Cutaneous immunology Autoimmune disease and the skin
Types of allergic reaction
Allergic and other immune reactions may occur in the skin the “immunological battleground of the body” rather than involving internal organs.
An acute vasculitis occurring in the skin is unpleasant and requires treatment but the same reaction occurring in the kidneys can be life threatening.
The pattern of skin changes can indicate the type of immune process involved and also whether there is likely to be systemic involvement.
The immune response of the skin is also used clinically in the tuberculin skin test to detect the level of immunity to tuberculosis.
It is also the means of immunisation when an injection of inactivated organisms induces an immune response that protects the entire body.
The different types of immune reaction are all manifested in the skin as part of a normal response to pathogens or as an allergic reaction.
The difference is expressed by the word “allergy”, first used by Von Pirquet in 1906, derived from the Greek, meaning literally “other work”.
In other words it is a response that is appropriate for pathogenic organisms such as a tubercle bacillus but is misdirected against a harmless substance such as a rubber glove or the metal of a watch strap buckle.
Immunological reactions are of four types five if autoimmunity is counted of responses mediated by antibodies known as the humoral response and one by the lymphocytes known as the cell mediated response.
Immediate hypersensitivity
This type of reaction is caused by “reagin” antibodies, which consist mainly of lgE, that react with allergens such as housedust mite, animal dander, or grass pollens. These reactions may occur in both the skin or the lung to produce asthma.
Allergic reactions to insect stings can cause severe systemic effects “anaphylaxis”, which literally means “without protection”.
Food proteins can also cause an immediate type of hypersensitivity reaction.
The IgE molecule is attached to specific receptors on the surface of mast cells and when activated by linkage to specific allergen inflammatory mediators are released.
This is an acute process, hence the name “immediate hypersensitivity”.
The initial response occurring within five minutes is due to by the release of histamine, heparin, tryptophan.
This is followed by inflammatory mediators released in five to 30 minutes leukotrien, prostaglandin. The later response, occurring after some hours, is caused by cytokines predominantly tumour necrosis factor alpha (TNF-alpha) and interleukin 4 (IL4).
Severe reactions cause shock that is made worse by stress and exercise, as in the case of a young woman, allergic to wasp stings, who had a wasp sting when picnicking by a lake.
She then plunged into the cold water, swimming vigorously, leading to a fatal anaphylactic reaction.
Acute anaphylactic reactions to peanuts may be life threatening.
Cytotoxic reactions
In this case cells become the target of attack by circulating antibodies.
There are a number of causes, such as drugs or proteins attached to the cell surface that act as haptens so they become antigenic.
This occurs in drug induced haemolysis from drugs. Alternatively, immune complexes are attached to the surface of the cell with the incorporation of complement leading to lysis.
In haemolytic anaemia and incompatible blood transfusions antibodies are formed against erythrocytes. They may also be destroyed by killer cells.
A typical example is haemolytic anaemia.
This immune response is the means of destroying cells that become antigenic as a result of being infected with virus.
In autoimmune diseases antibodies are directed against specific structures.
Antigen–antibody complex reactions
As a result of antibody production to antigens in the circulation, complexes form in the blood and these may be deposited in capillaries resulting in inflammatory changes. Similar changes may occur in the lung.
This involves the activation of complement and the release of mediators of inflammation, producing vasodilatation and the accumulation of polymorphs.
Delayed hypersensitivity
This type of reaction results from lymphocytes known as T cells, because of their derivation from the thymus, which react with antigen in the skin.
The reaction is initiated by antigen attached to Langerhan’s cells in the epidermis being transported to the paracortical area of the regional lymph node with the production of lymphocytes sensitised specifically for that antigen.
There is also the production of interleukin which has a feedback effect in stimulating the production of more sensitised lymphocytes.
The reaction of the T lymphocytes in the epidermis results in the accumulation of macrophages and the release of inflammatory mediators.
Autoimmune disease and the skin
There is always the risk that the well developed human immune system may react against the body’s own tissues, with a failure to distinguish between “self” and “non-self”.
An immune response develops which may be specific for a particular organ, such as the thyroid gland, or react against a number of different organs, as in connective tissue diseases.
The skin can manifest both types of autoimumme response.
The results of such reactions can be destruction of the cells concerned and the production of inflammation.
There is an inherited tendency to autoimmune disease, marked by specific HLA (human lymphocyte antigen) in some cases.
The most common types of skin disease in which this autoimmune mechanism occurs are the blistering disorders, pemphigoid and pemphigus, as well as dermatitis herpetiformis.
Pemphigoid
In this condition large, tense blisters develop in which there are antibodies attached to the upper layer of the basement membrane at the dermo-epidermal junction, with an underlying inflammatory reaction producing a split above the basement membrane.
Lysosomal enzymes are released damaging the basement membrane, resulting in separation of the epidermis and blister formation.
The presence of antibodies, usually IgG, can be shown by an antihuman IgG antibody labelled with fluorescein.
When viewed under the microscope with ultraviolet light illumination, the presence of the IgG antibody is shown by fluorescence.
The presence of circulating antibasement membrane antibodies in the serum can be shown either by direct immunofluorescence using a specimen of the patient’s skin or by incubation by attachment to skin which has been incubated in serum from the patient.
The blisters develop, frequently with an erythematous background, on the limbs, trunk, and flexures.
It is mainly seen in the elderly and is slightly more common in women.
Pemphigus
In this condition, antibodies are found to have developed against the epidermis above the basement membrane.
The main antibody is IgG, but IgM and IgA may also be found.
As a result of this reaction, there is separation of the epidermal cells with the formation of a superficial blister.
A row of basal cells remains attached to the basement membrane.
Direct immunofluorescence of the skin from affected patients shows that antibodies are deposited on the intercellular substance of the epidermis.
Circulating antibodies are often present.
Oral lesions are much more common than in pemphigoid.
Other organ-specific autoimmune diseases of the skin
Vitiligo
In this condition there is a loss of pigment as a result of antibodies developing against melanocytes in the skin in a limited area.
However, the areas affected tend to gradually increase.
There may be other autoimmune diseases in the same patient, causing, for example, pernicious anaemia, and thyroid disease.
Alopecia areata
There is evidence that this condition may be associated with an immune reaction against the hair follicle.
The increased incidence of antibodies to the thyroid gland and gastric parietal cells in patients with alopecia areata provides circumstantial support for an autoimmune aetiology.
Non-organ-specific skin autoimmune disease
Systemic lupus erythematosus (SLE)
The hallmark of this condition is the presence of antibodies against various components of the cell nucleus.
Although a wide range of organs may be affected, in three quarters of the patients the skin is involved, generally with an erythematous eruption occurring bilaterally on the face in a “butterfly” distribution.
There may also be photosensitivity, hair loss, and areas of vasculitis in the skin.
There is often intolerance of sunlight.
Subacute lupus erythmatosus is a variant that presents with an erythematous eruption in the skin and anticytoplasmic RNA molecules.
Discoid lupus erythematosus (DLE)
This is a condition in which circulating antinuclear antibodies are very rare. There are quite well defined inflammatory lesions, with some degree of atrophy occurring on the face and occasionally on the arms as well.
Treatment of SLE with the threatened or actual involvement of organs is important.
Prednisolone is usually required and sometimes immunosuppressant drugs such as azathioprine as well.
Treatment of DLE is generally with topical steroids.
Hydroxychloroquine by mouth is also used, generally in a dose of 200 mg daily.
This drug can diminish visual acuity and this should be checked every few months.
A simple chart, the Amsler Chart, is available for patients to use, consisting of a central dot with a grid which becomes blurred when held at arm’s length when there is any impairment of acuity.
Systemic sclerosis
This is a condition in which there is extensive sclerosis of the subcutaneous tissues in the fingers and toes as well as around the mouth (scleroderma), with similar changes affecting the internal organs, particularly the lung and kidneys.
There are vascular changes producing Raynaud’s phenomenon and telangiectasia around the mouth and fingers.
It is associated with antinuclear antibodies (speckled or nucleolar), and in about 50% of cases circulating immune complexes may be present.
Endothelial cell damage in the capillaries results in fibrosis and sclerosis of the organs concerned.
There is considerable tethering of the skin on the fingers and toes, which becomes very tight with a waxy appearance and considerable limitation of movement.
A variant is the CREST syndrome.
Morphoea is a benign form of localised systemic sclerosis in which there is localised sclerosis with very slight inflammation.
There is atrophy of the overlying epidermis. The early changes often consisit of a dusky appearance to the skin.
Dermatomyositis
This condition is described in chapter 16, but the main immunological features are deposition of IgG, IgM, and C3 at the dermo-epidermal junction in about half the cases in the early stages, as well as a lymphocytic infiltrate with CD4+ cells and macrophages.
There are reports of autoantibodies in some patients.
Dermatomyositis may represent an immune reaction to an underlying mechanism or derangement of the normal immune response.
Lichen sclerosus
This condition is also described in chapter 16 and is characterised by atrophic patches of skin.
It occurs mainly in females and predominantly involves the genitals and perineum.
The cause is unknown but in early lesions there is a band of lymphocytes, mainly CD3, CD4, and CD8.
Immunoglobulins and complement accumulate in the affected areas.
There is an association with vitiligo, morphoea, alopecia, and pernicious anaemia, suggesting an autoimmune association.
Graft versus host disease
This reaction occurs following bone marrow transplantation in immunosuppressed patients.
T lymphocytes produced by the graft react against the body’s own tissues, producing a skin eruption which may resemble measles.
There is lysis of the basement membrane with shedding of the skin and sometimes lichen planus-like eruption.
In the more chronic form, localised lesions develop, with immunoglobulins deposited in the walls of blood vessels with the activation of complement.
