A useful example of the contrast between diseases whose destructive mechanism is well understood and a similar condition in which it is much less well understood is Graves' disease and Hashimoto's thyroiditis.

Both diseases affect the thyroid gland specifically, in Graves' the thyroid is hyperactive whereas Hashimoto's results in thyroid hypoactivity.

Graves Disease

This is a rare example of an autoimmune disease which can be transferred with IgG antibodies. Firstly passive transfer of IgG from patients to rats often produces similar symptoms transiently in the animals. Secondly babies born to mothers with Graves' have shown transient symptoms of hyperthyroidism which disappear with catabolism of the maternal IgG (transferred via the placenta) and are relieved by plasma exchange.The disease causing antibodies can be shown to recognise the thyroid stimulating hormone (TSH) receptor and to stimulate thyrocytes in vitro.

Hashimoto's Thyroiditis

This disease is characterised by an intense mononuclear cellular infiltrate into the thyroid and by the presence of autoantibodies primarily directed at thyroglobulin and thyroid peroxidase. There are a number of theories about the mechanism of pathogenic damage to the tissue.

• Autoreactive T cells (T_H1) may cause tissue damage by release of cytokines, either directly (eg TNF) or by recruiting and activating macrophages, which subsequently mediate tissue destruction.
• Autoreactive antibodies, whose production requires the help of autoreactive T cells, may be directly responsible for the pathology, by for example interfering with iodine uptake and binding by thyroglobulin.
• Inflammation may cause tissue damage by triggering apoptosis in thyrocytes by inducing expression of a 'death' receptor (Fas, a molecule which triggers apoptotic death). Unusually the ligand for this 'death' receptor appears to be constitutively expressed by thyrocytes. It is also expressed by activated but not resting T cells.
  Click here to see a cartoon showing how this mechanism might work

Overall, while it is clear that activation of autospecific T cells is a prerequisite for this disease it is far from clear what the significance of the autoantibodies is.

Genetics

Genetic susceptibility plays an important role in almost all autoimmune conditions. The most significant influence is that of the MHC. The linkage between particular MHC allotypes and specific diseases has already been mentioned, in almost all cases these diseases have a strong autoimmune component (and those that don't are likely to be due to non-MHC genes in close linkage).
Click here to see a map showing linkage disequilibrium

With the advent of genome wide linkage maps of polymorphic DNA markers it has been possible to examine the influence of genes on the susceptibility to disease in a comprehensive way. Studies of this type have shown that within the human population there are multiple genetic loci which are involved in susceptibility to common autoimmune conditions such as diabetes (IDDM) and rheumatoid arthritis. It is likely that most autoimmune conditions have some genetic component.

It is important to distinguish these kind of genetic susceptibilities from traditional inherited disease. No single predisposing allele has to be present for the disease to occur, rather the presence of combinations of susceptibility alleles significantly increases the probability of that individual developing the specific disease.

Demonstrating the existence and approximate location of such susceptibility genes is now routine (given sufficient material) but conclusively identifying which of the many genes in the identified genetic interval is actually responsible is much harder and time-consuming. Apart from the MHC very few such loci have been definitely identified.

Added Value
One 'hot' candidate locus for a insulin susceptible diabetes locus is the gene encoding preproinsulin itself. There is a clearly identified genetic polymorphism associated with susceptibility to IDDM mapped to the region in which, among others, the insulin gene lies. It appears that polymorphism in the promoter region of the insulin gene may influence the level of expression of insulin in the thymus, with the susceptible allele expressed at a lower level. This could have an obvious effect on the induction of tolerance to insulin and thus increase the risk of developing autoimmunity.

Endocrine factors

Most autoimmune disease do not occur with equal frequency in males and females. For example Graves' and Hashimoto's are 4-5 times, and SLE 10 times, more common in females while Ankylosing Spondylitis is 3-4 × more frequent in males. These differences are believed to be the result of hormonal influences

A second well documented hormonal effect is the marked reduction in disease severity seen in many autoimmune conditions during pregnancy. Rheumatoid arthritis is perhaps the classic example of this effect. In some cases there is also a rapid exacerbation (rebound) after giving birth.

Environment

However, it is clear that environmental factors also play a role in autoimmune disease. If you examine how frequently identical twins both develop a disease (the concordance rate), it is only about 20-40% for common autoimmune diseases such as diabetes, SLE and rheumatoid arthritis. This makes it highly likely that environmental factors must also be important. While we might expect factors such as diet to play a role, we can postulate that infectious organisms are the most significant environmental factor.

In a few cases we have evidence for a direct link between a specific infection and an autoimmune disease.

The classical example is that of rheumatic fever following Streptococcal infection. More recently, persuasive evidence implicates infection with a variety of organisms (Yersinia, Shigella ,Chlamydia) and reactive arthritis (NB not rheumatoid). Nevertheless a causal link has been elusive in many other conditions for which the environmental factors must exist but remain unidentified (eg. diabetes).

Information provided by: http://www-immuno.path.cam.ac.uk