The obese strain (OS) chicken is the animal model which most closely resembles Hashimoto’s thyroiditis, even though the avian immune system is unusual in having a bursa of Fabricus and an absence of lymph nodes. The OS strain was derived from the Cornell C strain (CS) (Cole, 1966) and the OS strain is highly susceptible to development of autoimmune thyroiditis, both strains share the same MHC but the OS spontaneously develops thyroiditis in 95% of the females following sexual maturity. Phenotypically the females are smaller than normal and have long downy feathers and have large subcutaneous fat deposits. Spontaneous autoimmune thyroiditis (SAT) occurs in the OS strain within the first three weeks of hatching and is characterised by a large infiltration of the thyroid gland, hypothyroidism and circulating AAbs (autoantibodies) to Tg from approximately 4 weeks of age. From 6-8 weeks of age germinal centres can be detected which replace functional thyroid tissue and eventually result in gland fibrosis. C3 and IgG deposits which form immune complexes consisting of Tg and anti-Tg AAbs which have been transferred from the mother are present at the basal lamina of the hatchlings thyroid glands
(Katz é?/a/., 1981, 1986, Kofler gr aA, 1983).
It has been shown that T-cells from OS chickens are able to transfer the disease (Livezey
et al, 1981) but B-cells cannot (Polley et al, 1981). OS strain T-cells are also able to transfer disease to the Cornell strain chicken which would otherwise not develop the disease. The CS chicken has the same MHC haplotype as the OS chicken but lack other immunological defects seen in the OS chicken. However pathogenic cells from the OS chicken are not able to transfer the disease to normal strains with the same MHC that have normal thyroid function (Wick et al, 1990). Although B-cells are unable to cause disease themselves, it has been demonstrated that anti-Tg AAbs are able to cause pathological changes that can precipitate the disease in OS chickens (Jaroszewski et al, 1978, Neu et al, 1985). B-cells are intrinsically associated with the pathogenesis of SAT as early bursectomy (Bx) delays the onset and decreases the severity of disease; thus the disease has been shown to be mediated by both B and T-cells.
In common with Hashimoto’s thyroiditis, the OS model develops a polyglandular organ- specific autoimmunity. Accompanying the reactivity to thyroid antigens there is also reactivity to other autoantigens from the gastric mucosa/adrenal gland and pancreas (Khoury
et a l, 1982). The incidence of disease in the OS chicken appears to be linked to a generalised T-cell hyperactivity as indicated by an increase in T-cell proliferative responses, LL-2 production and CD25 expression (Schauenstein etal, 1985), this is also accompanied by a generalised B-cell hyper-responsiveness which accords with the observation that bursectomy in the embryo before hatching reduces the resulting disease severity (Wick et al, 1990). This effect can be replicated by the administration of cyclophosphamide 7-10 days after hatching and results in severe lymphocytic depletion and loss of antibody production. These effects are reversed following repopulation of the bursae with bursa cells (Rose et al, 1981, Bacon & Rose., 1979). In contrast neonatal thymectomy (Tx) has the opposite effect in that it induces maximal thyroid infiltration and high titres of circulating autoantibody (Wick et al, 1974). If this therapy is combined with the administration of turkey anti-chicken T-cell serum, which depleted the circulating T-cells, no SAT and no anti-Tg AAbs developed. Therefore this is evidence that T-cells might promote the appearance of disease or regulate immune cell function and therefore development of disease (De Carvalho et al, 1982).
The disregulation of the OS chicken immune system is suggested by the observation that 0 5 chickens show an imbalance between Th activity and T-cell regulatory activity (Wick
et al, 1985) also OS chickens have a deficiency in the thymic nurse cell population (Boyd
et al, 1984) which are sites of T-cell differentiation (Wekerle & Ketelsen 1980, Kyewski 6 Kaplan 1982), these cells express class II antigens and are involved in the processes of thymic selection. In the OS chicken, there is also a decrease in glucocorticoid production (Fassler et al, 1986) and a deficiency in the neuroendocrine feedback control of the immune
systems response to cytokine. It is also possible that the presence of an endogenous virus ev22 in OS chicken thyroid glands (Wick et al, 1985, 1986) may result in molecular mimicry of thyroid autoantigens which may cause inappropriate antigen specific T-cell activation and thus autoimmunity. These abnormalities together with disordered thymic maturation serve to ensure the incidence of autoimmune thyroiditis in the OS strain chicken is nearly 100% (Rose et al, 1976).
In common with Hashimoto’s patients, thyroglobulin that has been purified from CS chicken thyroid glands and when analysed for iodine content, shows a reduction of iodine content from 46 atoms/molecule (in the normal chicken) to 27 atoms/molecule even when those CS chickens have been provided with a normal level of iodine intake in the diet (Sundick
et al, 1991). This effect is also observed when the chickens are fed on a T4-supplemented diet which would be expected to reduce serum TSH and therefore reduce thyroid hormone secretion. This apparent abnormality of the thyroid gland appears to be present before thyroid infiltration begins. OS chickens injected at hatching with thyroglobulin have no mononuclear cell infiltration and no detectable autoantibodies at three weeks of age (Sanker
et al, 1985) but still have significantly reduced iodine/thyroglobulin ratios when compared to normal hatchlings. The iodine content of CS chicken thyroglobulin has been shown to be intermediate between that of normal chickens and that of OS chickens when maintained on a normal diet. The mechanism by which this defect in iodine metabolism modulates or causes thyroiditis is not known although it has been postulated that iodine levels may affect the immunogenicity of thyroglobulin. Highly iodinated thyroglobulin when injected into normal chickens induces a greater autoantibody response that by poorly iodinated thyroglobulin (Sundick et al, 1987). This has also been demonstrated in the induced mouse model and this will be discussed later in the text. However it has been shown that the autoantibodies produced in the OS chicken react equally well with highly and poorly iodinated thyroglobulin (Sundick et al, 1987); therefore the levels of autoantibody produced in relation to iodine content may be as a result of an effect on Th-cell function.
Although the OS chicken is a good model of human thyroiditis there are some differences; for example in the human, large amounts of inorganic iodide are demonstrable in the gland (Kivikangas et al, 1970 & Jonckheer et al, 1981) and this is not seen in the OS chicken. However this may reflect the fact that studies in man cannot be made before onset of disease so that it is difficult to ascertain the conditions in the gland prior to this; consequently iodination defects have only been described in clinical disease. It has been postulated that an abnormal iodine metabolism may promote thyroiditis through the formation of excess iodine radicals. Free radicals may cause thyroid cell damage directly or through the formation of reactive oxygen intermediates; damage may then lead to thyroid infiltration and the sensitisation of T and B cells. The antioxidant butylated hydroxyanisole has been shown to decrease the severity of thyroiditis in OS chickens (Bagchi et al, 1990); this is evidence that damage by free radicals may be contributory to thyroid damage and may
indicate another role for iodine in the pathogenesis of autoimmune thyroiditis.
In the obese strain chicken, the level of circulating Tg is greatly increased in comparison to the level seen in the parental CS strain. It is interesting to note that neonatal thyroidectomy of OS strain chicken prevents the development of autoimmunity unless normal soluble chicken Tg is administered subsequently, when Tg AAbs can be detected, if the gland is then removed it abrogates established autoimmunity (Bigazzi & Rose 1975); thus there appear to be intrinsic thyroid gland abnormalities which mediate disease. Following on from this it has been shown that the threshold for MHC II induction and expression by interferon-y in OS chickens is much lower than in normal strains and aberrant expression of class II on the chicken thyroid has been demonstrated (Wick et al, 1984). These workers have shown that class II antigens appear in the immediate vicinity of class II positive infiltrating T-cells but they were unable to detect class II antigens on thyroid epithelial cells in OS chickens before infiltration begins. This may have important implications in the induction and/or perpetuation of the disease.
A study by Bagchi et al, (1985) in the Cornell strain chicken has shown that dietary iodine can be causative of the development of thyroiditis. Hatchlings of the CS strain were supplemented with potassium iodide in the drinking water; by 6 weeks, autoantibodies to Tg, T3 and T4 were detected in a majority of hatchlings and by 12 weeks all had developed varying degrees of lymphocytic infiltration of their thyroid glands; this effect was directly related to the level of supplementation in the diet. Supplementation in normal strains, resulted in no autoantibody production. These results taken together indicate that excess iodide may well be important in the induction of thyroiditis but that other factors, not least the MHC, must play a crucial role in predisposition to the development of the disease.
Thyroglobulin prepared from CS chickens on either a high or low iodine diet ( 60 and 13 atoms of iodine/molecule respectively) was assessed for its ability to stimulate the production of autoantibodies. High iodine content Tg stimulated the production of antibodies that bound high iodine content Tg and the thyroid hormones but not low iodine content Tg. Low iodine Tg was a very poor immunogen generating a weak antibody response to high iodine Tg and little or no response to low iodine Tg, T4 and T3. Therefore the CS chicken appears to be tolerant to Tg that has a low iodine content even if it is administered when there are normal levels of iodine in the diet. By contrast obese strain chickens on a normal diet produce anti-Tg autoantibodies which are equally reactive to high or low iodine Tg, on a low iodine diet the levels of autoantibodies to high iodine Tg are reduced but those to low iodine Tg are maintained. Therefore the incidence of thyroiditis and autoantibodies in the OS strain chicken may be unrelated to the intrathyroidal levels of iodine.