Self Recognition And Self Tolerance & Autoimmune Disease

-immune cell non-reactivity to antigens.

Tolerance can be either:-

a) Self tolerance – Tolerance to innate antigens

c) Neonatal tolerance – Antigens encountered within hours after birth are tolerated

d) acquired tolerance

-The development of self tolerance along with self recognition is key in the maturation of both T and B cells

-To function correctly T cells have to 1) recognise self MHCs (self recognition), and 2) they must display self tolerance).

-B cells also show self tolerance. It is the loss if self tolerance that leads to the autoimmune diseases.

-Normally pre T cells in the thymus develop self recognition via positive selection.

-Self tolerance is acquired by negative selection.

-Of the T cells produced, only 1-5% will become fully mature immunocompetant cells. Deletion of self reactive T cells may also occur after they leave the thymus should they contact an unrecognised self protein.

-B cells also develop tolerance.

Describes a non reactivity to an antigen that should cause an immune response.

Examples

1) Failure of the immune system to destroy sperm and fertilised eggs

2) Oral tolerance. Very important – breakdown of oral tolerance could be linked to inflammatory bowel disease.

Main theory explaining maternal tolerance is the so called EU- FEDS theory.

Sperm cells and egg cells lack MHCs – so cannot be identified as self cells – so should be targeted by the immune system.

Glycoproteins (α – fetoprotein and CA125) and carbohydrates produced in the reproductive system and expressed on gametes may suppress the immune response.

Theory supported by some pathogens expressing similar surface proteins.

Example

HIV-1 expresses gp12 – this resembles CA125 very closely, and could explain the tolerance to the HIV-1 virus.

Hypersensitivity

Describes an over sensitivity of the immune system enabling the inappropriate activation of immune cells.

There are 5 main forms of hypersensitivity:-

1) Type 1

2) Type 2

3) Type 3

4) Type 4

5) Type 5

Related to IgE antibodies and can be transferred by serum.

IgE antibodies bind to antigen and antibody stimulates mast cells.

Mast cells secrete (degranulate) histamines, leukotriens, and prostaglandins. These cytokines induce an inflammatory response in minutes.

In highly sensitive individuals this response can be triggered by antigens that have little effect on others.

Can induce hay fever, asthma and localised urticaria. (example insect bites.

Atopic individuals tend to produce IgE antibodies against more environmental antibodies than do other people.

Can be caused by a range of stimuli, including.

1. Heat, cold and pressure – can lead to urticaria

1. Food – antigens derived from food can interact with IgE antibodies. Chemicals in food may also directly stimulate mast cell degranulation

1. Complement – may aid interaction with IgE antibodies.

1. Associated with anaphylactic shock

Antibodies attach to epitobes on self cells

Induces activation of compliment

Results in vasodilatation and migration of phagocytic cells to the effected tissue.

Promotes activation of membrane attack complex.

Used to refer to antibodies that attacked self blood cells, but now is used to describe antibodies that target other tissues.

Local Form Type 3 Hypersensitivity

If an individual is immunised against an antigen, subcutaneous injection of a high concentration of that antigen induces an inflammatory response peaking within 7 hours at that site.

Example - inhaled spores causing extrinsic allergic alveolitis.

Systemic Form Type 3 Hypersensitivity

Antigen complexes may form systemically – promoting system wide inflammatory responses.

Example – Post infectious glomerulonephritis – antibody complexes become stuck in the glomeruli of the kidney inducing an inflammatory response. Can be caused by any bacterial infection, but most common complication with streptococcal pharyngitis

Related to Helper T cells interacting with activated cytotoxic T cells, NK cells or macrophages.

Response is delayed and cannot be transferred in the serum.

Examples

BCG – injection of inactivated M.bovis will cause a localised inflammatory response after 2 days. Indicates that the individual has already encountered the TB bacillus.

Contact dermatitis

Donor organ rejection

Similar to Type 2 Sensitivity, but instead antibodies target cell receptors, not epitobes.

Examples

Graves disease – antibodies to thyroid stimulating hormone receptors cause thyrotoxicosis

Myasthenia gravis – antibodies target acetylcholine receptors in the postsynaptic membrane. The loss of these receptors inhibits synaptic transmission resulting in muscle weakness and fatigue.

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Autoimmune disease describes any disease state associated with the immune system targeting self antigens.

May be caused by:-

1. A breakdown in B cell self tolerance.

1. A breakdown in T cell self tolerance.

Diseases associated with no obvious infection sometimes mistakenly called autoimmune diseases. Examples include undetected viral infection – virus epitobes are antibody target, so not autoimmune.

Involves B cells that have avoided deletion in the bone marrow not exhibiting anergy. May be caused via 2 mechanisms:-

1. Recognition of mixed self/non self antigens. A non self epitobe may strongly resemble a self epitobe. Could allow the activation of B cells producing plasma cells that secrete antibodies that target both the foreign and native antigen. Called molecular mimicry. Could involve co-stimulation via a self – tolerant helper T cell.

1. Auto-reactive helper T cells could provide co-stimulation allowing the activation of an auto-reactive B cell in anergy

Autoreactive Antibodies

Activation of autoreactive B cells can result in the production of :-

1. Antibodies targeting self antigens as in Type 2 Hypersensitivity

1. Antibody targeting self antigens and forming antigen-antibody immune complexes as in Type 3 Hypersensitivity

1. Antibodies targeting self receptors as in Type 5 Hypersensitivity

Linked to the loss of self tolerance in B cells. Potentially caused by:-

1. Release of material from tissues protected from the immune system – i.e., lens proteins and sperm cells.

2.Highly specialised self cells that occur in small numbers presenting a highly specialised self protein via the MHC1 complex (Class 1 HLA). May form a self antigen that is immunologically invisible to the immune system. However T cells may be produced that are not tolerant of that self protein.

3.Immunologically invisible self antigens could promote T cell anergy, but a closely related viral protein presented by a slightly different MHC1 and MHC2 complex may allow those anergised T cells to escape anergy.

4) Autoreactive cells may be suppressed by cytokines. An infection by a pathogen may activate helper T cells. This could change the balance of cytokines allowing co-stimulation and activation of T cells anergised to self antigens.

-Mostly effects the synovial membrane

-can promote bone erosion and destruction of cartilage.

-Normally presents symmetrically in the small joints – i.e., toes, fingers, wrist etc. However can present asymmetrically.

-Can effect other tissues giving rise to fibrosing alveolitis, vasculitis and scleritis.

-Thought to be caused by molecular mimicry – non-self epitobes resembling self epitobes, thus activating B cells that secrete antibodies that target both self and non-self antigens. However causative antigen has not yet been identified.

Diagnosed by seropositive test for rheumatoid factor (RF).

RF describes IgM or IgG autoantibodies that target the Fc region of IgG antibodies – causing antigen complexes which activate phagocytic cells.

May be treated with TNF-α and interleukin blockers.

Genetic link – genes coding for HLA-DR4 associated with rheumatoid arthritis

ccurs 10 times more commonly in women than men. Typically appears between the ages of 20-40.

Symptoms include fever, weakness, arthritis, skin rash (often with a characteristic butterfly rash over the cheeks and nose), pleurisy and kidney disease.

Systemic Lupus Erythematosus

Typical Type 3 hypersensitivity related autoimmune disease.

Antibody antigen complexes activate the complement system resulting in the formation of membrane attack complex.

Severe SLE causes complement C3a and C5a concentrations in the blood to increase by up to four fold.

C5a causes dilatation of arteries, degranulation of mast cells, chemotaxis in phagocytic cells. C5a also up regulates C5 receptor expression in neutrophils. This aids neutrophil activation.

Diagnosis normally achieved by identification of antinuclear antibodies in blood samples.