Section of Medicine, Experimental Medicine & Therapeutics
negative chronic active hepatitis and in cryptogenic cirrhosis (Tage-Jensen et al. 1977). This may be useful diagnostically, particularly in identifying one type of HBSAg negative chronic active liver disease. The reagents are not currently available.
-855
Professor D S Munro (Temporary Clinical Sciences Centre, Northern General Hospital, Sheffield, S5 7A U) Autoimmunity and the Thyroid Gland
REFERENCES Anderson P, Small J V & Sobieszek A (1976) Clinical and Experimental Immunology 26, 57 Berg P A, Roitt I M, Doniach D & Horne R W (1969) Clinical and Experimental Immunology 4, 511 Bjorneboe M, Prytz H & Orskov F (1972) Lancet i, 58 Cherrick G R, Pothier L, Dufour J-J & Sherlock S (1959) New England Journal of Medicine 261, 340 Cochrane A M G, Thomson A D, Moussouros A, Eddleston A L W F & Williams R (1976) Lancet i, 441 Dehoratius R J, Henderson C & Strickland R G (1976) Clinical and Experimental Immunology 26, 21 Doniach D & Walker J G (1969) Lancet i, 813 Dudley F J, Fox R A & Sherlock S (1972a) Lancet i, 743 Dudley F J, Giustino V & Sherlock S (1 972b) British Medical Journal iv, 574 Eckhardt R, Henisch M & Meyer zum Buschenfelde K H (1976) Scandinavian Journal of Gastroenterology 11, 49 Edgington T S & Chisari F V (1975) American Journal of Medical Sciences 270, 213 Fox R A, Scheuer P J, James D G, Sharma 0 & Sherlock S (1969) Lancet i, 959 Galbraith R M, Smith R M, Mackenzie D-E, Tee D E, Doniach D & Williams R (1974) New England Journal of Medicine 290, 63 Havens W P, Shaffer J M & Hopke C J (1951) Journal of Immunology 67, 347 Hopf U, Meyer zum Buschenfelde K H & Arnold W (1976) New England Journal of Medicine 294, 578 Jacques E A, de Villiers D, Crimmins F, Thomas H C & Sherlock S (1976) Gastroenterology 71, 913 Lindberg J, Lindholm A, Lundin P & Iwarson S (1975) British Medical Journal ii, 77 Mackay I R & Morris P J (1972) Lancet ii, 793 Meyer zum Buschenfelde K H & Miescher P A (1972) Clinical and Experimental Immunology 10, 89 Miller J, Smith M G M, Mitchell C G, Reed W D, Eddleston A L W F & Williams R (1972) Lancet ii, 296 Paronetto F & Popper H (1976) New England Journal of Medicine 294, 606 Roux M E B, Florin-Christensen A, Arana R M & Doniach D (1974) Gut 15, 396 Schalm S W, Summerskill W H J, Gitnick G L & Elveback L R (1976) Gut 16, 781 Sherlock S (1975) Diseases of the Liver and Billiary System 5th edn. Blackwells Scientific, Oxford; p 390 Souhami R L (1972) Immunology 22, 685 Tage-Jensen U, Arnold W, Dietrichson 0, Hardt F, Hopf U, Meyer wm Buschenfelde K H & Nielson J 0 (1977) British Medical Journal i, 206 Thomas H C, MacSween R N M & White R G (1973) Lancet i, 1288 Thomas H C, Ryan C J, Benjamin I S (1976) Gastroenterology 71, 114 Triger D R, Alp M H & Wright R (1972) Lancet i, 60 Triger D R, Cynamon M H & Wright R (1973) Immunology 25, 941
Disturbances of autoimmunity are now identified in many common thyroid diseases. Hashimoto (1912) originally observed extensive lymphocytic infiltration of the thyroid in goitrous hypothyroid patients but it was not until 1957 that Doniach & Roitt (1957) described a circulating antibody to thyroglobulin in patients with Hashimoto's disease. Since then, other thyroid autoantibodies have been characterized and it has been noted that a variable degree of lymphocytic infiltration of the thyroid is found in many patients, who do not necessarily have disturbed thyroid function. This group of euthyroid patients are classified as 'lymphocytic thyroiditis' or 'lymphadenoid goitre'. Lymphocytic infiltration is also a common histological feature in the thyroid gland in Graves' disease. It has been proposed that disorders of thyroid function could be placed in a spectrum ranging from myxcedema at one end of the scale, through 'lymphadenoid goitre', to florid thyrotoxicosis at the other end. In the pathogenesis of thyroid disease it has long been recognized that genetic influences are important (Martin 1945). It has also been demonstrated that thyroid autoantibodies are found with increased frequency in the relatives of patients with thyroid disturbances (Hall & Stanbury 1967, Howell-Evans et al. 1967). So far, information obtained from studies of histocompatibility antigens have not been easy to interpret and advances in the identification of other antigens may be needed before any pattern of linkage emerges. It is also uncertain, at this stage, whether disturbances of T-, B- and K-cell function play an important role in autoimmune thyroiditis. It has been postulated that a deficiency in T cells may be the key factor in initiating the whole process but, ultimately, all three categories of lymphocyte may be involved (Urbaniak et al. 1973, Irvine 1974). Humoral Thyroid Autoantibodies The first thyroid autoantibody to be clearly identified was the antibody to thyroglobulin, originally detected by a relatively insensitive precipitation technique. It is now usual to use the much more sensitive 'tanned red cell' test. Similarly, microsomal antibodies were originally detected by complement fixation but this was displaced in turn by immunofluorescence studies and now by another tanned red cell technique in which the microsomal antigen is used to coat the red cell membrane (Bird & Stephenson 1973). The clinical significance of
856
Proc.
roy.
Soc. Med. Volume 70 December 1977
the second colloid antigen is unclear and the nonspecific antinuclear factor is also of little help diagnostically in thyroid disturbances. It is, however, true to say that the presence of significant levels of the long-acting thyroid stimulator or the long-acting thyroid stimulator protector is a good marker of thyrotoxicosis. Apart from these thyroid stimulating immunoglobulins, high titres of the other thyroid antibodies are not particularly useful diagnostically. Nevertheless, autoimmune thyroiditis may be predicted with confidence when the titres of either the microsomal or the thyroglobulin antibody are very high. Fortunately, there are now sensitive methods for the measurement of thyroid hormones, which simplify the assessment of thyroid function. Thus, whilst the detection of these autoantibodies is of considerable interest, the main clinical implication is that their presence greatly strengthens the clinical diagnosis of autoimmune thyroiditis unsupported by histological evidence, so that operation to confirm the diagnosis may be avoided in most cases. It is particularly important, however, to emphasize that, if carcinoma of the thyroid is suspected, then the presence of high antibody titres should not deter the surgeon from thyroid exploration. It does not appear probable that the circulating antibodies to thyroglobulin or the microsomal antibody play any significant role in the destructive aspects of thyroiditis but, in the case of the thyroidstimulating autoantibodies, there is evidence which suggests that they are responsible for the excessive thyroid activity of Graves' disease. Role of Thyroid-stimulating Autoantibodies in the Pathogenesis of Graves' Disease In 1949, Purves & Griesbach described the thyroid stimulatory effects of the injection of serum from patients with Graves' disease into guinea pigs treated with thyroxine. In contrast to control animals, the thyroids of those receiving thyrotoxic serum showed clear histological evidence of thyroid activation. Confident that there was a humoral thyroid stimulator in Graves' disease, Adams & Purves (1956) showed that the serum of patients with Graves' disease contained a longacting thyroid stimulator (LATS) which caused a sustained discharge of radioiodine from the thyroid glands of guinea pigs treated with thyroxine. The pattern of discharge of radioiodine-labelled thyroid hormone differed in its prolonged time course from the short-acting effects of pituitary extracts rich in thyroid-stimulating hormone (TSH). It was some years before this observation was generally accepted and even longer before it was recognized that the thyroid-stimulating activity in the serum of patients with Graves' disease was associated with immunoelectrophoretically
pure IgG molecules and that the activity could be located in the variable region of the H chain (Smith, Munro & Dorrington 1969, Smith, Dorrington & Munro 1969). The sustained time course of action led to the name long-acting thyroid stimulator (LATS) being adopted and considerable controversy ensued as to whether this particular IgG molecule, which was specifically bound by extracts of human thyroid tissue, was, as appeared to be the case for the other thyroid antibodies, merely the consequence rather than the cause of the excessive thyroid activity in Graves' disease. A major objection to accepting LATS as the sole cause of the hyperthyroidism of Graves' disease was its absence from the serum of some patients with undoubted severe thyrotoxicosis (Chopra et al. 1970). However, the hypothesis received an additional stimulus when Adams & Kennedy (1967) showed that in LATS-negative patients with Graves' disease, there was frequently another type of immunoglobulin G which bound to the same 4S human thyroid binding protein as does LATS-IgG. In various other experimental situations this second type of immunoglobulin, named LATS-'protector' (LATS-P) because of its ability to block LATS binding to its human thyroid-binding protein, has been shown to stimulate the human thyroid. Subsequent papers have used several different terms to describe immunoglobulin-G-associated thyroid-stimulating activity in Graves' disease (Table 1). The work of Smith & Hall (1974), which was developed from the observations of Manley et al. (1974), is of particular interest as they reported that the capacity of IgG, prepared from patients with Graves' disease, to block the binding of labelled TSH preparations to human thyroid membranes, was related to the extent to which adenylate cyclase activity was stimulated in their membrane preparations. Studies are now in progress in different centres attempting to relate measurements by these different methods to each other and it is most important that all experiments are related to the MRC standard for LATS which is available for such studies. Influenced by the very much greater prevalence of LATS-protector, Adams (1975) has claimed that LATS-P is the sole important pathoTable I Nomenclature for thyroid-stimulating activity associated with immunoglobulin G in thyrotoxicosis
Reference Adams & Purves 1956 Adams & Kennedy 1967 Onaya et al. 1973 Smith & Hall 1974
Orgiazzi et al. 1976
Nomenclature Long-acting thyroid stimulator (LATS) LATS-protector (LATS-P) Human thyroid stimulator (HTS)
Thyroid-stimulating immunoglobulin (TSI) Human thyroid adenylate cyclase stimulator (HTACS)
Section of Medicine, Experimental Medicine & Therapeutics
genetic agent in Graves' disease. It has been shown, however, that when LATS is present in a serum sample from a patient with Graves' disease there is, almost invariably, an excess of LATS-protector. Others have expressed the view that it is more likely that both LATS and LATS-P are members of a common population of thyroid autoantibodies to a membrane-bound antigen of the human thyroid, which occasionally will cross-react with the thyroid of mice and cause activation in the McKenzie type of assay, but which, more frequently, can bind to the same human thyroid binding protein but does not stimulate animal thyroids. It is, however, of relatively minor importance in relationship to the broader hypothesis that the excessive thyroid activity of Graves' disease is due to thyroid-stimulating autoantibodies. Direct evidence in support of this hypothesis is clearly difficult to obtain, but Adams et al. (1974) have shown that there is a relationship between LATS-P levels in serum and the rate of radioiodine turnover in patients with thyrotoxicosis. Studies in neonatal thyrotoxicosis have also provided convincing evidence that this self-limiting form of Graves' disease, which occasionally afflicts the newborn children of mothers with a history of Graves' disease, is due to direct maternal to fetal transfer of IgG molecules with thyroid-stimulating properties. Assay of cord and maternal blood, and the measurement of the levels of LATS and LATSP in mothers with a history of Graves' disease, clearly show that this syndrome is likely to occur if a critical thyroid-stimulating antibody titre is exceeded in maternal serum during the third trimester. In a study of 93 mothers with a history of Graves' disease it was possible to predict 12 cases of neonatal thyrotoxicosis prenatally by measurement of LATS and LATS-P levels. No satisfactory explanation has yet been obtained for the association between pretibial myxcedema and LATS (Kriss et al. 1964) and no clear relation between autoimmune disturbances and the ophthalmic manifestations of Graves' disease has been established. We are, clearly, still far from a full understanding of the pathogenesis of disturbances of autoimmunity in thyroid diseases. Nevertheless, study of this gland has been particularly illuminating because of the availability of sensitive methods for assessing the relationship between humoral antibodies and the state of thyroid function. A study of the role of thyroid-stimulating immunoglobulins in relation to the progress of Graves' disease under treatment is urgently needed. It is likely that future
857
advances will come in the area of cell-mediated immune mechanisms from a better understanding of the events which initiate the autoimmune abnormalities. REFERENCES Adams D D (1975) New Zealand Medical Journal 81, 22 Adams D D & Kennedy T H (1967) Journal of Clinical Endocrinology and Metabolism 27, 173 Adams D D, Kennedy T H & Stewart R D H (1974) Journal of Clinical Endocrinology and Metabolism 29, 1502 Adams D D & Purves H D (1956) Proceedings of the University of Otago Medicine School, 34,11 Bird T & Stephenson J
(1973) Journal of Clinical Pathology 26, 623 Chopra I J, Solomon D H, Johnson D E & Chopra N (1970) Metabolism 19, 760 Doniach D & Roitt I M (1957) Journal of Clinical Endocrinology and Metabolism 17, 1293 Hall R & Stanbury J B (1967) Clinical and Experimental Immunology 2, 719 Hashimoto H (1912) Archiv fur klinische Chirurgie vereinigt mit Deutsche Zeitschriftfair Chirurgie 97, 219 Howell-Evans A W, Woodrow J C, McDongall C 0 M, Chew A R & Evans W R (1967) Lancet i, 636 Irvine W J (1974) Proceedings of the Royal Society of Medicine 67, 548 Kriss J P, Pleshakov V & Chien J R (1964) Journal of Clinical Endocrinology and Metabolism 24, 1005 Manley S W, Bourke J R & Hawker R W (1974) Journal ofEndocrinology 61, 437 Martin L (1945) Quarterly Journal of Medicine 14, 207 Onaya T, Kotani M, Yamada T & Ochi Y (1973) Journal of Clinical Endocrinology and Metabolism 36, 859 Orgiazzi J, Williams D E, Chopra I J & Solomon D H (1976) Journal of Clinical Endocrinology and Metabolism 42, 341 Purves H D & Griesbach W E (1949) British Journal ofExperimental Pathology 30, 23 Snith B R, Dorrington K J & Munro D S (1969) Biochimica et biophysica acta 192, 277 Smith B R & Hall R (1974) Lancet ii, 427 Snith B R, Munro D S & Dorrington K J (1969) Biochimica et biophysica acta 188, 89 Urbaniak S J, Penhale W J & Irvine W J (1973) Clinical and Experimental Immunology 15, 345
The following paper was also read:
Immunological Disturbance in Diabetes Mellitus Professor Deborah Doniach (Middlesex Hospital School, London WI)
negative chronic active hepatitis and in cryptogenic cirrhosis (Tage-Jensen et al. 1977). This may be useful diagnostically, particularly in identifying one type of HBSAg negative chronic active liver disease. The reagents are not currently available.
-855
Professor D S Munro (Temporary Clinical Sciences Centre, Northern General Hospital, Sheffield, S5 7A U) Autoimmunity and the Thyroid Gland
REFERENCES Anderson P, Small J V & Sobieszek A (1976) Clinical and Experimental Immunology 26, 57 Berg P A, Roitt I M, Doniach D & Horne R W (1969) Clinical and Experimental Immunology 4, 511 Bjorneboe M, Prytz H & Orskov F (1972) Lancet i, 58 Cherrick G R, Pothier L, Dufour J-J & Sherlock S (1959) New England Journal of Medicine 261, 340 Cochrane A M G, Thomson A D, Moussouros A, Eddleston A L W F & Williams R (1976) Lancet i, 441 Dehoratius R J, Henderson C & Strickland R G (1976) Clinical and Experimental Immunology 26, 21 Doniach D & Walker J G (1969) Lancet i, 813 Dudley F J, Fox R A & Sherlock S (1972a) Lancet i, 743 Dudley F J, Giustino V & Sherlock S (1 972b) British Medical Journal iv, 574 Eckhardt R, Henisch M & Meyer zum Buschenfelde K H (1976) Scandinavian Journal of Gastroenterology 11, 49 Edgington T S & Chisari F V (1975) American Journal of Medical Sciences 270, 213 Fox R A, Scheuer P J, James D G, Sharma 0 & Sherlock S (1969) Lancet i, 959 Galbraith R M, Smith R M, Mackenzie D-E, Tee D E, Doniach D & Williams R (1974) New England Journal of Medicine 290, 63 Havens W P, Shaffer J M & Hopke C J (1951) Journal of Immunology 67, 347 Hopf U, Meyer zum Buschenfelde K H & Arnold W (1976) New England Journal of Medicine 294, 578 Jacques E A, de Villiers D, Crimmins F, Thomas H C & Sherlock S (1976) Gastroenterology 71, 913 Lindberg J, Lindholm A, Lundin P & Iwarson S (1975) British Medical Journal ii, 77 Mackay I R & Morris P J (1972) Lancet ii, 793 Meyer zum Buschenfelde K H & Miescher P A (1972) Clinical and Experimental Immunology 10, 89 Miller J, Smith M G M, Mitchell C G, Reed W D, Eddleston A L W F & Williams R (1972) Lancet ii, 296 Paronetto F & Popper H (1976) New England Journal of Medicine 294, 606 Roux M E B, Florin-Christensen A, Arana R M & Doniach D (1974) Gut 15, 396 Schalm S W, Summerskill W H J, Gitnick G L & Elveback L R (1976) Gut 16, 781 Sherlock S (1975) Diseases of the Liver and Billiary System 5th edn. Blackwells Scientific, Oxford; p 390 Souhami R L (1972) Immunology 22, 685 Tage-Jensen U, Arnold W, Dietrichson 0, Hardt F, Hopf U, Meyer wm Buschenfelde K H & Nielson J 0 (1977) British Medical Journal i, 206 Thomas H C, MacSween R N M & White R G (1973) Lancet i, 1288 Thomas H C, Ryan C J, Benjamin I S (1976) Gastroenterology 71, 114 Triger D R, Alp M H & Wright R (1972) Lancet i, 60 Triger D R, Cynamon M H & Wright R (1973) Immunology 25, 941
Disturbances of autoimmunity are now identified in many common thyroid diseases. Hashimoto (1912) originally observed extensive lymphocytic infiltration of the thyroid in goitrous hypothyroid patients but it was not until 1957 that Doniach & Roitt (1957) described a circulating antibody to thyroglobulin in patients with Hashimoto's disease. Since then, other thyroid autoantibodies have been characterized and it has been noted that a variable degree of lymphocytic infiltration of the thyroid is found in many patients, who do not necessarily have disturbed thyroid function. This group of euthyroid patients are classified as 'lymphocytic thyroiditis' or 'lymphadenoid goitre'. Lymphocytic infiltration is also a common histological feature in the thyroid gland in Graves' disease. It has been proposed that disorders of thyroid function could be placed in a spectrum ranging from myxcedema at one end of the scale, through 'lymphadenoid goitre', to florid thyrotoxicosis at the other end. In the pathogenesis of thyroid disease it has long been recognized that genetic influences are important (Martin 1945). It has also been demonstrated that thyroid autoantibodies are found with increased frequency in the relatives of patients with thyroid disturbances (Hall & Stanbury 1967, Howell-Evans et al. 1967). So far, information obtained from studies of histocompatibility antigens have not been easy to interpret and advances in the identification of other antigens may be needed before any pattern of linkage emerges. It is also uncertain, at this stage, whether disturbances of T-, B- and K-cell function play an important role in autoimmune thyroiditis. It has been postulated that a deficiency in T cells may be the key factor in initiating the whole process but, ultimately, all three categories of lymphocyte may be involved (Urbaniak et al. 1973, Irvine 1974). Humoral Thyroid Autoantibodies The first thyroid autoantibody to be clearly identified was the antibody to thyroglobulin, originally detected by a relatively insensitive precipitation technique. It is now usual to use the much more sensitive 'tanned red cell' test. Similarly, microsomal antibodies were originally detected by complement fixation but this was displaced in turn by immunofluorescence studies and now by another tanned red cell technique in which the microsomal antigen is used to coat the red cell membrane (Bird & Stephenson 1973). The clinical significance of
856
Proc.
roy.
Soc. Med. Volume 70 December 1977
the second colloid antigen is unclear and the nonspecific antinuclear factor is also of little help diagnostically in thyroid disturbances. It is, however, true to say that the presence of significant levels of the long-acting thyroid stimulator or the long-acting thyroid stimulator protector is a good marker of thyrotoxicosis. Apart from these thyroid stimulating immunoglobulins, high titres of the other thyroid antibodies are not particularly useful diagnostically. Nevertheless, autoimmune thyroiditis may be predicted with confidence when the titres of either the microsomal or the thyroglobulin antibody are very high. Fortunately, there are now sensitive methods for the measurement of thyroid hormones, which simplify the assessment of thyroid function. Thus, whilst the detection of these autoantibodies is of considerable interest, the main clinical implication is that their presence greatly strengthens the clinical diagnosis of autoimmune thyroiditis unsupported by histological evidence, so that operation to confirm the diagnosis may be avoided in most cases. It is particularly important, however, to emphasize that, if carcinoma of the thyroid is suspected, then the presence of high antibody titres should not deter the surgeon from thyroid exploration. It does not appear probable that the circulating antibodies to thyroglobulin or the microsomal antibody play any significant role in the destructive aspects of thyroiditis but, in the case of the thyroidstimulating autoantibodies, there is evidence which suggests that they are responsible for the excessive thyroid activity of Graves' disease. Role of Thyroid-stimulating Autoantibodies in the Pathogenesis of Graves' Disease In 1949, Purves & Griesbach described the thyroid stimulatory effects of the injection of serum from patients with Graves' disease into guinea pigs treated with thyroxine. In contrast to control animals, the thyroids of those receiving thyrotoxic serum showed clear histological evidence of thyroid activation. Confident that there was a humoral thyroid stimulator in Graves' disease, Adams & Purves (1956) showed that the serum of patients with Graves' disease contained a longacting thyroid stimulator (LATS) which caused a sustained discharge of radioiodine from the thyroid glands of guinea pigs treated with thyroxine. The pattern of discharge of radioiodine-labelled thyroid hormone differed in its prolonged time course from the short-acting effects of pituitary extracts rich in thyroid-stimulating hormone (TSH). It was some years before this observation was generally accepted and even longer before it was recognized that the thyroid-stimulating activity in the serum of patients with Graves' disease was associated with immunoelectrophoretically
pure IgG molecules and that the activity could be located in the variable region of the H chain (Smith, Munro & Dorrington 1969, Smith, Dorrington & Munro 1969). The sustained time course of action led to the name long-acting thyroid stimulator (LATS) being adopted and considerable controversy ensued as to whether this particular IgG molecule, which was specifically bound by extracts of human thyroid tissue, was, as appeared to be the case for the other thyroid antibodies, merely the consequence rather than the cause of the excessive thyroid activity in Graves' disease. A major objection to accepting LATS as the sole cause of the hyperthyroidism of Graves' disease was its absence from the serum of some patients with undoubted severe thyrotoxicosis (Chopra et al. 1970). However, the hypothesis received an additional stimulus when Adams & Kennedy (1967) showed that in LATS-negative patients with Graves' disease, there was frequently another type of immunoglobulin G which bound to the same 4S human thyroid binding protein as does LATS-IgG. In various other experimental situations this second type of immunoglobulin, named LATS-'protector' (LATS-P) because of its ability to block LATS binding to its human thyroid-binding protein, has been shown to stimulate the human thyroid. Subsequent papers have used several different terms to describe immunoglobulin-G-associated thyroid-stimulating activity in Graves' disease (Table 1). The work of Smith & Hall (1974), which was developed from the observations of Manley et al. (1974), is of particular interest as they reported that the capacity of IgG, prepared from patients with Graves' disease, to block the binding of labelled TSH preparations to human thyroid membranes, was related to the extent to which adenylate cyclase activity was stimulated in their membrane preparations. Studies are now in progress in different centres attempting to relate measurements by these different methods to each other and it is most important that all experiments are related to the MRC standard for LATS which is available for such studies. Influenced by the very much greater prevalence of LATS-protector, Adams (1975) has claimed that LATS-P is the sole important pathoTable I Nomenclature for thyroid-stimulating activity associated with immunoglobulin G in thyrotoxicosis
Reference Adams & Purves 1956 Adams & Kennedy 1967 Onaya et al. 1973 Smith & Hall 1974
Orgiazzi et al. 1976
Nomenclature Long-acting thyroid stimulator (LATS) LATS-protector (LATS-P) Human thyroid stimulator (HTS)
Thyroid-stimulating immunoglobulin (TSI) Human thyroid adenylate cyclase stimulator (HTACS)
Section of Medicine, Experimental Medicine & Therapeutics
genetic agent in Graves' disease. It has been shown, however, that when LATS is present in a serum sample from a patient with Graves' disease there is, almost invariably, an excess of LATS-protector. Others have expressed the view that it is more likely that both LATS and LATS-P are members of a common population of thyroid autoantibodies to a membrane-bound antigen of the human thyroid, which occasionally will cross-react with the thyroid of mice and cause activation in the McKenzie type of assay, but which, more frequently, can bind to the same human thyroid binding protein but does not stimulate animal thyroids. It is, however, of relatively minor importance in relationship to the broader hypothesis that the excessive thyroid activity of Graves' disease is due to thyroid-stimulating autoantibodies. Direct evidence in support of this hypothesis is clearly difficult to obtain, but Adams et al. (1974) have shown that there is a relationship between LATS-P levels in serum and the rate of radioiodine turnover in patients with thyrotoxicosis. Studies in neonatal thyrotoxicosis have also provided convincing evidence that this self-limiting form of Graves' disease, which occasionally afflicts the newborn children of mothers with a history of Graves' disease, is due to direct maternal to fetal transfer of IgG molecules with thyroid-stimulating properties. Assay of cord and maternal blood, and the measurement of the levels of LATS and LATSP in mothers with a history of Graves' disease, clearly show that this syndrome is likely to occur if a critical thyroid-stimulating antibody titre is exceeded in maternal serum during the third trimester. In a study of 93 mothers with a history of Graves' disease it was possible to predict 12 cases of neonatal thyrotoxicosis prenatally by measurement of LATS and LATS-P levels. No satisfactory explanation has yet been obtained for the association between pretibial myxcedema and LATS (Kriss et al. 1964) and no clear relation between autoimmune disturbances and the ophthalmic manifestations of Graves' disease has been established. We are, clearly, still far from a full understanding of the pathogenesis of disturbances of autoimmunity in thyroid diseases. Nevertheless, study of this gland has been particularly illuminating because of the availability of sensitive methods for assessing the relationship between humoral antibodies and the state of thyroid function. A study of the role of thyroid-stimulating immunoglobulins in relation to the progress of Graves' disease under treatment is urgently needed. It is likely that future
857
advances will come in the area of cell-mediated immune mechanisms from a better understanding of the events which initiate the autoimmune abnormalities. REFERENCES Adams D D (1975) New Zealand Medical Journal 81, 22 Adams D D & Kennedy T H (1967) Journal of Clinical Endocrinology and Metabolism 27, 173 Adams D D, Kennedy T H & Stewart R D H (1974) Journal of Clinical Endocrinology and Metabolism 29, 1502 Adams D D & Purves H D (1956) Proceedings of the University of Otago Medicine School, 34,11 Bird T & Stephenson J
(1973) Journal of Clinical Pathology 26, 623 Chopra I J, Solomon D H, Johnson D E & Chopra N (1970) Metabolism 19, 760 Doniach D & Roitt I M (1957) Journal of Clinical Endocrinology and Metabolism 17, 1293 Hall R & Stanbury J B (1967) Clinical and Experimental Immunology 2, 719 Hashimoto H (1912) Archiv fur klinische Chirurgie vereinigt mit Deutsche Zeitschriftfair Chirurgie 97, 219 Howell-Evans A W, Woodrow J C, McDongall C 0 M, Chew A R & Evans W R (1967) Lancet i, 636 Irvine W J (1974) Proceedings of the Royal Society of Medicine 67, 548 Kriss J P, Pleshakov V & Chien J R (1964) Journal of Clinical Endocrinology and Metabolism 24, 1005 Manley S W, Bourke J R & Hawker R W (1974) Journal ofEndocrinology 61, 437 Martin L (1945) Quarterly Journal of Medicine 14, 207 Onaya T, Kotani M, Yamada T & Ochi Y (1973) Journal of Clinical Endocrinology and Metabolism 36, 859 Orgiazzi J, Williams D E, Chopra I J & Solomon D H (1976) Journal of Clinical Endocrinology and Metabolism 42, 341 Purves H D & Griesbach W E (1949) British Journal ofExperimental Pathology 30, 23 Snith B R, Dorrington K J & Munro D S (1969) Biochimica et biophysica acta 192, 277 Smith B R & Hall R (1974) Lancet ii, 427 Snith B R, Munro D S & Dorrington K J (1969) Biochimica et biophysica acta 188, 89 Urbaniak S J, Penhale W J & Irvine W J (1973) Clinical and Experimental Immunology 15, 345
The following paper was also read:
Immunological Disturbance in Diabetes Mellitus Professor Deborah Doniach (Middlesex Hospital School, London WI)
