Immunological factors in disease



Immunological factors in disease


S.E. Marshall


The immune system has evolved to protect the host from pathogens while minimising damage to self tissue. Despite the ancient observation that recovery from some diseases results in protection against that condition, the existence of the immune system as a functional entity was not recognised until the end of the 19th century. More recently, it has become clear that the immune system not only protects against infection, but also influences healing and governs the responses that can lead to autoimmune diseases. Dysfunction or deficiency of the immune response leads to a wide variety of diseases, involving every organ system in the body.


The aim of this chapter is to provide a general understanding of immunology and how it contributes to human disease. A review of the key components of the immune response is followed by five sections that illustrate the clinical presentation of the most common forms of immune dysfunction. Clinical immunologists are usually involved in managing patients with allergy and immune deficiency. More detailed discussion of individual conditions can be found in the relevant organ-specific chapters of this book.



Functional anatomy and physiology of the immune system


The immune system consists of an intricately linked network of cells, proteins and lymphoid organs that are strategically placed to ensure maximal protection against infection. Immune defences are normally categorised into the innate immune response, which provides immediate protection against an invading pathogen, and the adaptive or acquired immune response, which takes more time to develop but confers exquisite specificity and long-lasting protection.



The innate immune system


Innate defences against infection include anatomical barriers, phagocytic cells, soluble molecules, such as complement and acute phase proteins, and natural killer cells. The innate immune system recognises generic microbial structures present on non-mammalian tissue and can be mobilised within minutes. A specific stimulus will elicit essentially identical responses in different individuals (in contrast with antibody and T-cell responses, which vary greatly between individuals).




Constitutive barriers to infection

The tightly packed, highly keratinised cells of the skin constantly undergo renewal and replacement, which physically limits colonisation by microorganisms. Microbial growth is inhibited by physiological factors, such as low pH and low oxygen tension, and sebaceous glands secrete hydrophobic oils that further repel water and microorganisms. Sweat also contains lysozyme, an enzyme that destroys the structural integrity of bacterial cell walls; ammonia, which has antibacterial properties; and several antimicrobial peptides such as defensins. Similarly, the mucous membranes of the respiratory, gastrointestinal and genitourinary tract provide a constitutive barrier to infection. Secreted mucus acts as a physical barrier to trap invading pathogens, and immunoglobulin A (IgA) prevents bacteria and viruses attaching to and penetrating epithelial cells. As in the skin, lysozyme and antimicrobial peptides within mucosal membranes can directly kill invading pathogens, and additionally lactoferrin acts to starve invading bacteria of iron. Within the respiratory tract, cilia directly trap pathogens and contribute to removal of mucus, assisted by physical manœuvres, such as sneezing and coughing. In the gastrointestinal tract, hydrochloric acid and salivary amylase chemically destroy bacteria, while normal peristalsis and induced vomiting or diarrhoea assist clearance of invading organisms.


Endogenous commensal bacteria provide an additional constitutive defence against infection (p. 136). They compete with pathogenic microorganisms for space and nutrients, and produce fatty acids and bactericidins that inhibit the growth of many pathogens. In addition, commensal bacteria help to shape the immune response by inducing specific regulatory T cells within the intestine (p. 78).


These constitutive barriers are highly effective, but if external defences are breached by a wound or pathogenic organism, the specific soluble proteins and cells of the innate immune system are activated.



Phagocytes

Phagocytes (‘eating cells’) are specialised cells which ingest and kill microorganisms, scavenge cellular and infectious debris, and produce inflammatory molecules which regulate other components of the immune system. They include neutrophils, monocytes and macrophages, and are particularly important for defence against bacterial and fungal infections.


Phagocytes express a wide range of surface receptors that allow them to identify microorganisms. These pattern recognition receptors include the Toll-like receptors, NOD (nucleotide-oligomerisation domain protein)-like receptors and mannose receptors. They recognise generic molecular motifs not present on mammalian cells, including bacterial cell wall components, bacterial DNA and viral double-stranded RNA. While phagocytes can recognise microorganisms through pattern recognition receptors alone, engulfment of microorganisms is greatly enhanced by opsonisation. Opsonins include acute phase proteins such as C-reactive protein (CRP), antibodies and complement. They bind both to the pathogen and to phagocyte receptors, acting as a bridge between the two to facilitate phagocytosis (Fig. 4.1).




Neutrophils

Neutrophils, also known as polymorphonuclear leucocytes, are derived from the bone marrow (Fig. 4.2). They are short-lived cells with a half-life of 6 hours in the blood stream, and are produced at the rate of approximately 1011 cells daily. Their functions are to kill microorganisms directly, facilitate the rapid transit of cells through tissues, and non-specifically amplify the immune response. This is mediated by enzymes contained in granules which also provide an intracellular milieu for the killing and degradation of microorganisms.



The two main types of granule are primary or azurophil granules, and the more numerous secondary or specific granules. Primary granules contain myeloperoxidase and other enzymes important for intracellular killing and digestion of ingested microbes. Secondary granules are smaller and contain lysozyme, collagenase and lactoferrin, which can be released into the extracellular space. Granule staining becomes more intense in response to infection (‘toxic granulation’), reflecting increased enzyme production.


When tissues are changed or damaged, they trigger the local production of inflammatory molecules and cytokines. These stimulate the production and maturation of neutrophils in the bone marrow, and their release into the circulation. The neutrophils are recruited to the inflamed site by chemotactic agents and by activation of local endothelium. Transit of neutrophils through the blood stream is responsible for the rise in leucocyte count that occurs in early infection. Once within infected tissue, activated neutrophils seek out and engulf invading microorganisms. These are initially enclosed within membrane-bound vesicles which fuse with cytoplasmic granules to form the phagolysosome. Within this protected compartment, killing of the organism occurs through a combination of oxidative and non-oxidative killing. Oxidative killing, also known as the respiratory burst, is mediated by the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase enzyme complex. This converts oxygen into reactive oxygen species such as hydrogen peroxide and superoxide that are lethal to microorganisms. When combined with myeloperoxidase, hypochlorous ions (HOCl, analogous to bleach) are produced, which are highly effective oxidants and antimicrobial agents. Non-oxidative (oxygen-independent) killing occurs through the release of bactericidal enzymes into the phagolysosome. Each enzyme has a distinct antimicrobial spectrum, providing broad coverage against bacteria and fungi.


The process of phagocytosis depletes neutrophil glycogen reserves and is followed by neutrophil cell death. As the cells die, their contents are released and lysosomal enzymes degrade collagen and other components of the interstitium, causing liquefaction of closely adjacent tissue. The accumulation of dead and dying neutrophils results in the formation of pus, which, if extensive, may result in abscess formation.



Monocytes and macrophages

Monocytes are the precursors of tissue macrophages. They are produced in the bone marrow and constitute about 5% of leucocytes in the circulation. From the blood stream, they migrate to peripheral tissues, where they differentiate into tissue macrophages and reside for long periods. Specialised populations of tissue macrophages include Kupffer cells in the liver, alveolar macrophages in the lung, mesangial cells in the kidney, and microglial cells in the brain. Macrophages, like neutrophils, are capable of phagocytosis and killing of microorganisms but also play an important role in the amplification and regulation of the inflammatory response (Box 4.1). They are particularly important in tissue surveillance, monitoring their immediate surroundings for signs of tissue damage or invading organisms.





Cytokines

Cytokines are small soluble proteins that act as multipurpose chemical messengers. Examples are listed in Box 4.2. They are produced by cells involved in immune responses and by stromal tissue. More than 100 cytokines have been described, with overlapping, complex roles in intercellular communication. Their clinical importance is demonstrated by the efficacy of ‘biological’ therapies (often abbreviated to ‘biologics’) that target specific cytokines (pp. 1102 and 18).




Complement

The complement system is a group of more than 20 tightly regulated, functionally linked proteins that act to promote inflammation and eliminate invading pathogens. Complement proteins are produced in the liver and are present in the circulation as inactive molecules. When triggered, they enzymatically activate other proteins in a rapidly amplified biological cascade analogous to the coagulation cascade (p. 995).


There are three mechanisms by which the complement cascade may be triggered (Fig. 4.3):




• The alternative pathway is triggered directly by binding of C3 to bacterial cell wall components, such as lipopolysaccharide of Gram-negative bacteria and teichoic acid of Gram-positive bacteria.


• The classical pathway is initiated when two or more IgM or IgG antibody molecules bind to antigen, forming immune complexes. The associated conformational change exposes binding sites on the antibodies for C1. C1 is a multiheaded molecule which can bind up to six antibody molecules. Once two or more ‘heads’ of a C1 molecule are bound to antibody, the classical cascade is triggered.


• The lectin pathway is activated by the direct binding of mannose-binding lectin to microbial cell surface carbohydrates. This mimics the binding of C1 to immune complexes and directly stimulates the classical pathway.


Activation of complement by any of these pathways results in activation of C3. This, in turn, activates the final common pathway, in which the complement proteins C5–C9 assemble to form the membrane attack complex. This can puncture target cell walls, leading to osmotic cell lysis. This step is particularly important in the defence against encapsulated bacteria, such as Neisseria spp. and Haemophilus influenzae. Complement fragments generated by activation of the cascade can also act as opsonins, rendering microorganisms more susceptible to phagocytosis by macrophages and neutrophils (see Fig. 4.1). In addition, they are chemotactic agents, promoting leucocyte trafficking to sites of inflammation. Some fragments act as anaphylotoxins, binding to complement receptors on mast cells and triggering release of histamine, which increases vascular permeability. The products of complement activation also help to target immune complexes to antigen-presenting cells, providing a link between the innate and the acquired immune systems. Finally, activated complement products dissolve the immune complexes that triggered the cascade, minimising bystander damage to surrounding tissues.



Mast cells and basophils

Mast cells and basophils are bone marrow-derived cells which play a central role in allergic disorders. Mast cells reside predominantly in tissues exposed to the external environment, such as the skin and gut, while basophils are located in the circulation and are recruited into tissues in response to inflammation. Both contain large cytoplasmic granules which contain preformed vasoactive substances such as histamine (see Fig. 4.9, p. 89). Mast cells and basophils express IgE receptors on their cell surface (see Fig. 4.5). On encounter with specific antigen, the cell is triggered to release preformed mediators and synthesise additional mediators, including leukotrienes, prostaglandins and cytokines. These trigger an inflammatory cascade which increases local blood flow and vascular permeability, stimulates smooth muscle contraction, and increases secretion at mucosal surfaces.



Natural killer cells

Natural killer (NK) cells are large granular lymphocytes which play a major role in defence against tumours and viruses. They exhibit features of both the adaptive and innate immune systems: they are morphologically similar to lymphocytes and recognise similar ligands, but they are not antigen-specific and cannot generate immunological memory.


NK cells express a variety of cell surface receptors. Some recognise stress signals, while others recognise the absence of human leucocyte antigen (HLA) molecules on cell surfaces (down-regulation of HLA molecules by viruses and tumour cells is an important mechanism by which they evade T lymphocytes). NK cells can also be activated by binding of antigen–antibody complexes to surface receptors. This physically links the NK cell to its target in a manner analogous to opsonisation, and is known as antibody-dependent cellular cytotoxicity (ADCC).


Activated NK cells can kill their targets in various ways. Pore-forming proteins, such as perforin, induce direct cell lysis, while granzymes are proteolytic enzymes which stimulate apoptosis. In addition, NK cells produce a variety of cytokines, such as tumour necrosis factor (TNF)-α and interferon-γ (IFN-γ), which have direct antiviral and antitumour effects.



The adaptive immune system


If the innate immune system fails to provide effective protection against an invading pathogen, the adaptive immune system (Fig. 4.4) is mobilised. This has three key characteristics:




There are two major arms of the adaptive immune response: humoral immunity involves antibodies produced by B lymphocytes; cellular immunity is mediated by T lymphocytes, which release cytokines and kill immune targets. These interact closely with each other and with the innate immune system, to maximise the effectiveness of the response.




Lymphoid organs







Lymphatics

Lymphoid tissues are physically connected by a network of lymphatics, which has three major functions: it provides access to lymph nodes, returns interstitial fluid to the venous system, and transports fat from the small intestine to the blood stream (see Fig. 16.14, p. 452). The lymphatics begin as blind-ending capillaries, which come together to form lymphatic ducts. These enter and then leave regional lymph nodes as afferent and efferent ducts respectively. They eventually coalesce and drain into the thoracic duct and thence into the left subclavian vein. Lymphatics may be either deep or superficial, and, in general, follow the distribution of major blood vessels.



Humoral immunity


B lymphocytes

These specialised cells arise in the bone marrow. Mature B lymphocytes (also known as B cells) are found in bone marrow, lymphoid tissue, spleen and, to a lesser extent, the blood stream. They express a unique immunoglobulin receptor on their cell surface (the B-cell receptor), which binds to soluble antigen. Encounters with antigen usually occur within lymph nodes, where, if provided with appropriate signals from nearby T lymphocytes, stimulated antigen-specific B cells respond by proliferating rapidly in a process known as clonal expansion. This is accompanied by a highly complex series of genetic re-arrangements, which generates B-cell populations that express receptors with greater affinity for antigen than the original. These cells differentiate into either long-lived memory cells, which reside in the lymph nodes, or plasma cells, which produce antibody.



Immunoglobulins

Immunoglobulins (Ig) are soluble proteins made up of two heavy and two light chains (Fig. 4.5). The heavy chain determines the antibody class or isotype, i.e. IgG, IgA, IgM, IgE or IgD. Subclasses of IgG and IgA also occur. The antigen is recognised by the antigen-binding regions (Fab) of both heavy and light chains, while the consequences of antibody-binding are determined by the constant region of the heavy chain (Fc) (Box 4.3).




Antibodies can initiate a number of different actions. They facilitate phagocytosis by acting as opsonins (see Fig. 4.1), and can also facilitate cell killing by cytotoxic cells (ADCC, p. 75). Binding of antibodies to antigen can trigger activation of the classical complement pathway (see Fig. 4.3). In addition, antibodies may act directly to neutralise the biological activity of toxins. This is a particularly important feature of IgA antibodies, which act predominantly at mucosal surfaces.


The humoral immune response is characterised by immunological memory: that is, the antibody response to successive exposures to antigen is qualitatively and quantitatively different from that on first exposure. When a previously unstimulated (naïve) B lymphocyte is activated by antigen, the first antibody to be produced is IgM, which appears in the serum after 5–10 days. Depending on additional stimuli provided by T lymphocytes, other antibody classes (IgG, IgA and IgE) are produced 1–2 weeks later. If, some time later, a memory B cell is re-exposed to antigen, the lag time between antigen exposure and the production of antibody is decreased (to 2–3 days), the amount of antibody produced is increased, and the response is dominated by IgG antibodies of high affinity. Furthermore, in contrast to the initial antibody response, secondary antibody responses do not require additional input from T lymphocytes. This allows the rapid generation of highly specific responses on pathogen re-exposure.



Cellular immunity

T lymphocytes (also known as T cells) mediate cellular immunity and are important for defence against viruses, fungi and intracellular bacteria. They also play an important immunoregulatory role, orchestrating and regulating the responses of other components of the immune system. T-lymphocyte precursors arise in bone marrow and are exported to the thymus while still immature (see Fig. 4.6 below). Within the thymus, each cell expresses a T-cell receptor with a unique specificity. These cells undergo a process of stringent selection to ensure that autoreactive T cells are deleted. Mature T lymphocytes leave the thymus and expand to populate other organs of the immune system. It has been estimated that an individual possesses 107–109 T-cell clones, each with a unique T-cell receptor, ensuring at least partial coverage for any antigen encountered.


T cells respond to protein antigens, but they cannot recognise these in their native form. Instead, intact protein must be processed into component peptides which bind to a structural framework on the cell surface known as HLA (human leucocyte antigen). This process is known as antigen processing and presentation, and it is the peptide/HLA complex which is recognised by individual T cells. While all nucleated cells have the capacity to process and present antigens, specialised antigen-presenting cells include dendritic cells, macrophages and B lymphocytes. HLA molecules exhibit extreme polymorphism; as each HLA molecule has the capacity to present a subtly different peptide repertoire to T lymphocytes, this ensures enormous diversity in recognition of antigens within the population.


T lymphocytes can be segregated into two subgroups on the basis of function and recognition of HLA molecules. These are designated CD4+ and CD8+ T cells, according to the ‘cluster of differentiation’ (CD) antigen expressed on their cell surface. CD8+ T cells recognise antigenic peptides in association with HLA class I molecules (HLA-A, HLA-B, HLA-C). They kill infected cells directly through the production of pore-forming molecules such as perforin, or by triggering apoptosis of the target cell, and are particularly important in defence against viral infection. CD4+ T cells recognise peptides presented on HLA class II molecules (HLA-DR, HLA-DP and HLA-DQ) and have mainly immunoregulatory functions. They produce cytokines and provide co-stimulatory signals that support the activation of CD8+ T lymphocytes and assist the production of mature antibody by B cells. In addition, their close interaction with phagocytes determines cytokine production by both cell types.


CD4+ lymphocytes can be further subdivided into subsets on the basis of the cytokines they produce:




Immune deficiency


The consequences of deficiencies of the immune system include recurrent infections, autoimmunity and susceptibility to malignancy. Immune deficiency may arise through intrinsic defects in immune function, but is much more commonly due to secondary causes, including infection, drug therapy, malignancy and ageing. This chapter gives an overview of the rare primary immune deficiencies. More than a hundred genetically determined deficiencies have been described, most of which present in childhood or adolescence. The clinical manifestations are dictated by the component of the immune system involved (Box 4.4), but there is considerable overlap and redundancy in the immune network so some diseases do not fall easily into this classification.




Presenting problems in immune deficiency


Recurrent infections


Most patients with an immune deficiency present with recurrent infections. While there is no accepted definition of ‘too many’ infections, features that may indicate immune deficiency are shown in Box 4.5. Frequent, severe infections or infections caused by unusual organisms or at unusual sites are the most useful indicator.



Baseline investigations include full blood count with white cell differential, acute phase reactants (CRP, see below), renal and liver function tests, urine dipstick, serum immunoglobulins with protein electrophoresis, and total IgE level. Additional microbiological, virological and radiological tests may be appropriate. At this stage, it may be clear which category of immune deficiency should be considered, and specific investigation can be undertaken, as described below.


If an immune deficiency is suspected but has not yet been formally characterised, patients should not receive live vaccines because of the risk of vaccine-induced disease. Discussion with specialists will help determine whether additional preventative measures, such as prophylactic antibiotics, are indicated.



Primary phagocyte deficiencies


Primary phagocyte deficiencies (see Fig. 4.2, p. 73) usually present with recurrent bacterial and fungal infections which may affect unusual sites. Aggressive management of existing infections, including intravenous antibiotics and surgical drainage of abscesses, and long-term prophylaxis with antibacterial and antifungal agents, is required. Specific treatment depends upon the nature of the defect; haematopoietic stem cell transplantation may be considered (p. 1017).






Complement pathway deficiencies


Genetic deficiencies of almost all the complement pathway proteins (see Fig. 4.3, p. 75) have been described. Many present with recurrent infection with encapsulated bacteria, particularly Neisseria species, reflecting the importance of the membrane attack complex in defence against these bacteria. In addition, genetic deficiencies of the classical complement pathway (C1, C2 and C4) are associated with a high prevalence of autoimmune disease, particularly systemic lupus erythematosus (SLE, p. 1109).


In contrast to other complement deficiencies, mannose-binding lectin deficiency is very common (5% of the northern European population). Complete deficiency may predispose to bacterial infections in the presence of an additional cause of immune compromise, such as premature birth or chemotherapy, but is otherwise well tolerated. Deficiency of the complement regulatory protein Cl inhibitor is not associated with recurrent infections but causes recurrent angioedema (p. 93).




Primary deficiencies of the adaptive immune system


Primary T-lymphocyte deficiencies


These are characterised by recurrent viral, protozoal and fungal infections (see Box 4.4). In addition, many T-cell deficiencies are associated with defective antibody production because of the importance of T cells in regulating B cells. These disorders generally present in childhood and are illustrated in Figure 4.6.








Apr 9, 2017 | Posted by in GENERAL SURGERY | Comments Off on Immunological factors in disease
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