The immune system exists to protect the organism from the consequences of infectious disease and, to a lesser extent, neoplasia. It does this by having a complex system of organs, cells and molecules that are distributed throughout the body. Most of the cells involved are highly motile, adding to the complexity of the system. The importance of the immune system in health and disease is highlighted by rare congenital abnormalities of components of the system, which in many cases result in early death due to uncontrollable infections.
The immune system plays an important role in a number of conditions of pregnancy including spontaneous abortion, pre-eclampsia and hypersensitivity reactions that damage the fetus. Pregnancy can also result in changes in the severity of autoimmune diseases. In addition, one of the most interesting questions in immunology is why a fetus is not recognised by the mother’s immune system and destroyed; if an equivalent organ were transplanted into a woman without massive immunosuppression, it would be rapidly rejected. This might seem an academic question, of little practical importance. However, new strategies for preventing graft rejection are being developed based on our knowledge of how the fetus/placenta blocks rejection.
The Immune System
Frequently, the immune system is characterised as differentiating between ‘self’ (anything originating from the organism) and ‘foreign’ (anything that is not self), and destroying anything it recognises as foreign. However, this is a gross simplification. When the immune system is first introduced to a foreign molecule or organism, it needs to decide whether to respond or not. Frequently it does not – we normally fail to produce immune responses to the large amounts of foreign antigen that we ingest as food or are present as commensal organisms in our gut. Having decided to mount an immune response, there is a secondary decision – what sort of response should be initiated? Different pathogens need to be dealt with in different ways, and an inappropriate immune response will not only be ineffective but may also damage the organism.
The decision-making is vital because there are important consequences to mistakes. The failure to mount an immune response when needed may cause uncontrolled infection or malignancy. However, mounting an immune response to foreign material when it is not needed can result in pathology, for example allergies. Immune responses against self can result in autoimmunity. Choice of inappropriate types of immune response will result in tissue damage. Even appropriate immune responses frequently damage the organism; the necessary immune responses against Mycobacterium tuberculosis , the bacteria that cause the deadly disease tuberculosis, result in scarring. In the context of pregnancy, the immune response against an infection may result in miscarriage of the fetus, although the consequences of failing to respond would be more serious.
There are two main parts to the immune system: the innate and the adaptive immune systems. The innate immune system contains both cells and soluble molecules and is often thought of as the first line of defence against pathogens. Unlike the adaptive immune system (see below), it does not recognise specific antigens on the pathogens, but rather responds to general common features of pathogens (for example sugar molecules expressed on the surface of bacteria but not mammalian cells). Every pathogen has a particular surface structure due to patterns of carbohydrates, lipids and charge distribution, collectively termed as pathogen-associated molecular patterns (PAMPs). A number of innate immune cells such as macrophages and dendritic cells have PAMP-recognising receptors (PRRs). PAMP–PRR engagement can thus lead to uptake of pathogens (phagocytosis), and/or generate an inflammatory reaction that would involve mobilisation of immune cells and proteins at the site of infection.
The innate immune system is always present and ready to recognise and destroy pathogens (though it can become more active during inflammation). The adaptive immune system, in comparison, recognises specific antigens using receptors (antibody and T-cell receptors (TCRs)). When first faced with a pathogen, the adaptive immune response must first select and then amplify cells bearing the appropriate receptors (clonal selection; see below). Only then can it produce a specific immune response, resulting in a delay of several days before it is effective.
The adaptive immune response is characterised by its memory; once it has responded to an antigen it will mount a rapid and vigorous secondary immune response if it is re-exposed to the antigen ( Fig. 8.1 ). This is the basis of both immunisation and protection by prior infection.
However, the divide between the adaptive and innate immune system masks the considerable interactions that occur. This is both at the level of regulation of the immune response (the innate immune system is essential in instructing the adaptive response), and at the level of effectors where components of the adaptive immune response amplify and focus the effector mechanisms of the innate system onto their targets.
Here, we will look first at the cells and molecules of the adaptive and innate immune systems. We will then go on to consider some examples of how they interact to control immune responses. Finally, we will turn to look at areas of particular interest to reproductive immunology.
Adaptive Immune Systems
The main cells of the adaptive immune system are the bone marrow-derived lymphocytes. There are two main categories of lymphocyte: the B lymphocyte (or B cell) and the T lymphocyte (T cell). B cells are responsible for producing the soluble antigen-specific effector molecule of the immune system, the antibody. T cells have two roles; one is to regulate the immune system (T helper cells and T regulatory cells) and the other is to kill virally infected or neoplastically transformed cells (cytotoxic T cells).
The main role of the B cell is to produce antibody molecules, or immunoglobulins ( Fig. 8.2 ). Immunoglobulins have a basic structure consisting of four polypeptide chains: two identical heavy chains and two identical light chains. When different antibody molecules are compared, most of the antibody is similar. However, the N-terminal regions of the heavy and light chains are variable in sequence. These come together to form, for each antibody, a unique three-dimensional shape. It is this part of the antibody that binds to the antigen. Because each antibody has a different antigen binding site, it binds to a different antigen.
The antibody molecule has three main functions ( Fig. 8.3 ). One of these is to act as the B cell receptor for antigen. The second is to bind directly to toxins, viruses and other molecules and block their ability to bind to a target cell (neutralising antibodies). This is how anti-toxin (diphtheria/tetanus) antibodies work. The third function of antibodies is to recruit effector mechanisms to the target cell. It does this with the part of the molecule that does not vary (the constant region – in particular the upright ‘stalk’ of the molecule, called the Fc region). The Fc region binds to receptors (Fc receptors) on cells of the innate system, such as macrophages, neutrophils and eosinophils, and focuses them onto the target that carries the antigen recognised by the antibody.
In addition to targeting cells, the antibodies can also recruit a group of soluble molecules that are present in the circulation, termed the ‘complement system.’ This consists of a large number of components that are organised in a cascade such that activation of one molecule leads to activation of the next molecule in the cascade (similar in many respects to the blood clotting system). Activation of the complement cascade results in the production of inflammatory proteins that cause increased vascular permeability, vasodilatation and recruitment of inflammatory cells. In addition, components of the complement cascade are coated onto the target cell. There they can act as recognition elements for cells of the immune system (phagocytes such as macrophages) and can also directly kill some pathogens. Complement can be activated in several manners, including innate recognition of pathogens. However, antibodies will also activate the complement system by binding of the first component of the cascade, C1q, to the Fc region of antibodies. This route of complement activation, called the classical pathway, is ably supported by two other complement pathways, termed the alternative and lectin pathways. In the alternative pathways, spontaneous recognition of charge surfaces by complement component C3 can complete the cascade, while in the lectin pathway, the recognition subcomponent is the carbohydrate pattern recognising Mannan-binding lectin (MBL). The recognition process in all three pathways is followed by generation of opsonins (that decorate the target cell surface and enhance phagocytosis), anaphylatoxins (which recruit more immune cells) and membrane attack complex (a cluster of terminal complement components which can punch holes in the pathogen in a similar manner to the secretory products of CD8 + cytotoxic T cells).
There are five different classes of antibody: IgM, IgG, IgD, IgA, IgE (in addition, there are subclasses of IgG and IgA). The different antibody classes have different functions. Thus, the different Fc regions recruit different effector responses – IgE, for example, binds strongly to mast cells and basophils and is important in allergic responses seen in asthma. IgA is found in mucosal secretions and provides protection for mucosal surfaces. IgM, which consists of five basic antibody units joined together, is important early in the immune response where the ability to bind to 10 antigen molecules simultaneously increases the strength of binding.
The adaptive immune response controls the production of antibody by a mechanism termed clonal selection ( Fig. 8.4 ). During development, a large number (10 8 in the mouse, 10 to 100 times more in the human) of B cells are generated, each of which makes a unique antibody molecule. These early (termed naive or virgin) B cells do not secrete their antibody molecules but express them on the surface of the cell as a receptor for antigen. These B cells are resident in the lymph nodes and spleen. When an antigen is introduced into the system (following infection or immunisation), it is ‘shown’ to the different B cells there. Most B cells will not recognise the antigen, but given the vast number of different antibody molecules, there will by chance be some that do bind to the antigen. The cells bearing these antibodies will start to divide, forming a clone of B cells recognising the antigen, resulting in a swelling of the lymph node. After a period of clonal expansion, the B cells start to differentiate, no longer expressing the antibody on their surface but secreting it. In addition, some of the B cells become memory cells, so that the next time the system encounters the antigen there is an increased pool of cells capable of recognising the antigen, providing the basis for the memory of the immune response.
In addition, the B cell will, under control of the T helper cell (see below), change the class of antibody that it makes. Initially all the antibodies are IgM, but if, for example, the antibody is needed on a mucosal surface, then the class will switch to IgA.
During the course of a response, the immune system will also mutate the sequence of the antigen binding site of the antibody, selecting molecules that bind better to the antigen. This process is known as affinity maturation and improves the ability of the antibody to recognise the antigen.
The T cells are so called because they mature in the thymus. They recognise antigen through the TCR. In the thymus, T cells are educated to ignore or not react to self-antigens prior to being exported to the circulation. Like the antibody molecule, the TCR has a variable region that binds to antigen. In a similar manner to the B cell, the T cell with an appropriate TCR specificity undergoes clonal selection during an immune response. However, unlike the antibody, the TCR is only a cell surface receptor and is never secreted by a cell.
The way in which the TCR recognises antigen is more complex. The TCR does not bind directly to pathogen-derived antigens, but rather recognises the antigen in association with molecules of the major histocompatibility complex (MHC, also known as HLA in human). There are two types of MHC molecule involved in TCR recognition: class I molecules that are expressed on all nucleated cells and class II molecules that, under normal conditions, are expressed only on B cells and specialised antigen presenting cells (such as macrophages and dendritic cells, see below). Both MHC class I and class II molecules have a structure which allows them to bind to short peptides derived from the antigens ( Fig. 8.5 ), and the TCR recognises a combination of the foreign peptide and the MHC molecule, and is unable to recognise either individually.