The immune system has become adapted to ensure that ‘self’ cells are not subject to an immune attack. The body is able to do this because tolerance is developed towards self-cells, should this tolerance be broken down by some means, the host becomes subject to autoimmune attacks which can be potentially damaging.
Tolerance is the acquisition of a state of non-reactivity towards particular antigens (known as tolerogens), for example the host’s cells. Tolerance to self-cells is typically established in embryonic life.
It is believed that both T and B cells are involved in the generation of tolerance, B-cells are particularly susceptible to tolerance induction when they are immature and yet to bind an antigen.
B-lymphocytes develop tolerance by:
- Clonal abortion – Immature B cells fail to mature in response to an antigen
- Clonal exhaustion – All B cells become plasma cells and no memory cells are formed
- Functional deletion – Either no T-Helper cells available to aid immune responses or there is an excess of an antigen which causes B cells to become unresponsive due to a receptor blockade
T Lymphocytes develop tolerance by:
- Clonal abortion – As with B-cells
- Functional deletion of a T-cell subset
- T suppression – T-cells are active and suppress T effector mechanisms
T Helper cell deletion is probably the most important in terms of developing tolerance. Therapy to prevent the rejection of transplants and desensitising allergies involves tolerance induction.
Autoimmunity occurs when the body fails to recognise self-cells from non-self, this results in immune responses and damage to the tissue of the host. The variety of autoimmune responses can be split generally in to two groups; organ specific and non-organ specific. In autoimmune responses it is thought that either over reactive T-helper cells or deficient T suppressor cells are the cause. Autoimmunity can also be induced by reactions to a foreign antigen that then reacts with a self-antigen to invoke a response, for example infection with a minor bacteria (streptococcus) can lead to antibodies being produced against an antigen displayed on heart valves that would lead to cardiac problems. Autoimmunity is diagnosed by autoantibodies and the deliberate induction of autoimmunity has been used to control fertility and tumours (immunotherapy).
Autoimmunity is an inappropriate reaction to self-antigens, hypersensitivity differs because it is an overactive immune response – to both self and foreign antigens.
Type I – Immediate
Type I hypersensitivity occurs when the IgE is produced instead of IgG or IgA in response to a foreign antigen. The mast cells in tissue bind the IgE to their surfaces by IgE Fc receptors. When the IgE binds to its specific antigen changes occur within the mast cell causing it to degranulate. This results in the release of inflammatory mediators (anaphylatoxins) such as histamine. This causes instant inflammatory changes at the site of the mast cell including smooth muscle contraction, increased vascular permeability and vasodilation (both lead to vascular leakage)
Type I hypersensitivity may also occur towards self-antigens. An example is ‘Milk Allergy’, this is a type I hypersensitivity response in cattle to the main protein present in milk – casein. Cattle that have undergone delayed milking suffer from high intramammary pressure that results in urticaria or systemic anaphylaxis.
The two main types of Type I hypersensitivity are systemic and local:
- Systemic Type I – These types of hypersensitivity reactions are known as anaphylaxis. They occur when mast cells degranulate extensively and throughout the entire body releasing large amounts of vaso-active substances. Symptoms include bronchiolar constriction and respiratory distress with a rise in pulmonary blood pressure. Systemic blood pressure falls and may result in the sufferer collapsing. (The dog differs, changes occur in the hepatic vein, leading to blood pooling in the liver.)
- Local Type I – These types of hypersensitivity reactions include the responses generated to arthropod parasites (e.g. fleas), inhaled antigens (e.g. hayfever), vaccines, foods and drugs. (Drugs have insufficient molecular weight to act as an antigen and so act as haptens – where they bind with other molecules such as proteins to elicit a response. The inflammation will typically develop at the site of the antigen entry.
Type II – Antibody dependent cytotoxicity
Type II hypersensitivity reactions occur when the IgG antibody binds to antigens on the cell surface of the host that results in cell lysis by activating complement or cytotoxic cells. Also known as antibody-dependent cell-mediated cytotoxicity (ADCC), any Fc bearing leukocytes are capable of inducing ADCC – these include monocytes, eosinophils, neutrophils, B-cells and NK cells. Tissue damage results, due to ‘frustrated phagocytes’ that release their lysosomal contents.
Transfusion of red blood cells to an animal that has antibodies to the transfused blood group will result in intravascular or splenic red-cell lysis (haemolysis). The same foreign blood group should not be transfused twice as specific antibodies will have been formed and may induce severe haemolysis.
In newborn foals, it is possible for foetal red blood cells to cross the equine placenta. These cells will bear the blood group antigens inherited from the parents. They may appear foreign to the mother who will produce antibodies against them. This only becomes hazardous if the foal obtains some of these maternal antibodies, as this would mean the foal had a supply of antibodies against its own red blood cells. Maternal antibodies are only transferred via colostrum, so symptoms of haemolysis will appear (if the condition is present) in the first few hours or days after sucking.
Another haemolytic condition is canine autoimmune haemolytic anaemia. This is caused by autoantibodies produced actively by the dog. IgG and IgM are produced which are anti-red blood cell. The IgM agglutinates red blood cells and activates complement-mediated lysis. IgG promotes red blood cell phagocytosis in the spleen.
Type III – Immune complex mediated
Immune complexes are deposited or formed in tissues, which are then damaged as a result of the activation of complement. Because the immune complexes persist, prolonged complement activation occurs. The polymorphs that are attracted to the site release proteolytic enzymes that then damage host tissue. Type III hypersensitivity often arises due to autoimmune responses.
Examples of naturally occurring diseases are allergic alveolitis in cattle, heaves in horses and farmer’s lung in humans. An example of how such a disease might cause a hypersensitive reaction – Dust from mouldy hay contains the spores of fungi (the inducing antigen), they are small enough to be inhaled into the alveoli. They complex with antibodies and induce alveolar and vascular inflammation – this causes tissue destruction.
The formation of complexes isn’t always local, the complexes may be found in the circulation where they can be deposited on vessel walls (particularly the joints and renal glomeruli which results in arteritis, arthritis and glomerular nephritis).
Type III hypersensitivity often occurs when large amounts of antigen are released into tissues or circulation. For example the condition of serum sickness appears in animals that have received large amounts of foreign serum (for the purpose of creating artificial passive acquired immunity).
Immune complexes being deposited in the glomerulus of the kidney cause glomerulonephritis.
Type IV – Delayed hypersensitivity
Sensitised T-cells react with specific antigens to release cytokines that induce the inflammatory response. This attracts and traps macrophages, which leads to granuloma formation e.g. tuberculosis. This type of reaction takes a few days for the result to become evident.
Type IV hypersensitivity reactions occur in a large number of infections and allergies involving mycobacteria, fungal or arthropod parasites. They are especially involved in infections involving the bacterium Brucella and the protozoon Leishmania. Skin testing is often used for diagnosis.
The host rejects foreign tissues when it recognises different MHC expressed in the graft tissues, therefore for a successful transplant, both host and recipient must express the same MHC (i.e. genetically identical twins). The rejection reaction is mainly Cytotoxic T-cell mediated (although antibodies may be involved in a second rejection of the same graft tissue).
- Tissue typing is employed to obtain maximum MHC matching
- Rejection of grafted tissue may be reduced by immunosuppressive therapy (e.g. cyclosporin A which reduces T-cell activation.)
- MHC matching is required for both MHC class 1 and 2 antigens, to identify useful tissue graft donors.
- Autoimmunity – Inappropriate immune response to self antigens
- Hypersensitivity – Overactive immune response to foreign and self antigens
- Immunodeficiency – Ineffective immune response
- Type I hypersensitivity – (IgE mediated, initiated in 2-30 minutes) Antigen induces cross-linking of IgE bound to mast cells with release of vasoactive mediators.
- Type II hypersensitivity – (Antibody-mediated cytotoxic, 5-8 hours) Antibody directed against cell-surface antigens mediates cell destruction via ADCC or complement.
- Type III hypersensitivity – (Immune complex mediated, 2-8 hours) Antigen-Antibody complexes deposited at various sites induces mast cell degranulation, neutrophil degranulation damages tissue.
- Type IV hypersensitivity – (Delayed cell-mediated, 24-72 hours) Memory TH1 cells release cytokines that recruit and activate macrophages.
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