Continuing Education

The immune system's principal role is to protect the body from infection and tumours. In order to understand the immunology of allergy and why it occurs, it is necessary to understand the workings of the human immune system.

This includes preventing infection and if infection occurs, producing a sustained effective response against the organism. The immune system also regulates the extent of this response, as an aggressive immune response can be damaging to the host.

The first parts of the immune system a pathogen will encounter are the physical barriers and external defences that prevent infection. These include the skin and mucus membranes. Pathogens can actively enter the host by penetrating the skin, or passively in food. In addition to the physical barrier, the body contains several mechanisms to prevent infection. The nose and bronchi contain small hair-like structures called cilia, which combine to form the muco-ciliary escalator. Pathogens are caught in the cilia and transported upwards away from the lungs.

The body produces a range of secretions. Tears wash the surface of the eye, preventing the build up of microbes. The body actively secretes substances into tears. These include IgA and IgG antibodies as well as lysozyme (anti-microbial enzyme) into tears. These antibodies prevent microbes attaching to the epithelial surface.

The epithelial surfaces are not sterile. There are colonised by non-pathogenic organisms called commensals. These bacteria reduce infection as they prevent pathogen attachment, release anti-bacterial compounds and compete for nutrients. Antibiotics remove these commensal organisms as well as treating infection. This increases the risk of a pathogenic microbe replacing the commensal and causing a secondary infection.

If infection breaches the physical barriers of the body, this stimulates the immune system. The response can be divided into two parts. These are the innate (cell-mediated) and adaptive (antibody-mediated) immune systems. The immune system is stimulated by antigen. Antigen can be protein, lipid and carbohydrate.

The innate immune response

The innate immune system is a first line of defence. It works using pattern recognition and is quickly activated. It recognises particular short sequences of molecules called epitopes, which are assumed to be part of a pathogen. The innate immune system is present at birth; its specificity does not change during life.

The innate immune system is composed of particular cell types and molecules. The principal type of cell is the phagocyte. These cells are classed into different types according to where they are found in the body and their morphology. The phagocyte is particularly important against extra-cellular pathogens. The phagocyte binds to the pathogen through receptors and internalises it. This 'phagosome' is then fused to a lysosome. A lysosome is a vacuole containing microbicidal substances, when it fuses to the phagosome it kills the pathogen.

To make the process of phagocytosis easier, the immune system uses molecules called opsonins to bind to foreign material. This process is called 'opsonisation'. Phagocytes use receptors that bind to opsonins, making phagocytosis of the pathogen more likely.

One of the major opsonins is complement. Complement is an enzyme cascade, which can be activated through one of two ways, the classical or alternative pathway.

The classical pathway is antibodymediated. The alternative pathway is stimulated by microbial products or acute phase proteins. The cascade begins with lysis of C3, producing C3b, which is very reactive. The actions of complement include activating mast cells to initiate an acute inflammatory response, attracting phagocytes to the site of the pathogen (chemotaxis), enhancing phagocytosis through opsonisation and killing the pathogen. Combination of complement proteins C3 through to C9 forms the membrane attack complex (MAC), which punch small holes (pores) in the target cell membrane, allowing cell contents to leak out and water to enter, killing the cell.

Acute phase proteins are a group of plasma-based proteins produced in the liver. They are activated by microbial products and maximise complement activation and opsonisation of the pathogen. These proteins also reduce host tissue damage by ensuring foreign material is removed.

In both the adaptive and innate immune system the cells need to communicate. This is primarily achieved through the production of small molecules called cytokines. There are many different cytokines. Production of cytokines like TNF and IL-12 by the innate immune system is a pro-inflammatory cytokine, it increases activation of macrophages.

The adaptive immune system

The adaptive immune response changes from birth to death of an individual depending on the pathogens it is exposed to. Many pathogens are not contained by the innate immune system. The adaptive immune system provides a more specific and aggressive response.

The first time it responds to a pathogen it takes time to respond. It leads to a more specific immune response. The adaptive immune response is responsible for the immune system memory. A second exposure to the pathogen should lead to a swift activation of the adaptive immune system. The availability of this feature is the basis for successful vaccination.

Like the innate immune system, the adaptive immune system relies on certain cell types and molecules. The principal cell is the lymphocyte. There are two types of lymphocyte. These are the B-lymphocyte (B-cell) and T-lymphocyte (T-cell). When activated, B-cells differentiate into either plasma cells (producing large amounts of antibodies) or memory cells (wait for a second exposure to the pathogen then produce antibodies). T-cells are divided into two types depending on their surface receptor. CD8+ T-cells are cytotoxic T-lymphocytes (CTLs).

They bind to MHC class I molecules. CD4+ T-cells are known as T-helper cells. These cells can differentiate into Th1 cells, which are pro-inflammatory cells, or Th2 cells that aid a humoral response. They bind to MHC class II molecules. A population of T-cell memory cells does exist.

Major histocompatability complex molecules (MHCs) appear in two classes. MHC class I appear on all nucleated cells in the body. Internal proteins are processed, cleaved and presented on MHC class I molecules to CD8+ CTLs. If a pathogen is in the cell, their protein can be presented to the CTL. If a pathogen molecule is detected, the CTL induces cell death.

MHC class II molecules are only found on antigen presenting cells (APCs), which are B-cells, dendritic cells and macrophages.They work in a similar way to MHC class I molecules; however, presence of a pathogen activates T-helper cells.

Activation of T-cells or B-cells specific to the antigen (clone) leads to proliferation and differentiation. Through cytokine production and cellular communication through receptor binding cellular activation is increased. B-cells proliferate and produce antibodies specific to the pathogen with T-helper cells maintaining the immune response.

Antibodies on the B-cell surface or in the plasma can activate complement through the classical pathway, aiding immune system activation. In humans there are five types of antibody IgA, IgD, IgE, IgG and IgM.

Allergy and hypersensitivity

When the immune system is activated it can cause damage to self. This 'hypersensitivity' can occur in response to microbial, inert and self antigen. Hypersensitivity reactions are divided into four types; however, stimulatory hypersensitivity has been described. This is a fifth type of reaction, but is seen as an extension of type II hypersensitivity. These reactions are an extension of normal immune system activity. They become evident through the symptoms they cause.

Hypersensitivity type I

A hypersensitivity type I reaction is what a lay person typically understands by the term allergy. This response is mediated by IgE antibodies, it occurs after the immune system has been primed. The severity of the clinical disease ranges from hay fever to anaphylactic shock.

IgE is usually found in small amounts in the systemic circulation. Its role in immunity is against worm infections. Those who live in areas with endemic helminth infections are appear less likely to suffer atopy. Allergic reactions can be induced by fungi or worm antigen. They can also be induced by otherwise innocuous substances such as pollen and particular foods. For a type I hypersensitivity reaction to occur the immune system has to be sensitised against the allergen. The B lymphocytes that are specific to the antigen and other APCs bind and internalise the antigen. The processed antigen is then presented in MHC class II molecules.

The Th2 cells specific to that allergen interacts with the presented antigen. It induces class switching in the B lymphocyte as the T-helper cell receptor CD154 stimulates the B-cell mounted CD40 receptor. The B-lymphocyte switches from producing IgM or IgD to IgE. The T-helper cell also produces IL-4. This induces a Th2 response and B-cell differentiation and proliferation. This leads to the production of IgE antibody by plasma cells and IgE memory cells to the antigen. These antibodies and memory cells spread through the body. They have an affinity for basophils and mast cells and bind to their surface membrane. These cells lie dormant until the body is exposed to the antigen again.

The first link in this reaction is for the allergen specific Th0 cell to become a Th2 cell. Th0 cells differentiate into Th2 when there is a higher concentration of IL-4 and a lower concentration of IFN. Why this occurs and why some individuals become sensitive to particular antigens through IgE reactions is not clear. Possibilities include genetics, environmental factors that lead to IL-4 production or defective production of IFN.

Whatever the reason for the production of the antibodies, exposure to the antigen after sensitisation causes immune system activation. Antigen binds to the IgE on specific mast cells causing IgE cross linking and mast cell activation. The cells degranulate. The cellular effects of these actions include an influx of eosinophils and immune cells into the tissue through the increased vascular permeability and the upregulation of adhesion molecules. Adhesion molecules attach to passing immune cells and then pull them into the tissues through relaxed tight junctions (caused by degranulation). The increased number of adhesion molecules and larger blood flow increase the chances of immune cells entering the tissue.

On a macro level the substances released cause smooth muscle contraction, increased mucus production, inflammation, tissue destruction, increased dilation of blood vessels. The sufferer will experience these effects as low blood pressure and the five signs of inflammation heat, redness, warmth, swelling and loss of function. Severe reactions can cause anaphylaxis.

Hypersensitivity type II

IgM or IgG antibodies can cause damage to self by attaching to cellular antigens or auto-antigens. Cell damage occurs through opsonisation, cell lysis or antibody dependent cellular cytotoxicity. Type II hypersensitivity is also known as cytotoxic hypersensitivity.

It is best explained using an example. A human has a specific blood group based on the antigens expressed on the surface, either A, B, AB or O. Someone who is group A has anti-B antibodies, group B means the presence of anti-A antibodies, someone who is group AB has no antibodies and group O means they have both A and B antibodies. If you give a person who is group A, group B blood, this will induce a hemolytic reaction. This is because the host immune system contains group B antibodies; it will treat the group B antigen as foreign material. This leads to immune system activation and lysis of the group B red blood cells.

Type II hypersensitivity has a role in autoimmune disease. If a failure to develop tolerance to self antigen occurs, it can lead to a cytotoxic reaction. Myaesthenia gravis is a disorder of the neuro-muscular junction. Auto-antibodies occur that bind to the acetylcholine receptors on the muscle fibre. The acetylcholine released from the nerve does not have any effect and there is no muscle contraction. Auto-antibodies to red blood cells can induce haemolytic anaemia.

Stimulatory hypersensitivity

This is the fifth type of described hypersensitivity. It is antibody-mediated and is seen as a sub-type of type II hypersensitivity. In stimulatory hypersensitivity the auto-antibodies stimulate a function of the body, rather than inhibiting it. An example can be seen in Grave's disease of the thyroid gland. Normally, thyroid stimulating hormone is produced by the pituitary gland, stimulating the release of thyroxine. Thyroxine creates a negative feedback loop by acting on the pituitary gland and preventing excess release.

In Grave's disease auto-antibodies act directly on the thyroid gland. The thyroxine prevents more TSH from being released. It does not, however, prevent the production of auto-antibodies. Excess thyroxine is produced and the patient becomes hyperthyroid.

Hypersensitivity type III

Type III sensitivity is also known as immune complex mediated hypersensitivity. It occurs when a large number of immune complexes are produced.
Immune complexes are usually removed by phagocytes. This mechanism prevents tissue damage. When the phagocytes become overwhelmed there are local and systemic effects. The local effect is called the Arthus reaction. Deposition of small immune complexes in the tissues triggers a mast cell-mediated acute inflammatory response. Damage is caused by complement activation and neutrophil activity. Immune complexes can also cause systemic effects depending where the immune complexes deposit. These include fever, weakness, arthritis, oedema, vasculitis (small blood vessels) and glomerulonephritis (kidney).

Hypersensitivity type IV

Type IV is a delayed hypersensitivity. It is the slowest of the five reactions described here. It is mediated by T-cells with macrophage, dendritic cell and cytokine activity.

Mycobacterium tuberculosis causes tuberculosis (TB), an infective organism that is commonly seen in the lungs, which can infect most organs of the body. It defies killing by the immune system so the antigen persists. This leads to the chronic stimulation of CD4+ T-helper cells and cytokine production. Macrophages surround the antigen. The macrophages and pathogen are then walled off from the body by fibroblasts, forming a granuloma.

The lack of space means that this is a concise introduction to immunology and allergy. The aim is to provide sufficient information to understand specific allergic eye disease covered in the next article.

Acknowledgement

The author would like to thank David Matthews for help in understanding and researching the immune system.

References

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5. Lydyard P, Whelan A et al. Instant Notes Immunology. BIOS Publishers Limited. Oxford, 2000.
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Iain Phillips is a junior doctor with a special interest in infectious diseases and a degree in immunology and parasitology

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