How well do the changes of Hashimoto's thyroiditis fulfill the criteria of an immunologic reaction? Neither the presence of autoantibodies in the serum of patients with Hashimoto's thyroiditis nor the demonstration in vitro of cytotoxicity of the serum constitutes definitive evidence that autoimmunity is the cause of the disease. Rarely, if ever, is there a well-defined initial immunizing event, and accordingly a shortened latent period after a secondary stimulus has not been observed. Further, experimental passive transfer of the immune state in normal recipients has not yet been attempted and has failed when human sera have been transfused into monkeys and other animals. This experiment is conducted by nature during pregnancy, since maternal antibodies cross the placenta. Transplacental passage of thyroid stimulating antibodies can produce neonatal thyrotoxicosis, and TSH blocking antibodies can produce transient neonatal hypothyroidism. Passage of TG-antibody or TPO-antibody has no detectable cytotoxic effect. The lack of response to passive transfer of this type of antibody is not surprising, since living syngeneic cells must usually be transferred for the development of experimental thyroiditis. The continuing improvements in assays for T cell reactivity in man, supplemented by data from animal models, provide compelling evidence of the autoimmune basis for Hashimoto’s thyroiditis, but this does not exclude an amplifying role for TG and TPO antibodies via ADCC, and, for TPO antibodies, via complement fixation. It may well be that T cell-mediated damage is required initially for all of these antibody-mediated events to take place, as this could be necessary for such access.
The evidence is now overwhelming that an immune reaction mediated by T lymphocytes is involved in the development of experimental thyroiditis in animals and several mechanisms may operate singly or together in man to injure TECs. Lymphocytes presensitized to antigens of the thyroid are present in the circulation of most if not all patients and are believed to localise to the thyroid itself. Since T cell mediated immunity is frequently lethal to cells, it is logical to assume that the T cell mediated immune response in thyroiditis could cause first a goiter, with lymphocyte infiltration and compensatory thyroid cell hyperplasia, and then gradual cell death and gland atrophy. The circulating antibodies may also be a functional part of this reaction. We can probably accept the idea that T cell mediated immunity is the major pathogenic factor in thyroiditis.
Even before the present era of immunologic study, the basic unity of Hashimoto's thyroiditis and myxedema was realized. To quote from Crile, writing in 1954 (365): "Struma lymphomatosa is responsible not only for large lymphadenoid goiters, but also for fibrosis and atrophy of the thyroid. The clinical spectrum of struma lymphomatosa extends from spontaneous myxedema with no palpable thyroid tissue to a rapidly growing goiter associated with no clinical evidence of thyroid failure."
Hubble (366) also drew attention to the occurrence of syndromes intermediate between those of myxedema and Hashimoto's thyroiditis, in which a small, firm thyroid gland can be felt on careful palpation. The histologic studies of Bastenie (367) and Douglass and Jacobson (368) revealed a close similarity in appearance of the thyroid remnant in myxedema and the Hashimoto gland. The immunologic studies of Owen and Smart (369), and the experience in most thyroid laboratories, indicate a similar incidence and titer of antibodies in myxedema and Hashimoto's thyroiditis. The familial association of myxedema and thyroiditis was described earlier and so far no clear genetic susceptibility difference has been reported in the two diseases. Attempts to ascribe atrophy of the thyroid gland in myxedema to particular antibodies, such as those inhibiting growth or TSH, or which mediate ADCC (370) have not been confirmed by other studies (reviewed in 255).
Thus, idiopathic myxedema is probably the end result of Hashimoto's thyroiditis, in which the phase of thyroid enlargement was minimal or was overlooked. We may assume that in idiopathic myxedema the cell-destructive T cell-mediated immune response is an important pathogenic factor in the illness, and that cytotoxic antibodies and TSH blocking antibodies contribute to the development of hypothyroidism, but perhaps in only a proportion.
Graves' disease is associated with a similar type of thyroid autoimmunity, since most hyperthyroid patients have circulating TG and TPO antibodies. High antibody levels are found in a small group of hyperthyroid patients, and histologic examination of their glands show changes of both cell stimulation and focal thyroiditis (371). Some patients with clinical Graves' disease have tissue changes in the thyroid that are typical of thyroiditis (372). This type of patient with Graves' disease most often becomes hypothyroid after operation (373), after 131I therapy (374), or possibly spontaneously (375). It is also well known that some patients fluctuate from hyper- to hypothyroidism over a period of months and others behave in the converse fashion, and of course the familial association of Graves’ disease with autoimmune hypothyroidism is well established.
The humoral response in Graves' disease leads to production of TG and microsomal TPO antibodies, but most importantly, as described in Chapter 10, B cells produce TSI, TBII and, in some, TSH blocking antibodies (376, 377). TSI stimulate thyroid release of hormone primarily via cyclic AMP, although other pathways may also be activated by TSI in a proportion of patients (378, 379). TSI are true cell stimulators and can even induce experimental goiter. However, the clinical picture in Graves’ disease will be a balance between the stimulation produced by TSI and the opposing effects of any TSH blocking antibodies which may be present. An example of this has recently been reported during pregnancy in Graves’ disease patients; the ratio of stimulatory to blocking antibodies decreases and this may explain the remissions usually seen in the last trimester (380).
Evidence also supports a role for T cell mediated immunity to thyroid antigens in Graves' disease, and against orbital antigens in patients with associated ophthalmopathy. We speculate that Graves' disease may be a condition representing a semistable balance between stimulatory, blocking, and cell-lethal immune responses. Thus, TSI could cause thyroid hyperplasia and produce hyperthyroidism. Other antibodies might block the action of TSI either directly or, as in the case of NIS antibodies, indirectly, and prevent this hyperplastic response in some patients. Cytotoxic T cells will also gradually destroy cells and produce hypothyroidism either spontaneously or after therapy. It must be admitted that the etiology of ophthalmopathy remains obscure, although the key role of cytokines in pathogenesis, causing fibroblast activation, seems firmly established.