Infection and autoimmune thyroid disease.

In many different ways, it is difficult to tolerate oneself. But if we fail, autoimmune disease may develop. Immunologically speaking, the body has a number of ways to recognize external danger, and this results in a fierce immune attack on the culprits. These reactions, however, may sometimes go astray and damage not only the external cause of the danger, such as bacteria, but also the endogenous standby—oneself. Luckily, or by design, depending on your point of view, there are multiple controls to help us tolerate ourselves and prevent self-immolation, and only when these systems fail do we develop autoimmune disease. Elimination, via apoptosis, of T and B cells with a high avidity to self is the overall goal that has to be maintained throughout life. This may occur centrally in the thymus (1), where almost all self-antigens can be found at low levels, or peripherally at the site where self-antigens are normally expressed. Any T and B cells that escape early removal are kept suppressed by specific T regulatory cells (2). Some of us are more apt to develop autoimmune reactions than others, and much has been written about the role of genetics and the environment in the susceptibility and subsequent development of these complex disorders. The autoimmune thyroid diseases (AITD) are very common examples of autoimmune disease in our population varying from thyroid overactivity (Graves’ disease) to underactivity (Hashimoto’s thyroiditis) and afflicting up to 10% of the population (3, 4). Familial clusteringofAITD, exemplifiedbyhigh sibling risk ratios (5), can actually be explained by both genetic and/or environmental influences. One of the commonest claims of evidence for the environment being important in the precipitation of AITD is the fact that identical twins are not always in synchrony. Although nonidentical twins have an expected low concordance for AITD of about 2%, identical twins have a concordance of only about 20– 40% rather than 100% (6). These types of data seen in many autoimmune diseases suggest that genes are not the only causative factor. But of course, life is more complicated than such a simplistic approach because the immune systems of identical, monozygous twins are far from identical. The variable (V) genes of T cell receptors and Igs undergo random rearrangements throughout life, and so identical twins become less similar as time goes by and different environmental stimuli are experienced (7). Hence, it is quite amazing that the concordance rate for AITD remains so high in identical twins, and this provides evidence for the powerful effects of non-V genes, such as the major histocompatibility genes, CTLA-4, PTPN22, etc. (8) on susceptibility and development of autoimmunity.However, suchobservations leave roomfor thepossibility that the environment is also an important component in the etiology of autoimmunedisease. Indeed, exploringaunique756 twinpairdata set, Hansen et al. (9) in 2006, using thyroid autoantibodies as a marker for AITD, determined, via structural equation modeling, that only 60–70% of the risk for such markers was genetic. I do not have enough insight to accept the validity of such model-fitting procedures, especially in the absence of family data, but it certainly does appear as though genetics cannot account for all susceptibility to these common thyroid diseases. So this logic leaves the environment as a secondary but likely important cause. And we are very familiar with some environmental precipitants (summarized in Table 1) (10). These include irradiation, as with the children of Chernobyl who developed increased thyroid autoantibodies (11, 12), and radioiodine treatment, which may precipitate Graves’ disease (13), and iodine, itself or within amiodarone, which can precipitate AITD (14, 15). Smoking has also been shown to be an important factor, especially in Graves’ ophthalmopathy (16, 17), and stress, although less well documented, is widely considered a precipitator by its effects on immune reactivity (18, 19). Yet these types of additive causes can account for only a small fraction of patients developing these disorders, leaving more environmental causes to be determined. What about infection (20)? The mechanisms by which infection may, theoretically, induce an autoimmune response are many (Table 2), and this makes infections an attractive hypothesis for disease initiation. Yet here we run into some difficulties because the literature is weak and polluted. The often quoted role of yersinia enterocolitica being associated with, and precipitating, AITD has fallen into disrepute (21), as have reported retroviral infection (22). With such lack of evidence, investigators would normally search for an animal model to strengthen the hypothesis. But here the literature is also