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Immunology and thyroid ophthalmopathy: where will the footprints lead us?
  1. M J JAGER
  1. Department of Ophthalmology, Leiden University Medical Center, Leiden, Netherlands m.j.jager{at}lumc.nl

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    The real question: why do some people at some time develop an autoimmune disease, is still unanswered. But we can see the footprints in the snow, and learn a lot from these. Immunohistochemical analyses show us the footprints: they illustrate the situation at a certain time. By looking at different moments in time, we may get a better overall picture, although this technique will still leave us with questions regarding the cause of the footprints.

    A frequently occurring autoimmune disease is thyroid autoimmune disease, which often leads to thyroid dysfunction. This disease is considered an autoimmune disease owing to the presence of antibodies and T cell responses directed against thyroid antigens. It is as yet unclear why such immune responses develop, but some predisposing factors have been identified. In the first place, family and twin studies indicate that genetic factors play a part. An association with specific HLA antigens, such as HLA-DR3, has also been found. Since HLA class II antigens have a role in the selection process of the T cell repertoire in the thymus and in the presentation of antigens to T cells, this HLA association suggests that T cells are essential in the development of thyroid autoimmunity. Antibodies have been implicated in the functional disturbances: in particular, the long acting thyroid stimulation antibodies (LATS) may stimulate thyroid cells to produce thyroid hormone and cause hyperthyroidism. Environmental factors have also been identified: a viral infection may trigger acute thyroiditis, perhaps through the induction of local HLA class II expression. Botazzoet al 1 showed aberrant HLA-DR expression on thyroid follicle cells in Graves' disease and in Hashimoto's thyroiditis. Stress may be another external factor that plays a part in the initiation of acute hyperthyroidism. The production of steroid hormones as a result of stress may influence the balance between different sets of T cells.

    Thyroid ophthalmopathy is often associated with thyroid autoimmune disease. Genetic factors are similar to those described for thyroid autoimmune disease. Smoking as an environmental factor increases the severity of thyroid ophthalmopathy. It is clear that the immune system has an important role in the initiation of this disease, but the exact pathogenesis has not yet been defined. The clinical picture is relatively well defined: patients may complain of pain, blurring of vision, pressure behind the eyes, double vision, and irritated eyes. Clinical signs include eyelid oedema, conjunctival injection and chemosis, lid lag, eyelid retraction, proptosis, extraocular muscle dysfunction, corneal exposure, etc. All of these are due to swelling of the various tissues in the orbit and dysfunction of muscles. Deposition of glycosaminoglycans and inflammatory oedema are considered the causes of this swelling. Is there a specific stimulus that causes deposition of glycosaminoglycans in these specific locations? There are suggestions that thyroid stimulating immunoglobulins also play a part in orbital disease: thyroid stimulating hormone (TSH) receptors have also been detected on the surface of cultured orbital fibroblasts. Anti-TSH antibodies might then be the stimulus that induces fibroblasts into making glycosaminoglycans. Autoantibodies against a specific 64 kDa extraocular muscle protein and a 23 kDa fibroblast protein have been described, but such antibodies are also often found in patients without ophthalmopathy. However, antibodies may be a secondary phenomenon caused by the release of tissue antigens following cellular destruction.

    A cellular immune response can also be the basis of the autoimmune ophthalmopathy. The presence of increased numbers of T cells in the orbital tissue especially in patients with early thyroid ophthalmopathy (as described by Pappa et al in this issue of the BJO, p 517) suggests that T cells have a role in the early development of this disease. Pappa and colleagues' article differentiates between early and late thyroid ophthalmopathy. A comparison was made between the cellular infiltrate in the extraocular muscles of five patients with early and nine patients with late thyroid ophthalmopathy, and of 14 healthy individuals. CD4 and CD8 positive T cells were present in the biopsies of early cases, but not in late cases and healthy controls. Expression of HLA-DR was seen on interstitial cells but not on muscle tissue, both in early and late cases. As mentioned earlier, HLA-DR is considered a major inducer of T cell responses. However, HLA-DR was also expressed on biopsies of normal controls, but at a lower level. In addition, stimulation of a T cell immune response can occur through macrophages or dendritic cells, and Pappa and colleagues observed increased numbers of macrophages in the biopsies of early cases compared with the two other groups. The fact that macrophages were also present in the biopsies of normal muscles gives a clue to the initiation of responses: resident tissue macrophages may capture antigen and present it to the immune system, thereby attracting tissue specific autoimmune T cells.2

    Several investigators have shown with various techniques that among peripheral blood lymphocytes from patients with thyroid ophthalmopathy, a subset responds to muscle antigens, but such responses are often not measurable. The best proof would be the isolation from extraocular muscle or the orbit of T cells carrying a specific receptor for muscle or orbital fibroblast specific proteins. One may speculate that this situation is comparable with herpes disease in the cornea, where infiltrating cells show very specific reactions to herpes virus antigens. Such cells can be isolated from the cornea, but their numbers in the peripheral blood are too low to be identified with the present techniques.3 No proof of a viral infection occurs in thyroid ophthalmopathy, but viral disease may have an indirect role in thyroid disease; for example, in patients with mononucleosis infectiosa antithyroid antibodies are frequently observed.

    In conclusion, thyroid autoimmune disease and thyroid ophthalmopathy may both be due to autoimmune T cell responses. Future work will be necessary to determine whether the T cell responses against the already known antigens can be regarded as an epiphenomenon or as a causal response. Following the footprints in the snow may help us to find the real culprit, the cause of this disease.

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