The immune system and disease

Chapter 3 The immune system and disease

Anatomy and principles of the immune system

Immunity can be defined as protection from infection, whether it be due to bacteria, viruses, fungi or multicellular parasites. Like other organs involved in human physiology, the immune system is composed of cells and molecules organized into specialized tissues (Fig. 3.1).

The primary lymphoid organs are where the cells originate. Cells and molecules of the immune system circulate in the blood; immune responses do not take place there but are at the site of infection (typically the mucosa or skin). They are then propagated and refined in the secondary lymphoid organs (e.g. lymph nodes). After resolution of the infection, immunological memory specific for the pathogen resides in cells (lymphocytes) in the spleen and lymph nodes, as well as being widely secreted in a molecular form (antibodies).

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).

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

Normal barriers

Events that may compromise barrier function

Physical barriers


 Skin and mucous membranes

Trauma, burns, i.v. cannulae

 Cough reflex

Suppression, e.g. by opiates, neurological disease

 Mucosal function

Ciliary paralysis (e.g. smoking)

Increased mucus production (e.g. asthma)

Abnormally viscid secretions (e.g. cystic fibrosis)

Decreased secretions (e.g. sicca syndrome)

 Urine flow

Stasis (e.g. prostatic hypertrophy)

Chemical barriers

Low gastric pH (gastric acid secretion inhibitors)

Resistance to pathogens provided by commensal skin and gut organisms

Changes in flora (e.g. broad-spectrum antibiotics)

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.

Cells and molecules of the innate immune system

Innate immunity provides immediate, first-line, host defence. The key features of this system are shown in Table 3.3. It is present at birth and remains operative at comparable intensity into old age. Innate immunity is mediated by a variety of cells and molecules (Table 3.4). Activation of innate immune responses is mediated through interaction between the:

Table 3.3 Features of the innate and adaptive immune responses

Innate Adaptive

No memory: quality and intensity of response invariant

Memory: response adapts with each exposure

Recognizes limited number of non-varying, generic molecular patterns on, or made by, pathogens

Recognizes vast array of specific antigensa on, or made by, pathogens

Pattern recognition mediated by a limited array of receptors

Antigen recognition mediated by a vast array of antigen-specific receptors

Response immediate on first encounter

Response on first encounter takes 1–2 weeks; on second encounter 3–7 days

a Antigen is a molecular structure (protein, peptide, lipid, carbohydrate) that generates an immune response.

Activation of certain cells in the innate immune system leads to activation of the adaptive immune response (see p. 58).

The dendritic cell is especially involved in this process, and forms a bridge between innate and adaptive systems.


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:

Table 3.5 Contents and function of key neutrophil granules

Function Primary or azurophilic granules Secondary or specific granules


Myeloperoxidase (MPO)

Respiratory burst components (e.g. cytochrome b558) producing reactive oxygen metabolites, such as hydrogen peroxide, hydroxyl radicals and singlet oxygen



Bactericidal/permeability increasing protein (BPI)


Cell movement




CD11b/CD18 (adhesion molecule)


N-formyl-methionyl-leucylphenylalanine receptor (FMLP-R)

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).


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 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

Mediators Effects





Vascular permeability ↑

Smooth muscle contraction in airways


Digestion of basement membrane causes ↑vascular permeability and aids migration

 Proteoglycans (e.g. heparan)

Anticoagulant activity

Synthesized de novo:


 Platelet-activating factor (PAF)



Neutrophil and eosinophil activators and chemoattractants

Vascular permeability ↑


 Prostaglandins (mainly PGD2)

Vascular permeability ↑





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

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.

Tissue macrophages

A key role of tissue macrophages is the maintenance of tissue homeostasis, through clearance of cellular debris, especially following infection or inflammation. They are responsive to a range of pro-inflammatory stimuli, using their pattern recognition receptors (PRR) to recognize pathogen-associated molecular patterns (PAMPs). Once activated, they engulf and kill microorganisms, especially bacteria and fungi. In doing so they release a range of pro-inflammatory cytokines and have the capacity to present fragments of the microorganisms to T lymphocytes (see below) in a process called antigen presentation. Recent evidence suggests that evolutionarily conserved molecular patterns in mitochondria (organelles that originally derived from bacteria) can also activate monocytes. These damage-associated molecular patterns (DAMPs) could play a major role in the systemic inflammatory response that follows extensive tissue damage (e.g. following ischaemic injury).

It has been observed that some PAMPs induce the cytoplasmic assembly of large oligomeric structures of PRRs termed inflammasomes. There are numerous examples: members of the Nod-like receptor (NLR) family can be activated by stimuli such as viruses, bacterial toxins, and interestingly, crystallized endogenous molecules, including urate. Inflammasomes have potent effects in activating caspases, leading to processing and secretion of pro-inflammatory cytokines such as IL-1β and IL-18.

Macrophages have pro-inflammatory and microbicidal capabilities similar to those of neutrophils. Under activation conditions, antigen presentation (see p. 57, 58) is enhanced and a range of cytokines secreted, notably TNF-α, IL-1 and IFN-γ. These are necessary for the removal of certain pathogens that live within mononuclear phagocytes (e.g. mycobacteria). Macrophages and related cells may also undergo a process termed autophagy (p. 32, Ch. 2). This self-cannibalization is a critical property of many cell types under starvation conditions, but is used by the immune system to destroy intracellular pathogens such as Mycobacterium tuberculosis, which otherwise persist within cells and block normal antibacterial processes. Autophagy is also a means of enhancing antigen presentation pathways.

Tissue macrophages involved in chronic inflammatory foci may undergo terminal differentiation into multinucleated giant cells, typically found at the site of the granulomata characteristic of tuberculosis and sarcoidosis (see p. 845).

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:

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).

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:

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:

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.

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

Hla molecules and antigen presentation

On the short arm of chromosome 6 is a collection of genes termed the major histocompatibility complex (MHC; known as the human leucocyte antigens, or HLA in man), which plays a critical role in immune function. MHC genes code for proteins expressed on the surface of a variety of cell types that are involved in antigen recognition by T lymphocytes. The T lymphocyte receptor for antigen recognizes its ligand as a short antigenic peptide embedded within a physical groove at the extremity of the HLA molecule (Fig. 3.6).

The HLA genes are particularly interesting for clinicians and biologists. First, differences in HLA molecules between individuals are responsible for tissue and organ graft rejection (hence the name ‘histo’(tissue)-compatibility). Second, possession of certain HLA genes is linked to susceptibility to particular diseases (Table 3.10).

Table 3.10 HLA associations with immune-mediated and infectious diseases

Disease process Disease HLA type


Type 1 diabetes

Class II:


 DQA1*0301/DQB1*0302 (susceptibility)

 DQA1*501/DQB1*201 (susceptibility)

 DQA1*0102/DQB1*0602 (protection)


Class I:


 HLA-A24; HLA-B*18; HLA-B*39

Multiple sclerosis

DRB1*1501 (susceptibility)

Rheumatoid arthritis

DRB1*0404 (susceptibility)

Autoimmune hepatitis

DRB1*03 and DRB1*04 (susceptibility)

Goodpasture’s syndrome (anti-glomerular basement membrane disease)

HLA-DRB1*1501 (susceptibility)

Pemphigus vulgaris

DRB1*0402; DQB1*0503 (susceptibility)


Coeliac disease

DQA1*0501/DQB1*0201 (susceptibility)

Ankylosing spondylitis

HLA-B27 (susceptibility)


HLA-Cw*0602 (susceptibility)


Human immunodeficiency virus infection

HA-B27; HLA-B*51; HLA-B*57 (associated with slow progression of disease)

HLA-B*35 (associated with rapid progression)

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).

HLA classes

Classical class I HLA genes (also termed Ia), are designated HLA-A, HLA-B and HLA-C. Each encodes a class I α chain, which combines with a β chain to form the class I HLA molecule (Fig. 3.6). While there are several types of α chains, there is only one type of β chain, β2 microglobulin. The HLA class I molecule has the role of presenting short (8–10 amino acids) antigenic peptides to the T cell receptor on the subset of T lymphocytes that bear the co-receptor CD8. As an example of HLA polymorphism, there are nearly 200 allelic forms at the A gene locus. Class I HLA molecules are expressed on all nucleated cells.

Non-classical HLA class I genes are less polymorphic, have a more restricted expression on specialized cell types, and present a restricted type of peptide or none at all. These are the HLA-E, F and G (Ib genes) and MHC class I-related (MIC, or class Ic) genes, A and B. The products of these genes are predominantly found on epithelial cells, signal cellular stress and interact with lymphoid cells, especially natural killer cells (see p. 61, 62).

The class II genes have three major subregions, DP, DQ and DR. In these subregions are genes encoding A and B genes that combine to form dimeric αβ molecules that present short (12–15 amino acid) peptides to T lymphocytes that bear the CD4 co-receptor. Class II HLA genes (apart from DRA) are highly polymorphic. Other genes in this region encode proteins with key roles in antigen presentation (e.g. TAP, HLA-DM, HLA-DO, proteasome subunits; see below). Class II HLA genes are expressed on a restricted cohort of cells that go by the general term of antigen presenting cells (APCs; DCs, monocyte/macrophages, B lymphocytes).

HLA class III genes encode proteins that can regulate/modify immune responses, e.g. tumour necrosis factor (TNF), heat shock protein (HSP) and complement protein (C2, C4).

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:

image The endogenous route (Fig. 3.8) is a property of all nucleated cells: the internal milieu is sampled to generate peptide–HLA class I complexes for display (‘presentation’) on the cell surface. In a healthy cell, the peptides are derived from self-proteins in the cytoplasm (Fig. 3.8) and are ignored by the immune system. In a virus-infected cell, viral proteins are processed and presented. The resulting viral peptide–HLA class I complex is presented to CD8 T lymphocytes that have cytotoxic (killer) function. In an immune response against a virus infection, CD8 T lymphocytes recognizing viral peptide–HLA complexes on the surface of an infected cell will kill it as a means to limit and eradicate infection.

image The exogenous route (Fig. 3.9) is a property of APCs: the external milieu is sampled. Antigens are internalized, either in the process of phagocytosis of a pathogen, through pinocytosis, or through specialized surface receptors (e.g. for antigen/antibody/complement complexes). The antigen is broken down by a combination of low pH and proteolytic enzymes for ‘loading’ into HLA class II molecules. At the APC surface the pathogen peptide–HLA class II complex is presented to and able to interact with CD4 T lymphocytes. Presentation by DCs can initiate an adaptive immune response by activating a naive, pathogen-specific CD4 T lymphocyte. Presentation by monocyte/macrophages and B lymphocytes can maintain and enhance this response by activating effector and memory pathogen-specific CD4 T lymphocytes.

image Cross-presentation refers to the ability of some APCs (mainly DCs) to internalize exogenous antigens and process them through the endogenous route (Fig. 3.8). This is an essential component in the activation of CD8 cytotoxic T cell responses against a virus.

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Mar 31, 2017 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on The immune system and disease
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