8.2 Autoimmune disease71
8.3 Transplantation72
• A defective (insufficient) immune response will compromise the host defences against microorganisms and predispose to infection. In severe cases, there is also a predisposition to certain neoplasms.
• In hypersensitivity reactions, host tissue is secondarily destroyed during an immune response.
• If the immune system fails to distinguish between self and non-self antigens, the immune system will attack normal tissues. This is autoimmunity.
• Undesirable immune responses are also seen in patients in whom there is rejection of tissue transplants.
8.1. Hypersensitivity
Hypersensitivity is a process whereby the host’s tissue is injured during an immune response to a foreign antigen. When this process is inappropriate ‘hypersensitivity diseases’ occur. They are divided into four types; types I–III are mediated by antibodies (humoral immunity), whereas type IV is mediated by cellular immunity.
Type I hypersensitivity
Type I hypersensitivity is commonly called allergy. It is due to the interaction of antigen with IgE antibody previously bound to the surfaces of mast cells and basophils. In this context, the antigen is referred to as an allergen. Type I hypersensitivity is rapid (hence its alternative name, immediate hypersensitivity) and triggers mast cells and/or basophils to release substances that cause blood vessels to dilate and become leaky and cause smooth muscle contraction in bronchial walls and elsewhere. Later, eosinophils and other inflammatory cells infiltrate the tissue, causing further damage. The reaction can be localised or generalised.
Localised reactions
Common examples of localised type I hypersensitivity reactions are asthma, hay fever and urticaria. In susceptible, sensitised individuals, exposure to antigen (allergen) results in an immediate and acute immune response mediated by IgE. The reaction can be triggered by substances which are commonly found all around us. For example, asthma can be triggered by house dust or animal proteins, and hay fever can be caused by pollen.
Generalised reactions
Rarely, antigen enters the bloodstream of a sensitised individual and binds to IgE on circulating basophils. This can lead to a severe reaction known as anaphylaxis in which there is acute bronchospasm, shock (circulatory collapse as a result of peripheral vasodilatation), and even death. This may happen to people who are sensitised to penicillin or bee stings, for example.
Sequence of events
This is the same in both localised and generalised type I hypersensitivity reactions. In sensitised people, IgE is bound to the surface of tissue mast cells (and also their circulating counterparts, basophils), which have specific receptors for the Fc portion of the antibody, leaving the antigen-binding sites free to link with antigen. This binding has high affinity. After antigen and IgE have linked together, there follows an increase in membrane permeability to calcium with activation of a cascade of intracellular signals. This leads to degranulation of mast cells, which release histamine, a powerful vasodilator and constrictor of smooth muscle, and an eosinophil chemotactic factor (Table 13). Degranulation of mast cells can also be caused by substances other than IgE, e.g. drugs such as morphine, activated complement components C3a and C5a, and by physical stimuli such as heat, cold and trauma.
| Substances found in mast cell granules | Action |
|---|---|
| Eosinophil and neutrophil chemotactic factors | Chemotaxis |
| Histamine | Vasodilatation, increased permeability |
| Heparin | Late phase reactions |
| Trypsin | Late phase reactions |
| Substances made by mast cells during response | |
| Leukotrienes | Chemotaxis, smooth muscle contraction |
| Prostaglandins | Vasodilatation, smooth muscle contraction |
| Platelet-activating factor | Platelet aggregation, smooth muscle contraction, increased permeability |
Type II hypersensitivity
In type II hypersensitivity reactions, antibody binds directly to tissues: antibodies are directed against and bind with normal or altered components on the cell surface which they recognise as non-self. The presence of bound antibody induces damage by three main mechanisms:
• complement-mediated cytotoxicity: fixation of complement to the cell surface produces lysis via the membrane attack complex
• opsonisation: cells coated with antibody and complement C3b fragments are susceptible to phagocytosis
• antibody-dependent cell-mediated cytotoxicity: target cells are coated with IgG (or occasionally IgE); the cells are attacked by cells which have receptors for Fc that enable them to recognise and kill cells that have immunoglobulin bound to them. Such cells are the natural killer (NK) cells, neutrophils, macrophages, and (in the case of IgE) eosinophils. However, NK cells appear to be most important in this process.
Examples of such reactions are transfusion reactions, haemolytic disease of the newborn and Goodpasture’s syndrome.
Incompatible blood transfusion reaction
Antibodies against a blood group antigen, e.g. rhesus or ABO, bind directly to the surface of the blood cells, causing haemolysis. Thus, a patient who has antibodies to blood group B but is inadvertently given type B blood will experience massive intravascular haemolysis.
Haemolytic disease of the newborn
Rhesus (Rh) blood group antigens are present in about 85% of people (rhesus positive); the remainder of the population are rhesus negative. Rhesus antigen is inherited through a dominant gene (D) so that rhesus-positive individuals can be homozygous (DD) or heterozygous (Dd). Haemolytic disease of the newborn may arise if a rhesus-negative mother carries a rhesus-positive fetus. When fetal red cells enter the maternal circulation, usually at delivery, maternal antibodies against fetal rhesus antigen will be produced. The first rhesus-positive baby from a rhesus-negative mother is usually normal, but the mother will have become sensitised to the rhesus antigen during delivery of this pregnancy. The next time she carries a rhesus-positive fetus, she will be able to mount a secondary immune response to the rhesus antigen, causing haemolysis of the red cells in the developing fetus. Therefore, subsequent babies from a sensitised mother will tend to develop progressively more severe haemolysis. The disease can be prevented by injecting the mother with IgG rhesus antibody immediately after delivery to ‘mop up’ any fetal cells and prevent her producing natural antibody.
Goodpasture’s syndrome
Goodpasture’s syndrome is an autoimmune disease. Autoantibodies to type IV collagen develop and bind to the type IV collagen in the basement membrane of the glomeruli and the lungs. Consequently, complement is fixed and antibody-dependent cell-mediated cytotoxicity is activated, causing glomerulonephritis (see Ch. 23, Section 23.3) and inflammation of the lung.
Type III hypersensitivity
Type III hypersensitivity is caused by antigen–antibody complexes. When antibody reacts with antigen in certain proportions, complexes form that can be deposited either locally or at a distant site. The antigen–antibody (immune) complexes cause tissue damage where they are deposited, usually in blood vessel walls, where they induce an inflammatory reaction as a result of complement activation and infiltration by neutrophils.
Localised immune complex disease (Arthus reaction)
The Arthus reaction is an example of immune complex damage following injection of an antigen into the skin of an individual with high levels of preformed antibody. Within 2–8 hours, a haemorrhagic oedematous reaction occurs. After 12–24 hours, skin necrosis occurs as a result of localised vasculitis (inflammation of vessels causing necrosis of the wall) from local immune complex deposition. Histologically there is an acute inflammatory reaction with numerous neutrophils.
Systemic immune complex disease
When an antigen first stimulates the formation of antibody, there is antigen excess. As levels of antibody rise, antigen/antibody equivalence occurs and as antigen is removed, there is a relative excess of antibody in the circulation. Small soluble immune complexes are formed when there is antigen excess. They are not easily phagocytosed and may be deposited in the walls of blood vessels in the kidney (glomerulus), heart, joints and skin. Here they activate complement and cause tissue damage. Large immune complexes are formed when there is antigen/antibody equivalence or antibody excess and these are readily cleared from the circulation by macrophage phagocytosis.
There are various clinical situations in which systemic immune complexes can form and cause disease:
• infection, e.g. post-streptococcal glomerulonephritis
• autoimmune disease, e.g. systemic lupus erythematosus (see Box 8).
Box 8
Definition. Chronic autoimmune illness with fluctuating activity. Multisystem involvement, especially skin, joints, kidneys and serosal surfaces.
Age/sex. Young to middle-aged females typically.
Cause. Most cases are spontaneous and probably mediated by polyclonal B cell hyperactivity with autoantibody production and immune complex formation. The autoantibodies are antinuclear (anti-double-stranded DNA antibodies); this is diagnostic of the disease. Some cases occur in patients on drugs (hydralazine). The tissue injury is caused by a type III hypersensitivity reaction.
Pathological processes. The main pathological changes and their resulting symptoms are:
• vasculitis (inflammation of vessels) with necrosis: rashes, muscle weakness
• glomerulonephritis: haematuria, proteinuria, renal failure
• synovitis: arthritis
• pleuritis, lung inflammation: chest pain, breathlessness
• pericarditis, endocarditis: chest pain, heart failure.
Clinical course. Very varied. A few patients die rapidly with heart/renal failure. Most have a chronic illness requiring repeated courses of immunosuppressive drugs.
Type IV hypersensitivity
Type IV hypersensitivity is a reaction mediated by sensitised T cells rather than antibodies. It characterises the host response to a variety of microorganisms, including viruses, fungi, protozoans and mycobacteria, but it is also seen in many other circumstances, e.g. transplanted organs, inflammatory drug reactions, and contact sensitivities (such as poison ivy reaction). It takes time for primed T cells to react and hence there is a delay of at least 12 hours before the reaction can be seen. For this reason, type IV hypersensitivity is sometimes called ‘delayed hypersensitivity’.
The prototype of this reaction is the tuberculin test. If a small amount of protein derived from tubercle bacilli is injected into the skin of a non-immune person, there will be no reaction. However, in people who have already had tuberculosis (TB) or been immunised with BCG (bacille Calmette–Guérin derived from TB) and therefore have primed T cells, an area of reddening develops in 12 hours. The reaction is maximal at 1week and histologically the tissue at the reaction site shows granulomas, which are accumulations of lymphocytes and macrophages. The macrophages are typically transformed into epithelioid cells, and some fuse together to form giant cells (see Ch. 9).
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