominantly trigger a Th2 response and secretion of IL-3, IL-4, IL-5, IL-6, IL-10 and IL-13 which activate eosinophils, leukocytes and B lymphocytes (which produce antibodies). The Th1 and Th2 systems suppress each other; the Th1/Th2 balance is important. For instance, some viruses produce proteins that mimic IL-10 and drive the differentiation of Th0 cells into Th2 cells which are less effective at attacking viruses so viral survival is enhanced. In pregnancy, the Th1/Th2 balance shifts in favour of Th2; this downregulation of Th1-induced cellular immunity and enhancement of Th2-induced humoral responsiveness in the maternal immune system in pregnancy is mediated by progesterone and is important in preventing fetal rejection (see below).

Regulatory T cells limit the activity of the immune cells and prevent damage to the body's own cells maintaining immune system homeostasis and tolerance to self-antigens (and are thus important in preventing autoimmune disorders) (Guerin et al., 2009). Treg cells are involved in maintaining peripheral tolerance. Treg cells accumulate in the lymph nodes draining the uterus and spleen in early pregnancy probably because they migrate towards human chorionic gonadotrophin (hCG) and chemokines produced by the trophoblast. Treg cells appear to be important in immune tolerance of the conceptus tissue (see below) and the sperm and oocytes.

B lymphocytes and T lymphocytes interact (Fig. 10.7). The B lymphocyte binds to the native (intact) antigen via the sIg receptors on its cell surface. The antigen is then internalized by the B lymphocyte and processed so fragments appear on its cell surface associated with the MHC molecule. In this form, the T lymphocytes can recognize it so helper T cells are activated, producing the signal that allows the B lymphocyte to start cell division and differentiation.

The innate system is an integral part of the immune response. It initiates an immune response by the macrophages, processing an antigen in association with the MHC and presenting it to lymphocytes; this is called signal 1. The full response requires adjuvants, such as endotoxin, which produce signal 2, pro-inflammatory cytokines or co-stimulatory surface molecules. This signal conveys the biological significance of the antigen and effectively instructs the adaptive system to respond (or not). Signals 1 and 2 stimulate T cells to become effector Th1 or Th2 cells. Macrophages secrete cytokines which activate other macrophages, NK cells and granulocytes.

The immune system in pregnancy; acceptance of the fetus

Humans are ‘outbred’. The genetic diversity resulting from sexual reproduction means that the fetus is phenotypically unique and immunologically distinct from both of its parents. The fetus has a unique combination of histocompatibility antigens. The fetus is classified as an allograft: foreign tissue from the same species but with different antigenic make-up. Half of the fetal antigens are derived from the father. There is a marked antigenic difference between the maternal tissues and the paternally inherited antigens expressed by the fetus. If tissue from the offspring is grafted on to its mother, a strong maternal immune response is mounted and the tissue is rejected. It seems surprising therefore that the mother does not reject the fetus because of its foreign antigens. Medawar (1953) proposed several possibilities to explain why the fetus is not rejected: as fetal tissue is antigenically immature, it may not express normal antigens, the uterus may be a privileged site (or not in contact with fetal tissue) or pregnancy may affect the maternal immune system and normal immune responses. However, it is the placenta and not the fetus that is the ‘transplant’, and the placenta has very different characteristics than that of a transplanted tissue or organ, and the interaction of the trophoblast with the maternal immune system orchestrates cooperative modulation of the components of the immune system.

Fetal tissue is antigenically mature and does express antigens and immunocompetence from an early stage (Koga and Mor, 2010). MHC class I and II antigens, albeit in smaller amounts, are present on embryonic cells from the time of implantation throughout the pregnancy. The MHC antigens are the molecules that are normally recognized by a transplant-recipient's immune system and cause rejection of allografts (foreign tissue transplants), but trophoblast cells are an exception (Weetman, 2010). Paternal antigens are apparent at the eight-cell stage of the cleavage, and major histocompatibility antigens begin to be expressed at later stages of cell division. Dendritic cells from fetal skin are in contact with maternal blood and enter the maternal circulation; these cells express MHC antigens (Zenclussen et al., 2007). The zona pellucida and early trophoblast have glycoprotein coatings, which may limit the cell-mediated immune responses. Immunological problems are usually not a problem prior to implantation because the endometrium secretes immunosuppressive factors.

Both the mother and other individuals reject grafts of fetal tissue because fetal tissue expresses antigens. Maternal responses to transplanted tissue remain competent in pregnancy; a pregnant mammal rejects tissue from the father of the fetus and tissue from the fetus grafted to areas other than the uterus. Some tissues, such as the testis and parts of the eye and brain, lack components required in immune responses or are not accessible to them (Mellor and Munn, 2008). These sites are immunologically privileged and can accept transplanted tissue with fewer problems. However, the uterus is not a privileged site as was suggested (Billingham, 1964); the development of ectopic pregnancies shows that the uterus is not a uniquely immunoprivileged site. The increased vascularization of the pregnant uterus allows efficient delivery of lymphocytes and other maternal immune cells so non-fetal allogenic tissue transplanted in the uterus is rejected (Beer and Billingham, 1974). Maternal and placental tissue are closely situated and in close proximity. There are a number of interfaces between maternal immune cells and placental cells that change as the pregnancy progresses.

The fetus is separated from the mother by the placenta and fetal membranes. It is suggested that the chorionic membranes are resistant to maternal rejection and can protect the fetus from maternal antibodies and immune cells. The placenta and chorion originate from cells derived from the fertilized zygote, which are therefore genetically and antigenically different to the maternal cells. Maternal blood bathes the chorionic villi (see Chapter 8) and is therefore in immediate contact with trophoblast cells which are derived from the zygote and thus have non-maternal antigens. This means that maternal blood containing immunologically responsive cells is in apposition with the syncytiotrophoblast (outer layer of non-mitotic cells; see Chapter 8).

Some cytotrophoblast cells (the dividing cells underlying the syncytiotrophoblast) penetrate the syncytiotrophoblast layer to form the cytotrophoblast columns, which anchor the villi to the maternal tissue. During implantation and placental development, other invasive trophoblast cells and fragments break away from the mass of placental tissue and enter the uterine veins and maternal venous system. It is this extravillous (non-villous) trophoblast that remodels the uterine spiral arteries to allow increased maternal blood flow to the intervillous space (see Chapter 8). This extravillous trophoblast layer of cells therefore makes extensive contact with the maternal tissue. Some of the cells breach the trophoblast and invade the maternal blood system, forming minute emboli which lodge in the pulmonary circulation where they are destroyed. However, even within the maternal circulation, the extravillous trophoblast cells do not appear to provoke a normal inflammatory or immune response (Johnson and Christmas, 1996). So, the trophoblast appears to provide an insulating barrier, protecting the fetus from the immunologically responsive maternal cells.

The trophoblast cells have low levels of expression of MHC class I antigens (HLA-A and HLA-B) and class II molecules are absent (Weetman, 2010) so they are not recognized by cytotoxic T lymphocytes. Non-trophoblastic placental cells, such as macrophages and stromal cells, do express fetal HLA antigens but are separated from the maternal cells by the HLA-negative trophoblastic barrier. Placental macrophages seem to have diminished ability to present antigens. Effectively, the trophoblastic tissue is presented to the mother's immune system as antigenically neutral. However, the expression of non-classical HLA-G antigen on the trophoblast cells protects the tissue from cytotoxic T lymphocyte activity and inhibits NK cells which recognize and lyze cells that are deficient in class I HLA expression. In addition, the trophoblast cells may actively contribute to maternal tolerance by secreting soluble factors which modulate the maternal immune response (Zenclussen et al., 2007).

The mother is tolerant to fetal antigens but it is not a single mechanism as suggested by Medawar but many local and systemic changes that cause tolerance. Different mechanisms operate at different stages of the pregnancy to mediate tolerance; some of the mechanisms operate locally at the placenta to prevent the fetal antigens being recognized and other mechanisms act on T cells to suppress fetal rejection. The mother does respond immunologically to fetal antigens on the trophoblast or on the fetal haemopoietic and stem cells that enter the maternal circulation. The placenta seems to be a site of active antigen-specific tolerance. Both lymphocytes and antibodies that recognize fetal antigens are present in maternal blood in pregnancy. In fact, an immune reaction by the mother to the paternal histocompatibility antigen seems to be essential for a successful outcome of pregnancy. During pregnancy, maternal T cells become transiently and reversibly tolerant to paternal alloantigens both systemically and at the uteroplacental surface (Weetman, 2010). The maternal recognition of fetal antigens stimulates the generation of blocking antibodies (Johnson and Christmas, 1996). The blocking antibodies are asymmetrical so they mask the antigenic sites preventing maternal cells from binding to the antigens (Gutierrez et al., 2005). They bind fetal cells in the maternal circulation so they do not interact with maternal lymphocytes or cross the placenta to bind to antigenic sites. Progesterone, augmented by oestrogen and placental growth hormone, is important in both inducing the factor that pushes the helper T cells towards producing Th2 cytokines and up-regulating a number of other immunologically active molecules.

It is suggested that a lack of maternal immune response to the fetus could be harmful. The success of fertility and pregnancy is enhanced when the parents are genetically dissimilar (a concept described as ‘hybrid vigour’). The incidence of pregnancy where the parents are closely related (consanguineous), as in incest, is far less frequent; thus, heterozygosity is promoted within the population. A close relationship between the parents means that the fetal antigens will be more similar to the maternal antigens so the maternal immunological response will be less.

Conversely, embryo implantation into a surrogate mother, where the embryo is less related to the mother than in a normal implantation, has a higher success rate. It has been suggested that some of the cases of unexplained recurrent pregnancy loss (RPL, also known as recurrent spontaneous abortion (RSA); more than three consecutive early pregnancy miscarriages) may be due to a failure of maternal cell immune responses and immunological adaptation (Kwak-Kim et al., 2009). Other known causes of RPL include chromosome and endocrine abnormalities, anatomical and haematological problems, and infections of the mother's reproductive system. It was controversially hypothesized that increased similarities of antigens between parents (described as HLA parental sharing) would result in the fetus having a high degree of antigen similarities with its mother. The mother would then not produce such a strong immune response to fetal cells, with perhaps fewer blocking antibodies, which would prejudice the outcome of the pregnancy. However, immunotherapy treatment for RPL where women are immunized with paternal leukocyte cells or antibodies has not been successful (Porter et al., 2006).

Fetal lymphocytes inhibit replication of stimulated lymphocytes in both the mother and unrelated individuals. This may account for the increased number and increased severity of maternal viral infections, especially in the later part of gestation. Trophoblastic cells express high levels of three membrane-bound complement-regulatory proteins that thwart potential complement-mediated damage to the trophoblast by either the classic or alternative pathways (Rooney et al., 1993).

The placenta is in contact with fluids containing high concentrations of progesterone, corticosteroids and hCG, which may act as local immunosuppressants and inhibit the effectiveness of immune cells. The uterine endometrium has extensive numbers of white blood cells, constituting up to a third of endometrial cells (Luppi, 2003). From early pregnancy, numbers and activity of monocytes and granulocytes progressively increase. The macrophages are highly activated and secrete substantial amounts of interleukin and IgE, which may play a vital role in immunosuppression and rapid non-specific anti-inflammatory activity. T lymphocytes are present but B lymphocytes are uncommon. Cytotoxic activity and interferon production by circulating or peripheral NK cells decreases; it seems that these cells migrate to the uterine tissue where they become known as uterine NK cells or uterine large granular leukocytes (uNK or uLGL or CD56+ cells). There seems to be two distinct populations of uNK cells, those associated with the endometrium and the more active uNK cells which are associated with the decidua underlying placental development. The uNK cells seem to be hormonally regulated as they occur in decidualized tissue in extrauterine ectopic pregnancies, and their association with the uterine tissue actually occurs before implantation during the secretory phase of the menstrual cycle (Manaster and Mandelboim, 2010). uNK have low cytolytic activity and are probably not involved in removal of damaged embryonic cells or regulation of trophoblastic invasion. However, they do produce cytokines, which are important in immunosuppression and growth regulation. The uNK cells may also be important in the protection against viral pathogens (Le Bouteiller and Piccinni, 2008). When uNK cells migrate to the endometrium, they proliferate and cluster around the spiral arteries where they are involved with both trophoblastic invasion and the first wave of remodelling of the uterine spiral arteries into the low-resistance vessels supplying the placenta (see Chapter 8). Progesterone stimulates the uNK cells to produce progesterone-induced blocking factor (PIBF) which is important in immunomodulation as it alters the profile of cytokine secretion by activated lymphocytes and keeps NK-cell activity low. IgA, secreted from the cells lining the uterine tubes, may also be important in protecting the uterine environment. It is suggested that a pregnancy-specific adjuvant, signal P, produced by the placenta, has opposing effects, activating components of the maternal innate immune system and suppressing the adaptive responses (Sacks et al., 1999). Signal P may also be responsible for the remission of autoimmune disease, such as rheumatoid arthritis and multiple sclerosis, in pregnancy. However, suppression of T-cell activity increases susceptibility to viral infections and to specific intracellular pathogens such as Listeria.

In summary, human pregnancy is a unique immunological situation. It takes place in the specialized environment of the uterus protected by the decidua. The immunological challenge intensifies very gradually and is moderated by hormones and cellular signals from maternal and fetoplacental sources which, together with fetal cells and DNA, can access the maternal compartment. The fetus avoids rejection because the trophoblast has limited expression of MHC class I or II molecules and the maternal adaptive immune responses are altered. So, the maternal immune system responds to the fetus which actively tolerizes the maternal immune response.

Effects of pregnancy on the immune system

The maternal immune response is affected by pregnancy. Many of the cells of the immune system are affected by the hormonal changes. For example, macrophages and T lymphocytes have oestrogen receptors. In pregnancy, the number of white blood cells, particularly neutrophils, increases and the cells respond more readily to challenges. hCG stimulates neutrophil production and response (Luppi, 2003). The high levels of oestrogen and progesterone decrease the number of helper T cells and increase the number of Treg cells. Yeast infections increase in pregnancy, possibly because of the effect of oestrogen on the flora of the reproductive tract. Women have a much higher incidence than men of autoimmune diseases, most frequently in child-bearing years. It is notable, however, that women who are not pregnant or who have never been pregnant still have a higher incidence of autoimmune diseases (due to the loss of self-tolerance—see above) than men. The exposure to female sex steroids is thought to drive this increased susceptibility (Hewagama and Richardson, 2009) so women experience a higher Th1-mediated response pattern. However, an alternative explanation is that the second X chromosome may create this genetic predisposition to autoimmune diseases.

Local concentrations of corticosteroids around the fetus and placenta suppress phagocytic activity, especially in response to Gram-negative bacteria. This means that pregnant women have a decreased ability to respond to Gram-negative infections of the reproductive tract such as gonorrhoea and Chlamydia (Hosenfeld et al., 2009) and Escherichia coli. Components of the complement cascade increase from the end of the first trimester so chemotaxis and opsonization are enhanced. Changes like this, which do not occur at the beginning of pregnancy, may be delayed to protect the fetus during implantation.

It has been suggested that the maternal immune response is important at all stages of pregnancy and may sense the reproductive fitness and compatibility of the male partner and the developmental competence of the conceptus to ensure biological benefits for the woman and her offspring (Robertson, 2010). This ‘immune-mediated quality control’ hypothesis proposes that the immune system expedites pregnancy loss if the pregnancy is not in the best interest of the female, for instance, because the conceptus is not developing appropriately or when external conditions do not favour the risk of investing maternal resources into pregnancy. The corollary is that pregnancy loss may not be pathological but may be a normal and beneficial part of optimal and healthy reproductive function.

Progesterone receptors on NK cells are upregulated as part of the immune responses to pregnancy. NK-cell activity around the uterus is suppressed by local increased concentrations of prostaglandin E₂ and other cellular signals (Dunn et al., 2003). This suppression of NK cells may be important in preventing rejection of the fetus. However, maternal resistance to intracellular pathogens such as Toxoplasma and Listeria may also be reduced (Wegmann et al., 1993). The relative proportions of cytokines change in pregnancy. The association between chorioamnionitis and premature rupture of membranes may be related to cytokine-mediated stimulation of proteolytic enzyme released from neutrophils.

Theoretically, the fetus could be perceived by the maternal immune system as a tumour. The conceptus may secrete cytokines, which affect tissues locally, promoting trophoblast growth and fetal survival (Wegmann et al., 1993). Concentrations of cytokines that attack tumours, such as TNF, and stimulate NK-cell activity, such as IL-2, are suppressed. Local secretion of such cytokines may be important in protecting the fetus without compromising maternal immune function.

TLRs are expressed by immune cells at the maternal–fetal interface and also in the non-immune cells of the trophoblast and decidua. Their expression in the human placenta is not constant and varies in a temporal and spatial manner (Koga and Mor, 2010). The expression of the TLRs increases throughout gestation, suggesting that the placenta in early pregnancy is less responsive to microbial challenges. It is suggested that pregnancy has three distinct immunological phases characterized by different immune responses and cytokine profiles (Mor and Cardenas, 2010). The first phase of implantation and placentation is an inflammatory phase (mediated by a Th1-dominant response) to ensure repair of the uterine endometrium and removal of cellular debris after the embryo breaks through and invades the maternal tissue. At this stage of pregnancy, the placental site has been likened to an ‘open wound’, with the cellular responses affecting the mother's well-being. The second phase is the period of rapid fetal development and growth and is an anti-inflammatory state (mediated by a Th2-dominant response) when the mother feels well. Then, the third phase is another inflammatory (Th1-dominant) state leading to uterine contraction, expulsion of the fetus and delivery or rejection of the placenta.

The other notable aspect is the relative lack of TLRs on the syncytial tissue compared to the villous cytotrophoblast and extravillous trophoblast, which suggests that the placental tissue only responds to bacterial and viral products that penetrate the outer layer of the placenta. It is suggested that the differential expression of TLRs is regulated by changing levels of sex steroids and that TLRs may be involved in tissue remodelling of the endometrium and preparation for implantation (Koga and Mor, 2010). Clinical observations and studies on animal models have demonstrated that TLRs are involved in a variety of pregnancy disorders, including spontaneous abortion, pre-eclampsia and premature labour. Activation of TLRs can inhibit trophoblastic migration which might be linked to the incomplete remodelling of the spiral arteries by trophoblastic cells in preeclampsia. TLRs are also important in identifying and responding to pathogens in amniotic fluid (Koga and Mor, 2010).

The levels of most antibodies do not change during pregnancy. However, IgG concentrations may fall. This fall may be due to haemodilution, increased loss in urine or placental transfer of IgG in the third trimester and it can increase the risk of streptococcal infection. Fetal secretion of cytokines may suppress cell-mediated immunity and enhance humoral responsiveness (Wegmann et al., 1993). SLE, an autoimmune condition causing tissue damage in the joints and kidneys, has an increased ‘flare-up’ frequency in pregnancy, which may be related to enhanced activity of B lymphocytes. This enhanced responsiveness by B lymphocytes may compensate for decreased T lymphocyte activity. B lymphocytes may also produce blocking antibodies which protect the fetus from attack by maternal T lymphocytes.

T lymphocytes are involved in graft rejection and could therefore pose a serious threat to the fetus. However, T-cell function is suppressed in pregnancy, especially in the first trimester (Koga and Mor, 2010). Circulating numbers of T lymphocytes are lower and they have decreased ability to proliferate, to produce IL-2 and to kill foreign cells. Ratios of helper and Treg cells change and the Th1/Th2 balance is shifted in favour of Th2, generating non-inflammatory responses, mediated by interleukins such as IL-4 and IL-10, which are compatible with trophoblast growth, survival of the fetus, fetal and infant growth and maintenance of pregnancy. IL-10 inhibits the activity of Th1 cells (Thaxton and Sharma, 2010). A Th1 reaction in the placenta generates inflammatory responses and is correlated with miscarriage; the cytokines secreted from Th1 cells are harmful in pregnancy as they inhibit embryonic and fetal development (Wegmann et al., 1993). A Th1 dominant pattern (upregulation of IL-2, IL-6, INF-γ and TNF-α) occurs in miscarriage; the inflammatory responses seem to mediate fetal rejection. An imbalance in the Th1/Th2 shift is also associated with preeclampsia and an inflammatory host response mediated by Th1 cytokines (Zenclussen et al., 2007). Trophoblastic production of cytokines promotes the change in Th1/Th2 balance as does progesterone and the decidual production of leukaemia inhibitory factor. Although the shift in the Th1/Th2 balance explains some of the changes in the immune system during pregnancy, the observations that Th2 knockout mice had normal pregnancies (Svensson et al., 2001) led to further scrutiny of the hypothesis. Furthermore, uNK cells were shown to be necessary for successful pregnancy and INF-γ was shown to be critical in remodelling of the spiral arteries (Chaouat, 2007). So, the new model includes a new lineage of T cells, Th17 cells, which produce IL-17, a pro-inflammatory cytokine which induces inflammation and acknowledges the role of Treg cells in inhibiting proliferation and cytokine production from Th1, Th2 and Th17 cells (Saito et al., 2008). The number of Treg cells in the circulation and in the decidual tissue and the lymph nodes draining the uterus expand markedly in pregnancy (Leber et al., 2010). Initial expansion of the Treg cell population begins before pregnancy is established, probably in response to the presence of paternal allergens from sperm and seminal fluid in the female reproductive tract, although hormonal changes in the menstrual cycle may also play a role.

Rheumatoid arthritis, a cell-mediated autoimmune disease, frequently goes into remission during pregnancy, because of the suppression of T lymphocytes. The amelioration of symptoms in pregnancy led to the identification of glucocorticoids as anti-inflammatory agents (Hench, 1952). Hormonal changes in pregnancy may augment the suppression of T lymphocytes. As T lymphocytes are involved in the responses to viral infection, pregnant women are at increased risk of viral infections and may experience more severe viraemia.

The Treg cells are also involved in acceptance of paternal antigens expressed by the semi-allogenic fetus. The Treg population of cells are activated in very early pregnancy by paternal antigens, possibly when paternal antigens are present in the vagina even before fertilization (Zenclussen et al., 2007). The Treg cells undergo expansion and migrate to the lymph nodes and then to fetal–maternal interface after implantation. This Treg cell population which are specific for paternal antigens generates a tolerant microenvironment at the maternal–fetal interface throughout the pregnancy. Maternal and fetal cells are reciprocally recognized by each other's immune systems, which means that the mother can tolerate the fetal allograft and the fetus acquires a tolerogenic environment that helps to protect it against autoimmune diseases.

A number of the immune cells utilize and metabolize the essential amino acid, tryptophan. In response to inflammatory stimuli, the syncytiotrophoblast expresses and secretes indoleamine 2,3-dioxygenase (IDO), an enzyme which metabolizes tryptophan. As tryptophan is depleted, the T cells are starved, which promotes their differentiation into Treg cells (Mellor and Munn, 2008). So, IDO acts as a switch to promote the number of Treg cells; in the absence of IDO, Treg cells are reprogrammed to become pro-inflammatory Th17 cells. The products of tryptophan metabolism prevent T-cell and B-cell activation and proliferation. IDO also suppresses complement-mediated damage.

It has been suggested that as maternal immune responses are suppressed in pregnancy and the Th1/Th2 balance altered to favour acceptance of the fetus, pregnant women would have increased susceptibility to infection. Historically, pregnant women were observed to contract smallpox and poliomyelitis more readily. Today, viral hepatitis infections, particularly in developing countries, pose a major threat to pregnant women, who have 10 times the infection rate of non-pregnant women and experience higher morbidity and mortality rates. The prevention of vertical transmission to the fetus or neonate is also an important consideration. Women who lack immunity and are exposed to primary cytomegalovirus have an increased susceptibility to infection in pregnancy, which is associated with fetal congenital abnormalities and is one of the most prevalent causes of mental retardation. Pregnant women have an increased susceptibility to listeriosis, influenza (Box 10.2), varicella (chickenpox), herpes, rubella (German measles), hepatitis and human papillomavirus. In addition, a number of latent viral diseases and other infections may be of greater severity. These include malaria, tuberculosis (TB), Epstein–Barr virus and HIV-associated infections (Wegmann et al., 1993), which can be reactivated in pregnancy. Pregnancy-induced suppression of helper T-cell numbers may be permanent so pregnancy can cause a progression of HIV-related disease. Pregnant women appear to have increased immunological responses to bacterial infection. However, increased incidences of urinary tract infections are probably related to anatomical changes rather than to altered immunological responses. Likewise, the increased severity of respiratory infections is usually associated with changes in diaphragm position which reduces secretion clearance and functional residual capacity. The immune changes in pregnancy may be responsible for the increased risk of breast cancer in the years immediately following pregnancy, particularly in women who are older at their first full-term pregnancy (Shakhar et al., 2007); however, a first full-term pregnancy at a younger age exerts a protective effect on lifetime risk of breast cancer. Some conditions, such as multiple sclerosis, improve in pregnancy because of the expansion of the Treg cell population. The postpartum period can also be an immunologically sensitive time, as the rapid reversal of the changes that occurred in pregnancy and a rebound of inflammatory responses can cause latent or quiescent infections to become full symptomatic diseases (Singh and Perfect, 2007). Thyroid autoantibody levels fall in pregnancy so conditions such as Graves disease are ameliorated, but the antibodies then peak in the postpartum period (Weetman, 2010) so postpartum thyroiditis and mild autoimmune hypothyroidism are relatively common in the first 6 months following delivery (see Chapter 12).

Box 10.2

Seasonal influenza

The immune changes in pregnancy mean that pregnant women who contract seasonal influenza (flu) are at increased risk of developing severe complications that can cause morbidity and mortality, especially during the third trimester. Physiological changes in the respiratory system probably contribute to the increased severity of respiratory complications. Flu viruses are classified as A, B or C types; types A and B are the main causes of mortality and type A is associated with pandemics (Toal et al., 2010). The surface antigens of flu viruses demonstrate ‘antigenic drift’ and change subtly so at-risk groups require annual vaccination. In the 1918 flu pandemic, one study of pregnancy showed that approximately half the women infected with influenza developed pneumonia and about half of these women with pneumonia died—a death rate of 27%. Surveillance of the swine flu pandemic in 2009/2010 showed that, like previous flu pandemics, pregnant women were at significant risk from the H1N1 virus (swine flu). Pregnant women who are colonized by bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae are at a higher risk of developing pneumonia if they are infected with the H1N1 influenza virus (Cheng et al., 2009). There is a higher rate of fetal abnormalities, premature delivery and stillbirths in pregnant women who contract influenza in early pregnancy which is probably caused by high fever; however, vertical transmission of flu virus has not been demonstrated. The presenting signs of seasonal flu are usually fever, cough, vomiting, breathlessness, myalgia, sore throats and chills. The World Health Organization advises pregnant women to have seasonal flu vaccines because of the high risks associated with pregnancy. Flu vaccines are fragmented, meaning that they contain parts of the virus and are not whole or attenuated (mild form of virus). The use of antiviral drugs such as neuraminidase inhibitors (oseltamivir and zanamivir) is also advocated in pregnancy because the risks associated with their use are outweighed by the risk of flu infection in pregnancy (Tanaka et al., 2009). Public health measures for containing infection include hand and domestic hygiene, cough etiquette and avoiding unnecessary travel and crowds if possible.

For decades it has been assumed that maternal and fetal blood never mixes, but transplacental passage of a few cells appears to be normal. Microchimerism is the presence of a tiny number of cells or DNA within an individual, both in the circulation and in other tissues, that have come from another individual. The most common cause of microchimerism is fetal microchimerism, the trafficking of fetal cells in pregnancy; the cells could be blood cells or trophoblast cells which are continually shed during pregnancy (see Chapter 8). Fetal cells have been demonstrated to multiply and then persist in their mother's blood for decades after delivery (Sarkar and Miller, 2004) and, in some cases, a maternal cellular immune response against the fetal antigens is mounted. It has been suggested that fetal microchimerism might be associated with an increased risk of miscarriage (Lissauer et al., 2009) and that the higher incidence of autoimmune diseases in women is related to microchimerism, inducing a graft-versus-host disease. The transfer of cells is bidirectional and maternal cells are also transferred from the mother to the fetus, maternal microchimerism (Lissauer et al., 2009). Diseases thought to be associated with microchimerism include scleroderma, Sjögrens syndrome, Graves' disease and SLE. This hypothesis is applicable to men, children and women who have never been pregnant, because microchimerism can result from other sources such as transplantation and blood transfusion, and cells from a twin. Fetal microchimerism may have a protective function playing a role in tissue repair; in addition, studies have also implicated both an increased and a reduced risk of cancer associated with microchimerism (Lissauer, 2009). A recent and controversial hypothesis suggests that microchimerism offers evolutionary benefits (Apari and Rozsa, 2009); the mother benefits from receiving fetal cells, as their immune system will benefit from receiving paternal resistance alleles via the fetus and the fetus will benefit because the maternal immune system is thus strengthened.

Fetal and neonatal passive immunity

The neonate's immune system is augmented by maternal transfer of immunoglobulins across the placenta to the fetus and in breast milk. The profile of immunoglobulins transported across the placenta and secreted into breast milk depends on specific transport mechanisms for the different classes of immunoglobulin (see Table 10.3). Maternal IgG crosses the placenta into the fetal circulation via a specific active transport mechanism, which is effective from around 20 weeks' gestation but markedly increases in activity from 34 weeks. The mother will produce an immune response to antigens she encounters by producing IgG, which can cross the placenta. Even if maternal levels of IgG are low, they will be transported across the placenta. This means that the fetus will receive passive immunization against prevalent pathogens likely to be in the environment from birth. This passive immunity provides essential temporary protection postnatally until the neonate's own immune system matures and produces its own antibodies. Preterm babies are at risk of transient hypoglobulinaemia because they receive less IgG and they are born with immune systems that are less mature than a term infant's. Placental dysfunction limits the transfer of IgG; therefore, SGA (small for gestational age) babies have lower levels of IgG. IgA, IgM and IgD do not cross the placenta but are supplied in high concentrations in the colostrum.

As well as beneficial IgG, potentially harmful IgG can cross the placenta. Maternal antibodies to fetal HLA will be generated as the maternal immune system encounters a few fetal cells. The maternal anti-fetal HLA antibodies will cross the placenta but do not cause any damage as they bind to non-trophoblastic cells in the placenta, which bear fetal HLA and can sequester maternal IgG (Johnson and Christmas, 1996). In autoimmune diseases, however, pathogenic maternal antibodies can be transferred across the placenta. For instance, antiplatelet antibodies can cross the placenta into the fetus of a mother with autoimmune thrombocytopenic purpura (Johnson and Christmas, 1996). The passive transfer of autoimmune antibodies may affect fetal growth and development and can potentially cause at least transient symptoms of the disease in the neonate. The resulting increased risk of haemorrhage in babies born to mothers with thrombocytopenia means that traumatic procedures, such as fetal blood sampling and instrumental delivery, are avoided. Some autoimmune conditions such as congenital heart block associated with SLE can cause irreversible damage to the neonate (Buyon et al., 2009).

Preterm babies are at a higher risk of vertical infection of group B streptococci if their mothers are group B streptococcus-positive, because they do not gain passive immunity from the placental transfer of immunoglobulins until after 34 weeks' gestation. Term babies do have some degree of protection from group B streptococci and this can be extended if the infant is breastfed. The use of antibiotics in the intrapartum period does reduce the number of group B streptococcal infections in the neonate, and so any mother who is found to be group B streptococci-positive at any time, not just during the pregnancy, may be offered antibiotic therapy in labour (RCOG, 2006). The antibiotics reduce the bacterial load and so the risk of infection is less, although a small number of neonatal infections may still occur (Royal College of Obstetricians and Gynaecologists, 2003).

In the last trimester, the placental transfer of maternal IgG will include IgG antibodies directed against the fetus's own antigens. Most of these are thought to bind to non-trophoblastic cells bearing fetal antigens within the placental villous tissue so they do not reach the fetal circulation. However, antibodies to the Rhesus antigen can cause severe complications. People who express the Rhesus antigen on their own red blood cell surface do not make antibodies against the Rhesus antigen. These people are described as Rhesus positive (Fig. 10.8). A mother who is Rhesus-negative does not have the Rhesus antigen on her own red blood cell surface, and her immune system has the capability of making Rhesus antibodies. About 10% of pregnancies in Caucasian populations are Rhesus-negative women with a Rhesus-positive fetus; in other ethnicities, there is a lower incidence of Rhesus-negative individuals.

The Rhesus antibody is not preformed (existing from birth) like the antibodies of the ABO blood grouping system. Rhesus antibodies are produced if the immune system is given the opportunity to recognize the Rhesus antigen as a foreign protein. In practice, this means that a Rhesus-negative mother could produce antibodies to the Rhesus antigen of fetal cells (which would recognize and attack the red blood cells of a Rhesus-positive fetus) if her immune system encountered it. The immune response can be generated from exposure to red blood cells bearing the Rhesus antigen, for instance, from transplacental leakage of Rhesus-positive fetal cells or in rare instances from a Rhesus-positive blood transfusion (see Box 10.3 for conditions requiring anti-D administration).

Box 10.3

Prophylactic anti-D immunoglobulin treatment for women who are Rhesus-negative

• Delivery of Rhesus-positive baby

• Spontaneous abortion

• Therapeutic termination of pregnancy

• Threatened abortion

• Antepartum haemorrhage

• Following external cephalic version of breech presentations

• Following CVS (chorionic villus sampling), amniocentesis or other invasive intrauterine procedure

• Following abdominal trauma

The occasion when Rhesus isoimmunization is most likely to occur is at the time of the third stage of labour. During placental separation, there is the potential for a small amount of fetal blood (perhaps half a millilitre) to cross into the maternal circulation. Fetal blood can also enter the maternal circulation earlier in pregnancy, during therapeutic or spontaneous abortion, amniocentesis, abdominal trauma and in an ectopic pregnancy. If the fetal blood entering the maternal circulation is Rhesus-positive, it could stimulate the maternal immune cells to respond by clonal expansion, developing the capacity to produce large quantities of IgG. Once a woman makes antibodies to Rhesus antigens, she is isoimmunized for life. These IgG antibodies can then be transported across the placenta to the fetal circulation late in gestation of a subsequent pregnancy. The binding of maternal Rhesus antibodies to the Rhesus antigen on the surface of the fetal blood cells stimulates lysis of the red blood cells. Mild Rhesus incompatibility can cause mild anaemia and reticulocytosis (new immature red blood cells in the circulation). Severe Rhesus incompatibility is a cause of miscarriage, intrauterine death or hydrops fetalis (abdominal ascites, generalized oedema, polyhydramnios and enlarged placenta). In the neonate, Rhesus incompatibility can result in haemolytic disease of the newborn, where profound haemolysis causes anaemia, increasing the risks of heart failure, hyperbilirubinaemia (jaundice) and kernicterus (see Chapter 15).

Prophylactic treatment has been practised since 1967 (Box 10.3) and severe Rhesus D alloimmunization is now rarely seen. Giving passive immunization prevents primary sensitization of the mother and the formation of cells that can produce IgG anti-Rhesus antibody. Although there is actually a complex system of Rhesus antigens, controlled by three pairs of genes (Cc, Dd and Ee), the Rhesus D antigen predominates in incompatibility between the mother and the fetus.

In accordance with national guidelines (see Annotated Further Reading), the majority of Rhesus-negative women are offered routine anti-D administration at either as two smaller doses at 28 and 34 weeks' gestation or one larger dose at around 28–30 weeks gestation. Following delivery of the baby to a Rhesus-negative woman, the Rhesus status of the infant has to be determined. If this proves to be Rhesus-positive, then a second test is performed to estimate the amount of fetal blood in the maternal system (Box 10.4), as amounts greater than 4 mL may require more than the standard anti-D dose of 500 international units (i.u.). Although if both parents were Rhesus-negative, anti-D would not be required; the guidelines do not recommend testing of the father to identify his Rhesus status, because it is recognized that the apparent father might not be the biological father, which may create a difficult situation to manage. It is difficult to justify routine anti-D administration if the father is certain that he is Rhesus-negative; however, it is prudent to observe the infant for signs of early and excessive jaundice in case the conception occurred outside of the pair bond.

Box 10.4

Maternal and cord blood tests

When a mother is Rhesus-negative, a sample of the baby's blood is obtained from the umbilical cord. Two tests are performed:

1. The baby's blood group and Rhesus factor are identified; if the baby is Rhesus-negative, there is no possibility of maternal antibodies forming so the mother does not require anti-Rhesus-D antiserum (known as ‘anti-D’) administration

2. If the baby is Rhesus-positive or there is another maternal/fetal antibody/antigen incompatibility, then the direct Coombs' test would also be performed. The Coombs' test enables differentiation between normal neonatal haemolysis and abnormal haemolysis caused through the action of maternal antigens. It is based on three variables and is positive when there is reduced haemoglobin in conjunction with an increased reticulocyte count and raised bilirubin levels.

Maternal blood is also taken so that the Kleihauer-Betke test (Kleihauer et al., 1957) can be performed. The test is based upon the resistance of fetal blood cells to be destroyed by acid (acid elution test). Not only does the test allow the presence of fetal erythrocytes to be detected but the amount of fetal blood transfused into the maternal circulation can be estimated as well. The test is not as accurate if there are maternal haemoglobinopathies present, as abnormal maternal erythrocytes (such as sickle cell disease) are also resistant to acid destruction. The test may also be falsely negative if there is an A/B incompatibility as the maternal anti-A and/or anti-B antigens quickly destroy the fetal erythrocytes, especially if the Kleihauer test is delayed, so it should be conducted within half an hour of delivery of the third stage.

It is estimated that a fetal–maternal blood transfer occurs in approximately 50% of pregnancies (Zipursky et al., 1959). Usually, the amount of blood is small, less than 0.5 mL. However, in 8% of pregnancies, it may be in the range of 0.5–40 mL and in 1%, it may well exceed 40 mL. In most cases, 500 i.u. of anti-Rhesus-D antiserum is enough to eradicate the misplaced fetal erythrocytes. However, if a large transfusion is suspected, then larger doses will be administered.

If an exceptionally large transfusion is suspected following the administration of anti-Rhesus-D antiserum, the Kleihauer-Betke test should be repeated, and if fetal cells are still detected, then further doses of anti-Rhesus-D antiserum would be administered.

If a small volume (less than 4 mL) of fetal blood has entered the maternal circulation at delivery, the exogenous antibodies (‘anti-D’) will bind to the fetal Rhesus D antigen and cause cell lysis before the maternal lymphocytes have the opportunity to recognize the antigen and undergo subsequent clonal expansion. ABO compatibility exacerbates Rhesus isoimmunization so ABO incompatibility offers a degree of protection against Rhesus sensitization. If the fetal blood transfused is of a different ABO grouping, the existing natural maternal IgM anti-A or anti-B antigens will rapidly eliminate the fetal blood cells before an immune response can be mounted against the Rhesus D antigen.

Unnecessary administration of anti-D may be prevented by identifying the Rhesus state of the fetus early in pregnancy by isolating fetal DNA markers from maternal blood (Kolialexi et al., 2010). This will further minimize the risk of exposure to blood products by limiting administration to cases where it is required (and also better utilize the donor-dependent stock of anti-D).

Most antibodies in the ABO system are IgM type so they do not cross the placenta. However, in successive ABO-incompatible pregnancies in group O mothers, a degree of neonatal haemolysis, causing mild neonatal jaundice, may occur. Haemolytic disease can potentially occur with other blood group incompatibilities such as the Kell and Duffy antigen systems. However, the density of these minor antigens on fetal red blood cells is so low that maternal IgG antibodies usually do not elicit a cytolytic effect. Women who require or have had multiple or large blood transfusions, for example, following postpartum haemorrhage, are at risk of developing antibodies to surface antigens which could potentially put their unborn babies at risk.

Vulnerability of the neonate

Neonates are born immunocompromised and are susceptible to infection. An intriguing idea is that the immaturity of the fetal immune system is an adaptive response which helps to protect it from premature rejection by its mother (Clapp, 2006), but the cost of this is the increased risk of infections of the newborn, particularly if born prematurely. The natural flora colonizes and protects the external surfaces of the body, and those membranes that appear internal but come into contact with external pathogens, such as the upper respiratory tract, gut and urinary system. The natural flora may protect by competing with pathogenic microorganisms for resources or by altering the local environment, making it less hospitable to pathogens. The acid mantle of the skin promotes colonization of commensal microbes and restricts growth of pathogens (Behne, 2009). The neonatal skin is particularly vulnerable to change in pH through the use of detergents, resulting in atopic dermatitis raising the risk of skin infections in the neonate (Cork et al., 2009; see Chapter 15).

The fetus in the uterus is sterile because there is no route for colonization. Colonization takes about 6–8 weeks, which is similar to the time it takes for the resident flora of non-pathogenic bacteria to repopulate in NASA astronauts, who are made bacteriologically sterile before a space flight. As the bowel flora produces much of the body's vitamin K requirements, neonates have an increased risk of vitamin K deficiency until the resident flora is established. Colonization processes can be disrupted, for instance, by use of detergents, disinfectant swabs or antibiotic use. Colonization of the neonate begins at birth, with transfer of organisms from the mother's vagina, skin of her hands and breasts and the respiratory tracts of the baby's carers.

Neonatal skin is delicate and easily damaged, thus it can offer a route for opportunistic infection. The umbilical cord, which becomes necrotic, presents a locus for possible infection and offers a potential pathway to the liver. The neonatal defence mechanisms are further compromised by invasive procedures such as blood sampling or insertion of endotracheal or nasogastric tube or intravenous cannulae.

Infants have less efficient immune systems, especially if they are born prematurely or are small at birth. The cells of the immune system are immature and do not function as efficiently in early life; for instance, T lymphocytes have decreased responses and cytolytic function. The phagocytes exhibit decreased phagocytosis and bactericidal activity. Their function in severe illness, such as respiratory distress syndrome or meconium-aspiration pneumonia, is further limited. The complement cascade components at birth are 50–80% of the adult levels. Maternal mood in pregnancy may affect the development and functioning of the neonatal immune system following birth (Mattes, 2009).

The immature immune system of the neonate is supported by natural passive immunization from placental transfer of IgG and breast milk provision of IgA. It is also supported by programmes of deliberate immunization. Active immunization requires administration of an antigen in a form that is inactivated and does not produce a disease (Box 10.5). IgG levels start to increase by 3 months so immunization is delayed after birth. However, some protection is required before the immune system is mature. Therefore, immunization programmes are often started when the baby is 3 months old. At about this age, many babies receive the ‘triple’ vaccine of pertussis (whooping cough), diphtheria and tetanus antigens presented appropriately. Diphtheria and tetanus elicit strong antigenic responses despite the infant's immature immune system, whereas children are given further doses of pertussis vaccine. Live polio vaccine is given orally at the same time as the ‘triple’ vaccine. Although theoretically, only one dose is required, there are at least three strains and the immune response may not be produced the first time. Measles vaccine is usually delayed until the infant is about 1 year old, as maternal IgG, which is present for the first 6–9 months of life, tends to destroy the attenuated organisms of the vaccine before the infant's immune system has time to recognize and respond to them.

Box 10.5

Principles of immunization

Adjuvants

For example, aluminium hydroxide or phosphate: Increases antigenic properties of a vaccine that would otherwise produce only a weak immune response, for example, triple vaccine of diphtheria, tetanus and pertussis toxins.

Toxoid

Bacterial exotoxin treated so it does not cause a disease but still stimulates the immune cells. Examples include treatment of diphtheria and tetanus toxin with formalin.

Killed vaccine

Dead organisms such as pertussis, typhoid and paratyphoid: As with toxoid preparations, two or three doses and booster doses are required, as only a small number of antigens are introduced each time.

Attenuated vaccines

Live organisms that have been cultured to produce non-pathogenic strains: Very effective as organisms multiply within body mimicking a natural infection. Therefore, only one dose is required for full immune response (lifetime immunity), for example, smallpox, poliomyelitis, measles, rubella, TB.

Immunization using viral vaccines may be ineffective if the individual has had a recent viral infection, such as a cold. Levels of interferon persist after a viral infection so the virus in the vaccine preparation may not be able to reach concentrations adequate to stimulate the immune system. Therefore, immunization may not be effective until 2–3 weeks after a viral infection. Oral doses of vaccines may be ineffective if their absorption is compromised, for instance, with diarrhoea or vomiting. High levels of steroids suppress the immune response, so steroid therapy or overactive adrenal glands can limit the effectiveness of a live vaccine and compromise the immune response. Maternal antibodies in the neonate, for instance, from placental transfer of IgG, can abrogate the young infant's immune response to vaccination but subsequent booster vaccination usually surmounts this. Infants who are themselves HIV-negative but born to HIV-positive mothers may not respond efficiently to vaccines (Miles et al., 2010). Allergic reactions to vaccines can occur, especially to vaccines prepared in tissue culture or containing whole cells. Problems with allergic reactions are often associated with vaccines grown in egg-based tissue culture preparations or to which antibiotics have been added. Obviously, a severe reaction to a vaccine precludes its further use. Administration of live vaccines is not recommended in pregnancy. Immunization programmes benefit the health of the population unfortunately at the expense of the few individuals who may have an extreme reaction to a vaccine with irreversible effects.

Other immunological aspects of pregnancy

Antisperm antibodies can be present in both men and women. In seminal fluid, they can cause immune infertility by inhibiting spermatogenesis or fertilization (Chiu and Chamley, 2003). However, the Sertoli cell protects the developing sperm and seminiferous tubules from antibodies and Treg cells secrete immunosuppressive cytokines in the epididymis. Some are coated with glycoproteins and lactoferrin, which may be why some antigen sites are evident only after sperm capacitation. Seminal fluid has potent immunosuppressive and signalling properties and can inhibit a range of immune responses (Robertson, 2005). The presence of antisperm antibodies in the secretions from the genital tracts, rather than in the blood, seems important particularly in male infertility. The risk of developing antisperm antibodies is increased with exposure to sperm that is excessive, as in prostitutes, or in an inappropriate site, as in homosexual men (Johnson and Christmas, 1996). A significant proportion of men have been shown to have antisperm antibodies associated with retention of sperm due to obstruction of the vas deferens or epididymis and so have retention of sperm, so the presence of antisperm antibodies is a useful predictor that obstruction is the primary cause of male infertility (Lee et al., 2009). Generation of antisperm antibodies may reflect a lack of immunosuppressive factors in the seminal fluid. It has also been proposed that exposure to semen can positively affect the maternal immune responses that promote the success of pregnancy (Robertson, 2005). Insemination might present a ‘priming’ event which induces maternal tolerance to paternal antigens in the semen, many of which will also be expressed by the developing conceptus.

Endometriosis, which is deposition of endometrial tissue at non-uterine sites, can be very painful if the tissue becomes inflamed. Severe endometriosis can cause infertility, but many women have extrauterine endometrial tissue that neither causes pain nor affects fertility. The cause of endometriosis is not known, but an autoimmune aetiology has been proposed (Tomassetti et al., 2006).

Preeclampsia, inadequate placental development following inadequate remodelling of the spiral arteries, is also suggested to have an immune component (see Chapter 8). The incidence of preeclampsia is higher in first pregnancies and in subsequent pregnancies with a new partner, which suggests an immunological mechanism. However, a change of partner is often associated with a longer inter-pregnancy interval which is more strongly correlated with preeclampsia (Redman and Sargent, 2010) as is a short interval between first coitus (exposure to the partner's sperm) and pregnancy. It appears that pre-conceptual exposure to antigens on sperm or in seminal fluid (or both) tolerizes the mother to the fetopaternal antigens and protects against preeclampsia. Barrier methods of contraception, artificial insemination with donor sperm and ICSI are all associated with increased risk. It is essential that there is maternal immune recognition of the fetopaternal allergens to ensure the success of implantation, placentation and placental growth.

The effects of HIV and AIDS in pregnancy are detailed in Box 10.6 and Case study 10.2.

Box 10.6

HIV and AIDS in pregnancy

• HIV (human immunodeficiency virus) causes AIDS (acquired immune deficiency disorder).

• HIV is a retrovirus, which invades cells expressing CD4, including helper T cells, monocytes and neural cells.

• A retrovirus contains a single strand of RNA, which is incorporated into the host cell's DNA by an enzyme called reverse transcriptase.

• When the infected cell is activated, it will produce viral proteins, which can be released and infect other cells.

• HIV infection causes decreased numbers of helper T cells, which affect the organization of all the immune responses so the risk of opportunistic and pathogenic infection increases.

• In Britain, women usually acquire HIV from sexual exposure and intravenous drug use.

The biggest increase in HIV infection is heterosexual transmission in women.

HIV has to evade the mechanical, chemical and biological barriers of the female reproductive tract.

Progesterone-based contraception may accelerate HIV disease progression as progesterone inhibits cytotoxic T cells and NK cells; oestrogen may be protective.

Co-infections in the female reproductive tract which cause micro-ulcerations may increase HIV susceptibility.

Transmission of HIV is more efficient from men to women (compared to women to men) possibly because semen transforms the local environment of the female reproductive tract, for instance, increasing pH and upregulating pro-inflammatory cytokines.

• Pregnancy can mask some of the non-specific symptoms of HIV infection, such as fatigue, anaemia and dyspnoea.

• HIV can remain latent for years (estimated to be an average 11 years) before AIDS becomes evident.

• Progression to symptom development may be accelerated by pregnancy.

• HIV can be transmitted to the baby via the placenta, from exchange of body fluids at birth or from breast milk.

• Mothers with HIV may be advised to breastfeed their babies if the risk of fatal malnutrition is considered to be higher than the risk of HIV infection; lactoferrin is protective.

Case study 10.2

Mary is 16 weeks' pregnant. She has no fixed abode and has not previously been seen by a health professional in relation to her pregnancy. Mary attends the local hospital antenatal clinic in a state of distress. She informs the midwife that she is an intravenous drug abuser and her best friend has just died from an AIDS-related illness.

• How prepared would you be, as the midwife, to counsel and advise Mary?

• What referrals and expert advice would you seek on her behalf?

• What considerations are needed in relation to the unborn child, in relation to both HIV transmission and Mary's general situation?

Key points

• Pregnancy enhances humoral immunity and suppresses cell-mediated immunity so responses to bacterial infection are enhanced, but there may be increased susceptibility to viral infections.

• Histoincompatibility, such as the differences in fetal and maternal antigen expression, would normally lead to tissue rejection.

• The trophoblast cells lack classic HLA antigens, which prevent an anti-fetal response, but express HLA-G, which prevents non-specific cytolysis.

• Fetal cells entering the maternal circulation are important in the generation of blocking antibodies, which block any immune response that does occur.

• Maternal IgG is transferred to the fetus late in gestation, which provides the neonate with passive immunization during the period of immunological immaturity. Harmful antibodies against fetal antigens are sequestered by non-trophoblastic tissue in the placenta.

• The birth of a Rhesus-positive baby to a Rhesus-negative woman can initiate an immune response. Prophylactic administration of anti-Rhesus-D immunoglobulin is therefore given after possible or actual exposure.

• The neonate is immunocompromised at birth. Immunization programmes seek to address this lack of immunity.

Application to practice

Pregnancy results in an alteration of the immune system, so normal non-pregnant white cell counts cannot be applied in pregnancy. An understanding of changes within the immune system will enable the midwife to explain the consequences of such changes to the pregnant women.

An understanding of rhesus incompatibility is necessary as this is a common potential problem.

Conditions that affect the maternal immune systems may complicate pregnancy, affecting not only the mother but also the fetus and the neonate. Such conditions require careful management and treatment to optimize outcomes for both the mother and the baby.

Midwives may be involved in the administration of some vaccines such as rubella and TB so an understanding of the immune system is required. The interaction of the maternal immune system and the baby is an important aspect of lactation and breastfeeding.

Annotated further reading

Department of Health: Immunisation against infectious disease—‘The Green Book’. (2006) DoH, London ; (updated 2010).

This a comprehensive reference guide on all types of vaccination for all healthcare professionals involved in immunization.

Druckmann, R.; Druckmann, M.A., Progesterone and the immunology of pregnancy, J Steroid Biochem Mol Biol 97 (2005) 389–396.

A clear summary of the mechanisms by which the recognition of pregnancy upregulates progesterone receptors and alters cytokine production, thus suppressing the maternal immune responses to the fetus.

Gammill, H.S.; Nelson, J.L., Naturally acquired microchimerism, Int J Dev Biol 54 (2010) 531–543.

An in-depth and readable review of microchimerism which includes historical perspectives approaches to detect and confirm microchimerism and the relationship between persistent microchimerism and disease.

Kaushic, C.; Ferreira, V.H.; Kafka, J.K.; et al., HIV infection in the female genital tract: discrete influence of the local mucosal microenvironment, Am J Reprod Immunol 63 (2010) 566–575.

A well-written description of the factors which affect HIV susceptibility to infection by heterosexual transmission.

Kitchen, G.; Horton-Szar, D., Crash course: immunology and haematology. (2007) Mosby, London .

This book presents the fundamental principles of haematology and immunology in an easy-to-understand format and is a useful introductory text for healthcare professionals.

Liu, E.; Laurin, J., Viral hepatitis, A through E, in pregnancy, In: (Editors: Shetty, K.; Wu, G.Y.) Chronic viral hepatitis: diagnosis and therapeutics (2009) Humana Press, Washington, pp. 353–373.

This chapter gives an overview of viral hepatitis infections in pregnancy including screening, treatments and outcomes.

In: (Editor: McKibbin, S.) HealthScouter child immunization: childhood immunization schedule: parents guide for immunizations and vaccinations for children (2009) Equity Press, Brooklyn.

This is a useful guide for parents about the most common problems associated with immunization; includes hundreds of quotes, questions, and answers from patients themselves.

Mecacci, F.; Pieralli, A.; Bianchi, B.; et al., The impact of autoimmune disorders and adverse pregnancy outcome, Semin Perinatol 31 (2007) 223–226.

A review outlining the issues for pregnant women affected by the more common autoimmune connective tissue diseases: SLE, rheumatoid arthritis, scleroderma and Sjögrens syndrome.

National Institute for Clinical Excellence, Routine antenatal anti-D prophylaxis for women who are RhD-negative. (2008) NICE .

This review forms the basis of the current use of anti-D in the United Kingdom and provides a comprehensive and referenced guide to the use of anti-D.

Playfair, J.H.; Chain, B.M., Immunology at a glance. ed 9 (2009) Wiley-Blackwell .

Covers a wide range of immunological topics using clear, well-labelled diagrams to summarize and simplify the mechanisms of immunological processes together with succinct written explanations on facing pages.

Price, L.C., Infectious disease in pregnancy, Obstet Gynaecol Reprod Med 18 (2008) 173–179.

A thorough review of the main infectious diseases that can complicate pregnancies in the developed world and the screening, investigation and management principles.

Redman, C.W.; Sargent, I.L., Immunology of pre-eclampsia, Am J Reprod Immunol 63 (2010) 534–543.

A review of the relationship between the immune responses and preeclampsia which describes the early maternal adaptation to paternal/fetal antigens and the later non-specific, systemic inflammatory response which follows placental oxidative stress, thus explaining the first pregnancy preponderance and partner specificity of preeclampsia.

Royal College of Obstetricians and Gynaecologists, Prevention of group B streptococcus (GBS) infection in newborn babies. (2006) ; London, RCOG (amended 2007).

This leaflet gives a simple and concise explanation for the treatment of group B streptococcus; although primarily aimed at informing women, it provides a useful summary for healthcare professionals.

Sompayrac, L.M., In: How the immune system works ed 3 (2008) Wiley-Blackwell.

Clearly explained textbook, illustrated with useful diagrams, which covers progressive development of immune concepts.

Toal, M.; Agyeman-Duah, K.; Schwenk, A.; et al., Swine flu and pregnancy, J Obstet Gynaecol 30 (2010) 97–100.

This review provides a clear up-to-date summary of the current research and advice on the management of swine flu in pregnancy including the 2009 Department of Health and Royal College of Obstetricians and Gynaecologists' guidelines.

Wood, P., In: Understanding immunology (Cell & molecular biology in action series) ed 2 (2006) Prentice Hall.

A clear, well-illustrated introductory text which is written for students with little prior knowledge of immunology.

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