Autoimmunity describes an immune attack against a self antigen (an autoantigen). This results from a failure of tolerance mechanisms to a particular self component. Over 40 autoimmune diseases are recognised, affecting around 3% of the population in developed countries. These are divided into those that are organ specific, and those that are systemic. Although multiple effector mechanisms of adaptive immunity can be activated in autoimmune conditions, typically the main cause of pathology in a particular condition is antibody mediated, cell mediated, or both.


Causes of autoimmunity

Autoimmune conditions are thought to result from the combination of genetic susceptibility and an environmental trigger, however the specific triggers are not known. Concordance in monozygotic twins is between 10-50%, indicating a genetic predisposition but not sufficient in itself to cause disease.

Some rare single gene defects give rise to autoimmunity in individuals with the mutation. These are in components of the immune system involved in tolerance, and therefore alter the ability of the immune system to differentiate ‘self’ from ‘non-self’.

The common genetic contributions to autoimmunity are multigenic, and cause disease in a low proportion of the individuals carrying them. MHC alleles are commonly associated with either protection from or susceptibility to autoimmune diseases. Polymorphisms in costimulatory molecules also have a role.


Mechanisms of autoimmunity

The environmental trigger for most autoimmune diseases is likely to be infection. There are two mechanisms by which this could cause the activation of an autoantigen directed immune response; molecular mimicry or a tissue damage induced breakdown of tolerance.

  • Molecular mimicry: This hypothesis suggests that if an antigen in an infecting organism is similar to a self antigen, the immune response to the organism activates lymphocytes that recognise both the antigen of the infecting organism, and the similar self antigen. The cross-reacting antibodies or T cells then initiate the autoimmune disease.


  • Tissue damage induced breakdown of tolerance: This hypothesis suggests that during infection, sufficient damage to a particular organ can break tolerance of some self-reactive lymphocytes, which continue to respond when the infection has been eliminated, as the autoantigen to which they respond is still present. Tissue damage releases autoantigens that are not normally exposed to the immune system, and can stimulate an autoimmune response, and promote activation of lymphocytes that are reactive to other epitopes in the tissue- this is known as epitope spreading.


Antibody-mediated autoimmunity

Autoimmune diseases can be mediated by autoantibodies, cell mediated responses, or a combination of the two. Autoantibodies can recognise cells or components of extracellular matrix. Autoantibodies cause disease by three mechanisms:

  • Binding to cell surfaces or basement membrane components. Effector mechanisms are then activated through complement and Fc receptors of phagocytes, leading to damage to the cell (similar to type II hypersensitivity reactions).

Examples include autoimmune haemolytic anaemia (Ab to red blood cells), autoimmune thrombocytopenic purpura (Ab to platelets) and Goodpasture’s syndrome (Ab to type IV collagen in the basement membranes of kidney and lung)


  • Forming immune complexes, leading to deposition of complexes, which then activate phagocytes (similar to type III hypersensitivity)


  • Binding of the autoantibody to the autoantigen. This prevents normal function of the cell or tissue involved.

Examples include myasthenia gravis (Ab to nicotinic acetylcholine receptor, prevents binding of acetylcholine and induces degredation of receptors) and Grave’s disease (Ab to TSH receptor, causing continual stimulation of these receptors)

The first and third mechanisms mediate organ specific autoimmune tissue damage. The second mechanism, involving immune complexes, is seen in systemic autoimmune condition, particularly SLE.


Cell-mediated autoimmunity

Less is understood about cell-mediated autoimmunity than autoantibody mediated disease. Typically the antigens involved are more diverse and less well defined, due to epitope spreading. As with antibody-mediated autoimmunity, a breakdown in tolerance causes lymphocytes to recognise and become activated by autoantigens. Some are more prevalent in individuals with certain MHC class I molecules, suggesting CD8 mediated pathogenesis, whereas others are related to MHC class II. Some examples include;

  • Type I diabetes: insulin-producing b cells in the islets of Langerhans in the pancreas are destroyed by cell-mediated attack. Other hormone secreting cells of the islets are spared. Autoantigens implicated in diabetes include insulin and glutamic acid decarboxylase.


  • Autoimmune thyroiditis (Hashimoto’s thyroiditis): cell mediated attack causes inflammation of the thyroid gland, with destruction of the gland leading to thyroid deficiency. Antibodies to various autoantigens in the thyroid are also seen.


  • Multiple sclerosis: lymphocytes target the myelin sheath surrounding nerves in the central nervous system, resulting in demyelination, often in a relapsing-remitting course. Lesions are often focal, suggesting a local triggering process, although non has been identified.


Systemic autoimmunity

Systemic autoimmune conditions comprise a heterogeneous group in which the autoimmune response is not confined to a single organ or system. As with organ specific conditions, there is thought to be a multigenic predisposition and an environmental trigger. For example, reactive arthritis is far more prevalent in individuals with at least one allele of HLA-B27, and is triggered following bacterial infection (gastrointestinal or sexually transmitted infections).


The most common systemic autoimmune disease is rheumatoid arthritis. A CD4 mediated response to autoantigens in the synovium of joints results in inflammation of the joint, hyperplasia of the synovium and infiltration of T cells, B cells and macrophages. The autoantigens of the synovium are not well defined. There is a strong link with HLA-DR4, and MHC II molecule, supporting the importance of CD4 T cells in the pathogenesis of rheumatoid arthritis.


In systemic lupus erythematosus, autoantibodies are formed against nuclear components including dsDNA, histones and nuclear RNA-protein complexes. Immune complexes form, and deposition results in symptoms. Kidney disease is a common complication of SLE, and results from the deposition of anti-dsDNA-DNA complexes in the glomeruli. Local release of nuclear components from apoptotic cells causes other symptoms in SLE, such as photosensitive rashes. 



Nairn R, Helbert M. Immunology for Medical Students. Mosby 2007.

DeFranco A, Locksley R, Robertson M. Immunity. OUP Oxford 2007.



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