The Immune System and the Skin
Reviewed by Dr Victoria Lewis, specialist registrar in dermatology.
Skin provides protection from foreign invaders in several ways. Apart from the physical barrier there are specialised cells of the immune system throughout the layers of the skin. Some of these cells detect invasion by foreign proteins such as bacteria or viruses and other cells have the function of destroying and removing such material. When a foreign protein (called an ‘antigen’) comes into contact with cells of the immune system these cells produce proteins (called antibodies) that fit around the invading antigen in a unique way. A fair analogy is of a lock and key, in which the invader is the key and the immune system cells manufacture a lock with which to trap it.
The antibody-antigen combination is recognised by other cells within the immune system family, which then move in and destroy the invader. In the type of immune reaction called ‘hypersensitivity’, the presence of foreign material sets off reactions from skin cells called mast cells. These contain powerful signalling chemicals such as histamine which, when released, activate the other components of the immune system. Histamine has marked local effects on the skin, familiar to anyone who has brushed against stinging nettles. At the contact site the skin swells and becomes red, due to opening up of the blood vessels and leakage into the tissues of fluid from within the blood vessels and the lymphatic system. Surrounding the contact site the skin blood vessels contract, restricting the flow of blood and so causing the skin here to pale (the so-called ‘wheal and flare’ reaction). Such a hypersensitivity reaction occurs almost immediately after being pricked by stinging nettles, hence the common term ‘nettle rash’. The proper medical term is urticaria and a great many other agents apart from nettles, such as chemicals and food components, can trigger similar reactions. The ‘nettle rash’ form of sensitivity is the easiest to understand but there are several other ways in which immune reactions occur within the skin. These usually act over longer time scales.
In allergic contact dermatitis for example it takes two or three days for the immune system cells to recognise the presence of the irritation and to recruit more cells locally to deal with the situation. Such a delay makes it harder to work out what caused the allergic reaction in the first place.
Changes in eczema - a common immune reaction
In eczema the chain reaction of events triggered by the irritant causes alterations in the structure and function of the layers of the skin. These include splitting of the normally tight layers of the epidermis so that the protective function of the epidermis is partially lost. This can lead to irritation from the penetration of harmful substances that would be kept out by intact skin and by infection with skin bacteria. Loss of water holding capacity causes the skin to dry out and to flake off more easily, and the skin thickens in response to repeated scratching.
To the naked eye the mildest forms of eczema show as dry, paler patches of skin without much in the way of accompanying inflammation. In more active eczema there is skin thickening and splitting with surrounding redness or more obvious signs of infection such as overlying crusts. Always there is intense itching, which is an essential feature of the condition; ‘eczema’ that in the absence of treatment doesn’t itch isn’t eczema!
More detailed examination of the skin as well as other indirect tests of the immune system show that it is highly active in all forms of eczema. On blood tests for example increased levels are usually seen of proteins called immunoglobulins, particularly one called IgE. There are also increased numbers of a type of white blood cell usually associated with allergy. These features indicate that eczema is not only something that goes on within the layers of the skin but it is part of a general process of activity in the immune system.
Sophisticated techniques are increasingly being developed to detect the subtle changes in the biochemistry of the cells within the skin and how they interact with antigens and with the other cells of the body. Causes of eczema Why eczema occurs is still far from being well understood. It is useful to think of it as two types – endogenous (coming from within the body) and exogenous (due to contact with an irritant or allergen). Exogenous or contact dermatitis is caused by sensitivity to a particular substance which then causes a reaction in the skin. It does not explain why some people are sensitive in the first place and why some substances can trigger a reaction while others do not. The cause of endogenous eczema is often not found.
It is possible to have both types of eczema at the same time.
• Atopic eczema (an endogenous eczema), has a strong genetic component. The children of parents (especially the mother) who have eczema are very likely to develop it too, more so than asthma or hay fever for example, which also are allergic conditions.
• Work on gene patterns has begun to show some more specific associations with eczema but these are still early days in this type of research. The pace of advance in genetic research is however very rapid and the hope is that more treatments will be developed from the knowledge gained in this area.
• Immune system triggers
• Nearly 40 per cent of children with moderate to severe eczema will develop skin rashes in response to foods to which they are sensitive.
• General food group allergies can be detected by a blood test called a RAST test. The relationship between food allergies and eczema in young children is often important but as they get older the association becomes less clear.
• Allergens can also come into the body through the air. In this way house dust mite protein (from the droppings of the mite and not the mite itself), animal dander, moulds and weed spores can come into the lungs and set off the immune system there, resulting also in reactions in the skin. Effective removal of house dust mite is one strategy that can help improve eczema.
• Bacteria, particularly Staphylococcus aureus, are probably the most important triggers for eczema. This organism, found on the skin of over 90 per cent of people affected by eczema, produces a ‘superantigen’ which is powerfully able to activate immune system cells in affected skin.
• If superantigen extracted from Staphylococcus bacteria is applied to normal skin then an eczema reaction occurs. Scratching of the skin breaks the barrier function down and allows more bacteria to gain entry to the sub layers of the skin.
• Despite the activation of the immune system however the body’s ability to reject the bacterial infection is impaired. One of the treatments of active eczema is to kill off the bacteria with antibiotics.
Treatments acting on the immune system
In a way, antibiotics act to boost the effectiveness of our own immunity. Antibiotics act directly on bacteria to destroy them or prevent them from duplicating, thus allowing our scavenging cells to gain the upper hand and eliminate the remaining bacteria.
There are other means by which the immune system can be manipulated to our favour in eczema.
• The longest standing treatments of this type are steroid creams and ointments.
• ‘Steroid’ is a collective term for a range of hormones produced mainly by the adrenal glands, two walnut-sized pieces of tissue that are located on the top of each kidney.
• Steroids are now manufactured artificially and they have many and varied effects but among the most important are their anti-inflammatory properties. Steroids are therefore used in asthma inhalers to reduce the inflammation within the airways that occurs in that condition.
• In rheumatoid arthritis they reduce pain and swelling from inflamed joints, and in eczema steroid creams switch off the immune system attack within affected skin. By interrupting the inflammation the forces of repair are given an advantage over those which act to disrupt the skin.
• Although steroid creams are effective and can be used safely with care they do have several important side effects, including thinning of the skin in the long term. The may also cause problems with the liver in prolonged use. Inducing the natural steroids via the adrenals is a better option for long term use if required - see Reflexology.
• Cytokine inhibitors
• New treatments for eczema also inhibit the actions of the immune system within the skin but by a different mechanism to steroids.
• These are called cytokine inhibitors, cytokines being the name of the signalling compounds which marshal the immune response in eczematous skin. By switching off cytokine production the immune system attack on the skin is turned down.
There are two such medicines currently available in cream form; tacrolimus (Protopic) and pimecrolimus (Elidel). Both are available for use in the UK by dermatologists or GPs experienced in treating skin disease. Elidel can be used in children from two years upwards.
• The advantages of these new treatments over steroids are several. They do not cause thinning of the skin, have not shown significant long term side effects so far and they can be used on skin areas, such as the face, neck and skin folds, where steroid creams can give particular problems.
• As with any new treatments their exact place in the management of eczema is still being decided, partly because doctors need to gain experience in using them but also because they are more expensive than standard treatments and so are subject to constraints in the budgets under which doctors prescribe.
• Generally they will be used in people with moderate to severe eczema but Elidel is licensed also to be used at the first sign of eczema activity. In intermittent use over the long term it gives good eczema control.
• Cytokine inhibitor creams may eliminate the need for an individual with eczema to use any steroid creams, which is potentially a big advantage for those currently dependent on higher dose or long-term topical steroids.
References Leung DYM, Bleber T. Atopic Dermatitis. The Lancet (2003);361:151-160.
Based on a text by Dr Dan Rutherford, GP
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