Daniel Price, British Society for Immunology, UK
Immunology has its origins in the study of how the body protects itself against infectious diseases caused by microorganisms, such as bacteria, viruses, protozoa, and fungi, and also parasitic organisms, such as helminth worms.
Important initial barriers to infection are physical (e.g. the skin), enhanced by substances secreted by the body, such as saliva and tears, that contain molecules that can neutralise bacteria. The internal mucosal tissues (e.g. lungs & airways, and the gut) are coated with mucus that is able to trap potential infectants. In the airways, mobile ciliate hairs work together to transport contaminants away from vulnerable areas. Tissues such as the skin, mucosal surfaces and airways also contain populations of immune cells that can respond to infectants that breach these physical defences.
In its most complex forms, the immune system consists of two branches: the innate immune system that utilises certain ‘hard-wired’ strategies to provide a rapid, general, response when alerted by certain typical signals of infection (essentially forming a first-line of defence); and the adaptive immune system that is able to develop highly specific responses (and a persistent ‘immune memory’) to target infection with extraordinary accuracy. Both systems work in close cooperation and, to an important extent, the adaptive immune system relies upon the innate immune system to alert it to potential targets, and shape its response to them.
All immune cells originate in the bone marrow, deriving from haematopoietic stem cells, but an important set of immune cells (T lymphocytes) undergo maturation in an organ known as the thymus. The thymus and bone marrow are known as primary lymphoid tissues. Secondary lymphoid tissues, namely the lymph nodes, spleen and mucosa-associated lymphoid tissues (MALT) are important sites for generating adaptive immune responses and contain the lymphocytes (key adaptive cells). The lymphatic system is a system of vessels draining fluid (derived from blood plasma) from body tissues. Lymph nodes, that house lymphocytes, are positioned along draining lymph vessels, and monitor the lymph for signs of infection. MALT tissues are important in mucosal immune responses, and reflect the particular importance of the gut and airways in immune defence. The spleen essentially serves as a ‘lymph node’ for the blood.
Mast cells and basophils are innate cell types that, when activated, secrete histamine, which can be an important inflammatory mediator produced in response to initial tissue damage as a result of infection. Mast cells are tissue resident (e.g. in mucosal tissues) whilst basophils are found in the blood. In particular, they play a key role in the so-called allergic response.
Innate immunity comprises both cellular and humoral (‘in solution’) elements. The cellular elements are represented notably by phagocytes (specifically neutrophils and macrophages) that can respond to signs of infection (i.e. inflammation) in the tissues and home-in on infective bacteria before neutralising and engulfing them (‘phagocytosis’). Recognition of microorganisms by the innate system occurs via characteristic pathogen-associated molecular patterns (PAMPs) on microbial surfaces, and an important family of innate receptors called pattern-recognition receptors (PRRs) are responsible for this (notably including Toll-like receptors [TLRs]). The natural killer (NK) cell is another important innate cell that is able to detect and target intracellular infection of body cells by viruses. A further specialised innate cell is the eosinophil that plays a particular role in targeting larger infective organisms, such as parasitic worms.
The complement system represents the humoral arm of innate immunity, and consists of a number of proteins (found in solution in the blood) that can interact directly, or indirectly, with infective bacteria (through different activation pathways). Inflammation, as a result of infection, allows plasma, containing complement proteins, to enter infected tissues. Once activated, the member proteins assemble to form complexes on the surface of microbes that punch holes in the membrane. The complement activation pathways are termed: the classical pathway, the alternative pathway, and the mannose-binding lectin pathway.
Key to the adaptive immune response is the lymphocyte. There are several subtypes, however these fall under two broad designations: T lymphocytes and B lymphocytes (commonly known as T cells and B cells). Although both originate in the bone marrow, T cells mature in the thymus, whilst B cells mature in the bone marrow. During an organism’s early development a large number of B- and T cells are produced, each of which has the ability to recognise a specific, and essentially unique, molecular target. An important aspect of this maturation process is that, for both of these cell types, cells that recognise targets within the body (‘self’ tissue) are identified and weeded-out. An additional aspect of the maturation process for T cells is that further distinct subsets are produced – helper T cells (also called CD4+ T cells) and cytotoxic T cells (also called CD8+ T cells). The individual specificity of lymphocytes is key to the generation of adaptive responses.
Adaptive immunity utilises many kinds of receptor to coordinate its activities. T cells carry T-cell receptors (TCR), whilst B cells carry B-cell receptors (BCR), and variations in the fine structure of these receptors account for the individual specificity described above. In addition, another set of receptors, encoded by the major histocompatibility complex (MHC), play an important role in adaptive immunity. MHC class I receptors are displayed on a majority of body cells, whilst MHC class II receptors are restricted to antigen-presenting cells (APCs). Both of these receptor types interact with TCRs.
The adaptive immune response consists of two branches, a cellular adaptive response (effected by cytotoxic T cells) and a humoral adaptive response (effected by B cells). The former is directed especially towards pathogens that have colonised body cells or body cells that have become malignant (as in cancer). The latter generally targets pathogens or molecules (antigens) that are free in the bloodstream or present at mucosal surfaces. As suggested by its name, the helper T cell plays a central role in both of these responses since, once activated, it can shape the subsequent immune response through the particular molecules that it secretes – in particular, controlling the activation of other cell types – as such it is an important ‘gatekeeper’. Two subtypes of helper T cells (Th1 and Th2) have been identified as being responsible for guiding adaptive responses towards either a cellular profile (Th1) or a humoral profile (Th2). Th17 cells have recently been identified and are thought to play a further specialised role. Effective regulation of immune responses is also vital to ensure that they don’t themselves cause unnecessary tissue damage, and regulatory T cells (Tregs) are a subset of T cell that play an important role in this process.
Initiation of adaptive immunity
Antigen-presenting cells are functionally-defined cells that are able too initiate adaptive immune responses by presenting antigen to T cells. Major APCs are dendritic cells (DCs), which are found throughout the body – however macrophages and B cells may also serve as APCs, with the former providing an important link from innate immunity. Dendritic cells continuously monitor the bodily environment by absorbing protein fragments that they acquire from their surroundings, and presenting them on the their cell surface in association with MHC receptors. DCs may be activated by local innate immune signals (induced by infection) causing them to migrate through the lymph (or blood) to lymph nodes where they present antigen to T cells. If a protein fragment is recognised by a particular cytotoxic T cell this will suggest that it is of foreign origin (due to elimination of cells recognising ‘’self’’) leading to a cellular adaptive response. Similarly, B cells in the lymph node may encounter free antigen carried in the lymph, leading to a humoral adaptive response. In both cases, concurrent activation of helper T cells is usually necessary to ensure an effective overall response.
The cellular adaptive response
Body cells are continuously processing protein derived from the internal cellular environment and presenting it in association with MHC class I receptors. This will typically be ‘self’ antigen (that is ignored by the immune system), but can also be peptides derived from infecting viruses or bacteria, or aberrant cancer peptides. Activated cytotoxic T cells of a given specificity proliferate in the lymph and then migrate to sites of infection where they monitor body cells for signs of intracellular infection or aberrant self proteins associated with cancer – presented on MHC class I molecules – using their TCRs. If they encounter antigen that they recognise, this indicates infection or malignancy, and they are then able to induce apoptosis (autodestruction) of targeted body cells. This constitutes the cellular adaptive response.
The humoral adaptive response
As already stated, B cells can recognise antigen through direct recognition of antigen via their BCRs, without the need for prior processing or presentation via a receptor – so they are key to identifying extracellular pathogens (e.g. bacteria in the lymph). Once activated, B cells differentiate into plasma cells that are capable of secreting antibody molecules into the circulation (small molecules that match the individual specificity of the parent cell) that are then able to find their targets elsewhere in the body. Once bound to a target, antibody molecules can activate the classical pathway of the complement system, thereby directing it to neutralise its targets with great specificity. Binding of antibody also enhances phagocytosis.
It is important to note that an effective primary adaptive response (e.g. relating to a pathogen that hasn’t previously been encountered) takes some time to develop, since only small numbers of target-specific B- and T cells are present initially and, once activated, they must first proliferate through a process known as clonal selection, to form effector cells. A proportion of these effector cells go on to form a stock of long-lived memory cells ensuring that if a particular pathogen is encountered again, any subsequent secondary adaptive response (or ‘memory response’) develops more quickly and is thus more effective.
Cytokines and chemokines
Cytokines form an important family of proteins that function as immune mediators and have important roles during immune responses – they can serve to both stimulate or inhibit the differentiation, proliferation or activity of immune cells. A subset of cytokines, chemokines, play an important role in guiding immune cells to sites of infection by forming a chemical ‘trail’.
Important pathologies may result from immune dysfunction. Inborn (‘congenital’) immunodeficiencies, with a genetic basis, can disable all, or part, of the immune response (both innate and adaptive) – resulting in vulnerabilities to infection or cancers. Examples include severe combined immunodeficiency (SCID) and common variable immunodeficiency (CVID). In addition, autoimmunity occurs when the immune system mistakenly targets self tissues, resulting in chronic inflammatory conditions and tissue destruction. Examples include: type 1 diabetes, rheumatoid arthritis, and multiple sclerosis.
Identification of the important role of the MHC in allowing the body to discriminate between self/non-self tissues has greatly enhanced the success of tissue and organ transplantation, by allowing tissue matching. This has been aided by the development of immunosuppressive drugs that are becoming increasingly sophisticated as we identify more specific elements within the immune system to target.
Vaccines can utilise harmless elements from particular pathogens to prime the immune system, so that if the pathogen is actually encountered, it is met with a stronger secondary (‘memory’) response and dealt with more quickly. Alternatively, vaccines may also utilise live, but attenuated, variants of the pathogen to induce a protective immune response. The role of vaccines remains central to the importance of immunology as a healthcare science – with keystone contributions in the disease areas of smallpox, polio, tuberculosis, measles, mumps, rubella and papillomavirus, amongst many others. However, success can depend on the target pathogen, and effective vaccines for HIV, hepatitis C and malaria remain elusive, in large part due to the mutability of these organisms as targets for the immune system.
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