Cells involved in immune responses: origin and function

All immune cells have a common source in the pluripotent stem cells generated in the bone marrow (Fig. 3.1). They have diverse functions (Table 3.1). T lymphocytes undergo ‘education’ in the thymus to avoid self-recognition, and populate the peripheral lymphoid tissue, where B lymphocytes also reside. Both sets of lymphocytes undergo activation in the peripheral tissue, to become mature effector cells. B lymphocytes may further differentiate into antibody-secreting plasma cells. Lymphoid tissue is frequently found at mucosal surfaces in non-encapsulated patches, termed mucosa-associated lymphoid tissue (MALT).

Table 3.1 Main cells involved in the immune response: functions and origin

The immune system

Cells and molecules involved in immune responses are classified into innate and adaptive systems:

There are also non-immunological barriers that are involved in host protection, and very often it is the lowering of these that allows a pathogen to take a foothold (Table 3.2).

Table 3.2 Non-immunological host defence mechanisms

The immune system is immensely powerful, in terms of its ability to inflame, damage and kill, and it has a capacity to recognize a myriad of molecular patterns in the microbial world. However, immune responses are not always beneficial. They can give rise to a range of autoimmune and inflammatory diseases, known as immunopathologies. In addition, the immune system may fail, giving rise to immune deficiency states. These conditions are grouped under the umbrella of clinical immunology.

A major feature of the immune system is the complexity of the surface-bound, intracellular and soluble structures that mediate its functions. In particular, it is necessary to be aware of the CD (clusters of differentiation) classification (Box 3.1) and the functions of cytokines and chemokines.

Cytokines

These are small polypeptides released by a cell in order to change the function of the same or another cell. These chemical messengers are found in many organ systems, but especially the immune system. Cytokines have become markers in the investigation of disease pathogenesis; therapeutic agents in their own right; and the targets of therapeutic agents (see p. 72). The key features of a cytokine are:

The main immune cytokines are the interferons (IFNs) and the interleukins (IL). The IFNs are limited to a few major types (α, β and γ), whereas there are 35 interleukins.

Chemokines

The defining feature of chemokines is their function as chemotactic molecules, i.e. they attract cells along a gradient of low to high chemical concentration, particularly from the blood into the tissues and tissues into lymphatics. They also have the ability to activate immune cells. All chemokines have a similar structure relating to the configuration of cysteine residues, which gives rise to four families:

Receptors on the surface are denoted by ‘R’, and are all distinctive G-coupled protein receptors with seven transmembrane spanning domains.

Anti-inflammatory drugs that block chemokine functions, or drugs that promote cell activation and migration, e.g. into tumours, are being developed.

Complement

Complement proteins are produced in the liver. Each complement circulates in an inactive form until triggered to become enzymatically active, when it then activates several molecules of the next stage in a series. This complement cascade is initiated via three distinct pathways: alternative, classical and mannan-binding lectin (Fig. 3.2). These pathways are composed of three distinct enzyme cascades that culminate in the cleavage of C3 and C5. Cleavage of C3 has a number of biological consequences; breakdown of C5 achieves the same and, in addition, provides the triggering stimulus to the final common (‘membrane attack’) pathway, which provides most of the biological activity (Fig. 3.2).

Figure 3.2 The complement pathways and their effector functions.

The main functions of complement activation are to:

During an immune response, removal of immune complexes protects unaffected tissues from the deposition of these large, insoluble composites which could result in unwanted inflammation. Failure of this protective mechanism can result in immunopathology, e.g. in the joints, kidney and eye.

Neutrophils

Neutrophil: phagocytoses bacteria and kills them by releasing antimicrobial compounds (e.g. defensins).

Neutrophils (see p. 413) phagocytose and kill microorganisms. They are derived from the bone marrow, which can produce between 10¹¹ (healthy state) and 10¹² (during infection) new cells per day. In health, neutrophils are rarely seen in the tissues.

Neutrophil phagocytosis is activated by interaction with bacteria, either directly or after bacteria have been coated (opsonized) to make them more ingestible (Fig. 3.3). The contents of neutrophil granules are released both intracellularly (predominantly azurophilic granules) and extracellularly (specific granules) following fusion with the plasma membrane. Approximately 100 different molecules in neutrophil granules (Table 3.5) kill and digest microorganisms, for example:

Figure 3.3 Opsonization. Bacteria are coated with a variety of soluble factors from the innate immune system (opsonins), which enhance phagocytosis. This leads to engulfment of the bacteria into phagosomes and fusion with granules to release antibacterial agents. iC3b, inactive complement 3b.

Table 3.5 Contents and function of key neutrophil granules

Granule release is initiated by the products of bacterial cell walls, complement proteins (e.g. inactive complement 3b, iC3b), leukotrienes (LTB₄) and chemokines (e.g. CXCL8, also known as IL-8) and cytokines such as tumour necrosis factor α (TNF-α).

Eosinophils

Eosinophil: releases pro-inflammatory mediators to provide immunity against parasites.

In contrast to neutrophils, several hundred times more eosinophils are present in the tissues than in the blood, particularly at epithelial surfaces where they survive for several weeks. The main role of eosinophils is protection against multicellular parasites such as worms (helminths). This is achieved by the release of pro-inflammatory mediators, which are toxic, cationic proteins. In populations and societies in which such parasites are rare, eosinophils contribute mainly to allergic disease, particularly asthma (see p. 827). Eosinophils have two types of granules:

Eosinophils are activated and recruited by a variety of mediators via specific surface receptors, including complement factors and leukotriene (LT) B₄. In addition, the CC chemokines eotaxin-1 (CCL11) and eotaxin-2 (CCL24) are highly selective in eosinophil recruitment. Receptors are also present for the cytokines IL-3 and IL-5, which promote the development and differentiation of eosinophils.

Mast cells and basophils

Mast cell: releases pro-inflammatory and vasoactive mediators; has a role in allergy.

Mast cells and basophils share features in common, especially in containing:

Mast cells are found in tissues (especially skin and mucosae) and basophils in the blood. Both mast cells and basophils release pro-inflammatory mediators which are either pre-formed or synthesized de novo (Table 3.6).

Table 3.6 Mast cell and basophil mediators

Histamine is a low-molecular-weight amine (111 Da) with a blood half-life of less than 5 minutes; it constitutes 10% of the mast cell’s weight. When injected into the skin, histamine induces the typical ‘weal and flare’ or ‘triple’ response: reddening (erythema) due to increased blood flow, swelling (weal) due to increased vascular permeability, and distal vascular changes (flare) due to effects on local axons.

The complement-derived anaphylatoxins C3a, C4a and C5a activate basophils and mast cells, as does IgE. The mast cell also has a role in the early response to bacteria through release of TNF-α, in cell recruitment to inflammatory sites such as arthritic joints, in promotion of tumour growth by enhancing neovascularization and in allograft tolerance.

Monocytes and macrophages

Monocyte (blood)/macrophage (tissue): ingests and kills bacteria; releases pro-inflammatory molecules; presents antigen to T lymphocytes; necessary in immunity to intracellular pathogens, e.g. mycobacteria.

Cells of the monocyte/macrophage lineage are highly sophisticated phagocytes. Monocytes are the blood form of a cell that spends a few days in the circulation before entering into the tissues to differentiate into macrophages, and possibly some types of dendritic cells.

Dendritic cells

The major function of dendritic cells (DCs) is activation of naive T lymphocytes to initiate adaptive immune responses; they are the only cells capable of this. The definition of a dendritic cell is one that has:

Figure 3.4 Mature dendritic cell: ingests pathogens; migrates to lymph nodes and presents pathogen-derived antigen to T lymphocytes to enable adaptive immunity.

This is a powerful cell type that functions as a critical bridge between the innate and adaptive immune systems.

Types of dendritic cell

The major types are the myeloid DC (mDC), the plasmacytoid DC (pDC) and a variety of specialized DCs found in tissues that resemble mDCs (e.g. the Langerhans cell in the skin, see Fig. 24.1). DCs have several distinctive cell surface molecules, some of which have pathogen-sensing activity (e.g. the antigen uptake receptor DEC205 on mDCs) whilst others are involved in interaction with T lymphocytes (Table 3.7). Immature mDCs and pDCs are present in the blood, but at very low levels (<0.5% of lymphocyte/monocyte cells).

Table 3.7 Molecules on dendritic cells

Pathogen sensing is a key component of the function of immature DCs, as well as monocytes/macrophages, and is achieved through expression of a limited array of specialized PRR molecules capable of binding to structures common to pathogens, aided by long cell dendrites and pinocytosis (constant ingestion of soluble material).

PRRs include:

Mannan-binding lectin, which initiates complement activity inducing opsonization (p. 51, 52).

Signalling receptors such as the PRR known as TLR4 (for toll-like receptor 4), which binds lipopolysaccharide, a molecular pattern found in the cell walls of many Gram-negative bacteria (Table 3.8), whilst others bind double-stranded and single-stranded RNA from viruses. Innate immunity critically depends on toll-like receptor signalling. These receptors act through a critical adaptor molecule, myeloid differentiation factor 88 (MyD88), to regulate the activity of nuclear factor kappa B (NF-κB) pathways.

Endocytic pattern recognition receptors, which act by enhancing antigen presentation on macrophages, by recognizing microorganisms with mannose-rich carbohydrates on their surface or by binding to bacterial cell walls and scavenging bacteria from the circulation. All lead to phagocytosis.

TREM-1 (triggering receptor expressed on myeloid cells) is a cell surface receptor which, when bound to its ligand, triggers secretion of pro-inflammatory cytokines. It is upregulated by bacterial lipopolysaccharides but not in non-infective disorders.

Table 3.8 Toll-like receptors (TLR)

The key principle at play here is that the immune system has devised a means of identifying most types of invading microorganisms by using a limited number of PRRs recognizing common molecular patterns, or PAMPs. This recognition event has been termed a ‘danger signal’: it alerts the immune system to the presence of a pathogen. Sensing danger is a key role of the DC and a key first step towards activation of the adaptive immune system.

DCs and T cell activation

In a sequence of events that spans 1–2 days, immature DCs are activated by PAMPs or DAMPs in the tissues binding to a PRR on DCs. The immature pDC is a small rounded cell that develops dendrites upon activation and secretes enormous quantities of IFN-α, a potent antiviral and pro-inflammatory cytokine. On activation, the DC migrates to the local lymph node with the engulfed pathogen. During migration the DC matures, changing its shape, gene and molecular profile and function within a matter of hours to take on a mature form, with altered functions (Table 3.9, Fig. 3.5), in particular upregulating machinery required to activate T lymphocytes. Once in the lymph node, the mature DC interacts with naive T lymphocytes (antigen presentation), resulting in two key outcomes:

1. Activation of T cells with the ability to recognize peptide fragments (termed epitopes) of the pathogen

2. Polarization of the T cell towards a functional phenotype (see below) that is tailored to the particular pathogen.

Table 3.9 Myeloid dendritic cell (DC) maturation

Immature mDC	Mature mDC
Highly pinocytotic	Ceases pinocytosis
Low level expression of molecules required for T lymphocyte activation	Upregulates CD80, CD86 and HLA molecules
Low level expression of machinery required to process and present microbial antigens	Begins to process microbial antigens (break down into small peptides) in readiness to present them to T lymphocytes (using HLA molecules)
Generally localized and sedentary	Begins active migration to local lymph node
Minimal secretion of cytokines	Active secretion of cytokines in readiness to stimulate T lymphocytes; in particular IL-12

mDC, myeloid dendritic cell.

Figure 3.5 (a) Immature dendritic cells (DCs) in the tissues are activated by pathogens through PAMP–PRR interaction. (b) Multiple rapid changes in gene expression lead to migration to the lymph node as the DC takes on the mature phenotype. During migration there is synthesis of the machinery required for activation of T lymphocytes, shown here in response to signals 1–3.

The mature DC provides three major signals to naive T cells Fig. 3.5):

Signal 1 = presentation of peptide fragments from the pathogen bound to surface HLA molecules.

Signal 2 = co-stimulation through CD80 and CD86 interacting with CD28 on T cells.

Signal 3 = secretion of cytokines, notably IL-12.

Natural killer (NK) cells

These are described on pages 61, 62.

The human major histocompatibility complex

The human MHC comprises three major classes (I, II and III) of genes involved in the immune response (Fig. 3.7).

Figure 3.7 The HLA system in man. On chromosome 6 are three major HLA regions (classes I–III) including genes that encode the HLA class I and II molecules, complement genes, the cytokine TNF and other genes involved in antigen presentation (HLA-DO, -DM; transporter associated with processing, TAP; proteasome subunit beta, PSMB; and the non-classical HLA class Ic molecule, MICA).

Antigen presentation

HLA molecules bind short peptide fragments which are processed (‘chopped up’) from larger proteins (antigens) derived from pathogens. The peptide–HLA complex is presented on antigen presenting cells (APCs) for recognition by T cell receptors (TCRs) on T lymphocytes. There are three major routes to antigen processing and presentation:

Figure 3.8 The endogenous route of antigen presentation to CD8 T lymphocytes. Cytosolic proteins derived from self (resting cells) or viruses (virus-infected cells) are broken down by the proteasome (a sort of ‘protein recycler’) into fragments 2–25 amino acids long. Some of these are taken into the endoplasmic reticulum (ER) by a transporter (TAP), trimmed and loaded into empty HLA class I molecules. These are exported to the surface membrane for presentation to CD8 T lymphocytes.

Figure 3.9 The exogenous route of antigen presentation and cross-presentation. External material (e.g. virus particles) is taken into an antigen presenting cell and broken down into specialized compartments by a combination of low pH and proteolysis. Peptides are then loaded into HLA class II molecules for presentation to CD4 T lymphocytes. Material may also be transferred across the cell so that it is loaded onto HLA class I molecules for presentation to CD8 T lymphocytes. This process of cross-presentation is restricted to specialized APCs such as DCs.

Antigen receptors on T and B lymphocytes

One of the key features of the adaptive immune system is specificity for antigen. For example, if you are immunized against the measles virus, you do not have immunity to hepatitis B, and vice-versa. Specificity is conferred by two types of receptor: the TCR on T lymphocytes and an equivalent on B lymphocytes, the BCR. BCRs are also termed surface immunoglobulin (sIg) and differ from TCRs in also being secreted in large quantities by end-stage B lymphocytes (plasma cells) as soluble immunoglobulins, also known as antibodies.

To maintain protection against the multiplicity of pathogens in our environment, each of us generates great diversity amongst TCRs and antibodies. This is achieved through a mechanism shared by both TCR and antibody, in which distinct families of genes are encoded in the germline, each family (called constant, variable, diversity and joining) contributing a sequence to part of the receptor. Recombination between randomly selected members of each family ensures diversity in the end product. Recombination frequently involves base deletions and additions, adding to the diversity. In the case of antibodies, the result is a potential capacity of >10¹⁴ different antibody molecules; for TCRs it may be as high as 10¹⁸.

Immunoglobulins

In structural terms, antibodies have four chains; two identical heavy and two identical light chains (Fig. 3.10). Each chain contains both highly variable and essentially constant regions. The variable parts of the heavy and light chains pair to form the potentially diverse part of the antibody molecule that binds antigen. The constant region of the heavy chain dictates the function of the antibody, and belongs to one of the classes M, G1–4, A1–2, D and E, giving rise to antibodies called IgM, IgG1–4, IgA1–2, IgD and IgE. The characteristics of these different isotypes are shown in Table 3.11.

Figure 3.10 Immunoglobulin structure. (a) Basic subunit consisting of two heavy and two light chains. (b) Genes on the Fab and Fc regions of an immunoglobulin. The chain is made up of a V (variable) gene, which is translocated to the J (joining) chain. The VJ segment is then spliced to the C (constant) gene. Heavy chains have an additional D (diversity) segment which forms the VDJ segment that bears the antigen-binding site determinants.

Table 3.11 Characteristics of the immunoglobulins

Antibody production

Essential points about antibody production are:

IgM is the first isotype to be made in a primary immune response and thus measurement of pathogen specific IgM is a useful diagnostic test for recent infection.

IgG dominates in the second exposure to antigen.

IgG and IgM are the most efficient complement activators when bound to antigen in an immune complex.

IgG antibodies cross the placenta, and can carry both immunity and disease to the unborn fetus.

IgA antibodies are present in secretions (tears, saliva, GI tract) to give protection to the mucosae.

As it matures, and under the instruction of T lymphocytes, a B lymphocyte may change the class (class switching), but never the specificity, of the antibody it makes.

As B lymphocytes mature and are stimulated to undergo further division, minor changes in antibody gene sequence can arise (somatic mutation) potentially allowing antibodies with higher affinity to arise and be selected for the effector response (affinity maturation).

Antibody function

Essential points about antibody function are:

In host defence, antibodies target, neutralize and remove from the circulation and tissues infectious organisms and toxins, often through recruitment of innate host effector mechanisms such as complement, phagocytes and mast cells (by binding to specific surface receptors on these cells).

In clinical medicine, specific anti-pathogen antibody levels are used in diagnosing/monitoring infectious disease, and may also be administered as serum pools to passively provide host protection.

Antibodies can be raised in animals to generate monoclonal antibodies, which are commonly used in diagnostic immunology tests and increasingly used as therapeutics (e.g. to target cancer cells), often after ‘humanization’ (see below).

T lymphocyte development and activation

T lymphocytes are generated from precursors in the bone marrow, which migrate to the thymus (Fig. 3.11). Only 1% of the cells that enter the thymus will leave it as naive T lymphocytes to populate the lymph nodes. This process (termed thymic selection) leads to a cohort of cells (Table 3.12) with:

Figure 3.11 Development of T lymphocytes in the thymus and lifecycle in the secondary lymphoid tissue. DC, dendritic cell; TCR, T cell receptor.

Table 3.12 Identification of T lymphocytes

Thus, during thymic education most TCRs are rejected for further use (negative selection), either because they are unable to bind self HLA molecules, or because they bind with too strong an affinity, which would run the risk of self-reactivity and autoimmune disease. The chosen TCRs (positive selection) have low/intermediate affinity for self HLA molecules. During post-thymic activation of T lymphocytes in the lymph node, TCR interaction with HLA has to be bolstered by additional signals (co-stimulation) provided by DCs. This ensures that T lymphocytes are only activated when the checkpoint of DC maturation has been passed, which will only happen in the presence of pathogens.

Most naive T lymphocytes are resident in the lymph nodes or spleen, whilst 2% are present in the blood, representing a recirculating pool. Naive T lymphocytes are activated for the first time in the lymph node by antigens presented to their TCRs as short peptides bound to MHC molecules on the surface of DCs (Fig. 3.5). Provision of signals 1–3 (see p. 55) sets off an intracellular cascade of signalling molecule activation, leading to induction of gene transcription in T lymphocytes.

Nuclear factor kappa B (NF-κB) is a pivotal transcription factor in chronic inflammatory diseases and malignancy. It is found in the cytoplasm bound to an inhibitor IκB which prevents it from entering the nucleus (see Fig. 2.9). It is released from IκB on stimulation of the cell and passes into the nucleus, where it binds to promoter regions of target genes involved in inflammation. It is stimulated by, for example, cytokines, protein C activators and viruses. The outcome is T lymphocyte activation, cell division and functional polarization, which is the acquired ability to promote a selected type of adaptive immune response. These processes take several days to achieve. The best described polarities of T cell responses (Table 3.13) are:

Table 3.13 Identification of CD4 T lymphocyte subsets by function

Through cell division, a proportion of the T lymphocytes that are activated in response to a pathogen undertake these effector or regulatory functions, whilst a proportion is assigned to a memory pool. Once established, effector and memory T lymphocytes have lesser requirements for subsequent activation, which can be mediated by monocytes, macrophages and B lymphocytes.

Natural killer (NK) cells

These are bone marrow-derived, present in the blood and lymph nodes and represent 5–10% of lymphoid cells. The name is derived from two features. Unlike B and T lymphocytes, NK cells are able to mediate their effector function spontaneously (i.e. killing of target cells through release of perforin, a pore-forming protein) in the absence of previous known sensitization to that target. Also, unlike B and T lymphocytes, NK cells achieve this with a very limited repertoire of germline-encoded receptors that do not undergo somatic recombination. Despite their close resemblance to T and B lymphocytes in morphology, the lack of requirement for sensitization and the absence of gene rearrangement to derive receptors for target cells mean that NK cells are also categorized as a part of the innate immune system. For identification purposes, the main surface molecules associated with NK cells are CD16 (see below) and CD56 (note, NK cells are CD3- and TCR-negative).

The role of NK cells is to kill ‘abnormal’ host cells, typically cells that are virus-infected, or tumour cells. Killing is achieved in similar ways to CTLs. NK cells also secrete copious amounts of IFN-γ and TNF-α, through which they can mediate cytotoxic effects and activate other components of the innate and adaptive immune system. To become activated, NK cells integrate the signal from a potential target cell through a series of receptor-ligand pairings (Table 3.14). These pairings provide activating and inhibitory signals, and it is the overall balance of these that determines the outcome for the NK cell. The balance can be abnormal on a virus-infected or tumour cell, which might have altered expression of HLA molecules, for example, that mark them out for NK cytotoxicity.

Table 3.14 Examples of natural killer (NK) cell receptors

KIR, killer cell immunoglobulin-like receptor.

In addition, through CD16, which is the low-affinity receptor for IgG (FcgRIIIA), NK cells can kill IgG-coated target cells in a process termed antibody-dependent cellular cytotoxicity (ADCC).

One of the targets of NK cell activating receptors, MICA (non-classical HLA class Ic molecule), is induced under conditions of cellular ‘stress’, such as might arise during infection or neoplastic transformation. Many viruses have developed immunoevasion strategies that avoid presentation of viral proteins to CTLs by interfering with the MHC class I presentation pathway, or circumvent target cell recognition by reducing MICA expression. NK cells detect the reduced levels of MHC class I molecules, which renders infected cells susceptible to killing by NK cells. Likewise, tumours that escape immune surveillance by CTLs through the outgrowth of daughter cells that have low MHC expression also become NK cell targets. That NK cells are vital to antiviral immunity, is indicated by the associations between KIR and susceptibility to chronic infection with viruses, notably the human immunodeficiency virus (see p. 173).

Acute inflammation: events and symptoms

This is the early and rapid host response to tissue injury. Taking a bacterial infection as the classic example:

Figure 3.14 Hypoxia and inflammation. At the site of pathogen invasion and necrosis, the oxygen tension is low. Hypoxia acts upon the inflammatory process by amplifying innate immune cell responses and dampening down the adaptive response. Overall, this benefits the host by avoiding an excessive uncontrolled immune response.

Chronic inflammation: events and symptoms

Inflammation arising in response to immunological insults that cannot be resolved in days/weeks gives rise to chronic inflammation. Examples include infectious agents (chronic viral infections such as hepatitis B and C or intracellular bacteria such as mycobacteria) and environmental toxins such as asbestos and silicon. At the intracellular level, key processes of inflammasome generation and autophagy serve to enhance the chronic inflammatory process. Chronic inflammation is also a hallmark of some forms of allergic disease, autoimmune disease and organ graft rejection.

The common feature of these pathological processes is that the inciting stimulus is not easy to remove. For example, some viruses and mycobacteria remain hidden intracellularly; antigens that incite allergy (allergens) may be constantly present in the host’s environment; self or donated organs are a resident source of antigens. In many ways, the pathology that results is thus inadvertent; the immune system is caught between the repercussions of not dealing with the infection/insult, and the tissue damage that is caused by chronic activation of lymphoid and mononuclear cells.

Chronic inflammation may lead to permanent organ damage or impaired vascular function and can be fatal. If the inciting stimulus is removed, inflammation resolves. However, inflammation returns rapidly (24–48 hours) on re-exposure. This rapid recall response is the basis for patch testing to identify the cause of contact dermatitis, another form of chronic inflammation, and also for the Mantoux test of tuberculosis immunity.

The main immunological event is the presence of a proinflammatory focus comprising T and B lymphocytes and APCs, especially macrophages. If antigen persists, inflammation becomes chronic and the macrophages in the lesion fuse to form giant cells and epithelioid cells. Both Th1 and Th2 reactivity is recognized, but specific syndromes may be polarized towards one or the other (e.g. chronic mycobacterial or viral infection engenders Th1 responses, chronic allergic inflammation Th2).

When the inflammation is sufficiently chronic it may take on the appearance of organized lymphoid tissue resembling a lymph node germinal centre (e.g. in the joints in rheumatoid arthritis, p. 517). There is massive cytokine production by T lymphocytes and APCs, which contributes to local tissue damage. Granulomata, which ‘wall off’ the inciting stimulus, may also arise and result in fibrosis and calcification. Symptoms typically relate to the site of the inflammation and the type of pathology, but there may also be systemic effects such as fever and weight loss.

Crohn’s disease Chronic inflammation is a hallmark of several immune-mediated and autoimmune diseases, but it is often unclear what kick-starts or maintains the inflammatory process. Large scale studies that identify the genetic basis for these disorders (genome-wide association studies, GWAS) are beginning to provide some clues. A good example is Crohn’s disease (CD). Several of the polymorphisms associated with CD reside in genes known to be involved in inflammasome induction, such as NOD2. Cytokine regulation has also emerged as a critical disease pathway in GWAS studies on CD: most notably the IL-23R (IL-23 receptor gene), which influences Th17 cell differentiation. Clues like these point to patients with CD having impaired ability to control or terminate inflammasome activity, as well as a predisposition to make polarized pro-inflammatory cytokine responses. This information can now be exploited to devise novel therapeutic approaches.

Secondary (acquired) versus primary immunodeficiency

Most forms of immunodeficiency are secondary to infection (mainly HIV) or therapy (e.g. corticosteroids, anti-TNF-α monoclonal antibody therapy, cytotoxic anticancer drugs, bone marrow ablation pre-transplant). Examples of other secondary immunodeficiencies are:

Primary immunodeficiency is rare and arises at birth as the congenital effect of a developmental defect or as a result of genetic abnormalities (Table 3.16). Gene defects may not become manifest until later in infancy or childhood, and some forms of immunodeficiency typically present in adolescence or adulthood.

Table 3.16 Classification of immunodeficiencies and the main diseases in each category: apart from AIDS, all diseases shown here are primary immunodeficiencies

Primary immunodeficiency

Leucocyte adhesion deficiency (LAD)

This results from defects in integrins (see p. 23). Numerous underlying defects in the gene encoding one of the component chains, CD18, have been described in LAD-I. LAD-I has an autosomal recessive inheritance presenting almost immediately after birth, with delayed umbilical cord separation. Recurrent infections similar to those in chronic granulomatous disease appear during the first decade of life. Blood neutrophil levels are high but cells are absent from the sites of infection, which require aggressive antimicrobial and antifungal treatment, and SCT for cure.

Hyper IgE syndrome (or Job’s syndrome)

This is an autosomal dominant (occasionally sporadic) immune disorder with high serum IgE levels, dermatitis, boils, pneumonias with cyst formation and bone and dental abnormalities. Mutations in STAT3 have been found.

Shwachman’s syndrome

This can resemble cystic fibrosis clinically with exocrine pancreatic insufficiency and pyogenic infections. A mild neutropenia is associated with a defect of neutrophil migration.

Chédiak–Higashi syndrome

This is a rare, recessive disorder due to a mutation in the lysosomal trafficking regulator gene (LYST) on chromosome 1q42–45. There are defects in neutrophil function with defective phagolysosome fusion and large lysosome vesicles are seen in phagocytes. Patients have recurrent infections, neutropenia, anaemia and hepatomegaly. Similar abnormalities in melanocytes cause partial oculocutaneous albinism.

Anaphylaxis

Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. It arises as an acute, generalized IgE-mediated immune reaction involving specific antigen, mast cells and basophils. The reaction requires priming by the allergen, followed by re-exposure. To provoke anaphylaxis, the allergen must be systemically absorbed, either after ingestion or parenteral injection. A range of allergens that provoke anaphylaxis has been identified (Table 3.20).

Table 3.20 Sources of allergens known to provoke anaphylaxis

Anaphylaxis is rare, and the symptom/sign constellation ranges from widespread urticaria to cardiovascular collapse, laryngeal oedema, airway obstruction and respiratory arrest leading to death:

Central to the pathogenesis of anaphylaxis is the activation of mast cells and basophils, with systemic release of some mediators and generation of others. The initial symptoms may appear innocuous: tingling, warmth and itchiness. The ensuing effects on the vasculature give vasodilatation and oedema. The consequence of these may be no more than a generalized flush, with urticaria and angio-oedema. More serious sequelae are hypotension, bronchospasm, laryngeal oedema and cardiac arrhythmia or infarction. Death may occur within minutes.

Serum platelet-activating factor (PAF) levels correlate directly with the severity of anaphylaxis whereas PAF acetylhydrolase (the enzyme that inactivates PAF) correlated inversely and was significantly lower in peanut sensitive patients with fatal anaphylactic reactions.

Common autoimmune diseases

There are now over 80 diseases classified as autoimmune. Some of the diseases are very clear cut in their autoimmune origin, but others are not and both major and minor factors must be defined.

Monoclonal antibody therapy (targeted therapy)

The combined power of monoclonal antibody (MAb) and recombinant DNA technology has led to a series of ‘designer’ drugs, which have been engineered so that they are:

In general, this has meant a process of ‘humanizing’ antibodies of mouse origin and selecting an appropriate effector function. For example, a MAb designed to remove a subpopulation of lymphocytes from the patient should have good complement-fixing ability or bind well to receptors on phagocytes, whereas a MAb designed to ‘modulate’ a cell without depletion should have these functions removed. An example of the latter is an anti-CD3 MAb that has modified Fc regions and is designed to functionally downregulate, but not deplete, T lymphocytes. Many examples of MAbs in current use are described in individual chapters.

Immunosuppressive drugs

Glucocorticosteroids (cortisone, hydrocortisone, prednisone and prednisolone) are the most commonly used steroids and have a variety of effects on immune function, including:

Ciclosporin, tacrolimus and rapamycin (sirolimus) have similar effects on T lymphocyte function. Ciclosporin and tacrolimus are calcineurin inhibitors and inhibit Ca²⁺-dependent second messenger signals in T lymphocytes following activation via TCR. By contrast, sirolimus achieves a similar effect but acts at the level of post-activation events in the nucleus.

Purine analogues such as azathioprine are also frequently used as anti-inflammatory drugs in conjunction with steroids and act by inhibiting DNA synthesis in dividing adaptive immune cells. Similar in mode of action, but more powerful, is mycophenolate mofetil (MMF).

Alkylating agents that interfere with DNA synthesis, such as cyclophosphamide, are also used for immunosuppression.