Hypersensitivity

Contents
Introduction
Type One
Type Two
Type Three
Type Four

Introduction

Hypersensitivity reactions are excessive responses of the immune system which are harmful rather than protective. The antigen that precipitates the hypersensitivity reaction may be either exogenous or endogenous and thus, in the latter case, hypersensitivity reactions can overlap with autoimmune diseases.

Four types of hypersensitivity reaction are described. Types one to three are produced by antibody dependent mechanisms while type four is caused by an overzealous T cell response.

Type One

Type one hypersensitivity reactions are caused by IgE. The main examples are asthma and anaphylactic shock. Previous exposure to the precipitating antigen causes the immune system to develop an aberrant IgE response. It is suggested that there is a genetic predispostion to the tendency to generate this dysfunctional IgE response, possibly mediated by inappropriate switching of helper T cells to the type two helper T cell subtype. The Th2 cells induce B lymphocytes to change their immunoglobulin production to IgE. This is accomplished by the secretion of interleukin 4 by the T lymphocytes. The T lymphocytes also stimulate the generation of eosinophils and mast cells. The team of IgE, mast cells and eosinophils is required in the immune system's anti-parasite response. However, in type one hypersensitivity the T cells have incorrectly identified the antigen as a parasite and the anti-parasite stance they induce is harmful.

If the antigen is encountered a second or subsequent time, the preprepared IgE immune reaction launches with full force. The binding of numerous IgE molecules to multiple copies of the target antigen triggers the degranulation of mast cells and eosinophils. The mast cells release histamine, proteases and cytokines. The second of these damage tissues (particularly as there is no parasite to bear the brunt of their assault) while cytokines recruit other inflammatory cells. However, histamine produces the most problems, particularly with regard to vasodilatation and pain.

The features which occur due to mast cell degranulation develop within a few minutes of exposure to the antigen and last for approximately an hour. However, a resurgence of the hypersensitivity reaction can take place eight to twelve hours later due to the generation of derivatives of arachidonic acid. Metabolism of arachidonic acid is also stimulated by the effect of IgE on mast cells and eosinophils but it can require time for the derivatives to be synthesised in adequate quantities to exert their effects and for these effects to become apparent. The prostaglandins and leukotrienes which result from the metabolism of arachidonic acid cause more vasodilatation, leucocyte recruitment and bronchospasm.

Substances that are especially prone to provoking a type one hypersensitivity reaction possess structures which feature multiple repeats of the same antigenic region. This permits numerous IgE molecules to bind closely together on the antigen and facilitates them activating mast cells. Examples of substances which commonly cause type one hypersensitivity responses are the contents of bee stings, pollen, the faeces of the house dust mite and nuts.

Anaphylaxis

Anaphlyaxis is an extreme form of type one hypersensitivity that can be life-threatening. It happens if the antigen which precipitates the type one hypersensitivity reaction enters the blood. Once in the circulation the antigen is disseminated across the body and the IgE response therefore takes place at a systemic level. The massive histamine release causes systemic vasodilatation and a severe fall in blood pressure. Vascular permeability is also increased by the contents of the mast cell granules and this produces oedema. Laryngeal oedema can obstruct the airway, a problem that is exacerbated by the accompanying marked bronchospasm.

The treatment of anaphylaxis is proportionately dramatic. Adrenaline is given to combat the vasodilatation aggressively. A minor action of adrenaline is that is stabilises mast cells and opposes their degranulation. However, dedicated antihistamines are needed to neutralise the effects of the mast cells. Steroids are also given for the general anti-inflammatory properies, which include blocking the breakdown of arachidonic acid.

Type Two

Type two hypersensitivity involves an IgG or IgM response to cell surface antigens that are fixed within the tissues (this qualification is necessary to distinguish the process from type three reactions). The antigens which are targeted may be foreign antigens that have become incorporated into the cell membrane (some drugs can exhibit this phenomenon) or may be host antigens which the immune system has incorrectly deemed to be foreign.

Binding of immunoglobulins to the antigen triggers the usual sequence of events of the antibody response. The bound antibodies target the affected cells for phagocytosis and attack by complement and bring them to the attention of natural killer cells.

The type two response is slower than the type one hypersensitivity reaction and can require up to 24 hours to develop.

Examples of type two hypersensitivity diseases include Goodpasture's disease (the antigen is type four collagen of the basement membrane of the renal glomerulus and the lung) and haemolytic disease of the newborn.

Type Three

Type three hypersensitivity diseases are also centred around the production of inappropriately targeted IgG and IgM antibodies. However, the antigens in type three reactions are not fixed to the tissues but are soluble, in that they are present in the blood or can enter the blood. This solubility of the antigens means that the resulting combination of antibody bound to antigen (an immune complex) can be carried in the blood and then be deposited in various tissues such as the joints and the glomerulus of the kidney. Macrophages can catch immune complexes before they have the chance to impact in the tissues, but their capacity to do this is overwhelmed in type three hypersensitivity.

Once in the tissues the immune complexes excite a mixed inflammatory response because this is the expected reaction of the immune system when it encounters antibody bound to antigen.

The type three process tends to require a little longer to occur than type two and typically does not manifest until hours to a few days after the initial exposure. Systemic lupus erythematosus, extrinsic allergic alveolitis, Henoch-Schonlein purpura and acute diffuse proliferative (post-streptococcal) glomerulonephritis are examples of a type three hypersensitivity response.

Type Four

T cells take their turn as the causative agents in the phenomenon of hypersensitivity in the type four form of the disorder. Instead of being directed against a pathogenic antigen, the T cells are targeted against a host antigen or innocuous environmental agent that does not warrant such as eager response. The remainder of the process follows the standard pathways for the T cell immune response. The key aspect of the pathology is that the T cells are engaging in battle when it is not necessary.

Contact dermatitis is the typically invoked example of a type four hypersensitivity disorder. The Mantoux test employed in tuberculosis makes use of the type four hypersensitivity phenomenon, although unusually is an instance of hypersensitivity being put to beneficial use.