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particular, the complement-fixing antibodies reacting with thyroid microsomal antigens. An alternative in vitro test for the presence of soluble immune complexes is the inhibition of K cell cytotoxicity as described by Jewell & MacLennan (1973) which has been used to detect complexes in patients with ulcerative colitis or Crohn's disease. Soluble immune complexes inhibit LDA cytotoxicity by competing for the Fc receptor on the effector cytotoxic K cell. Current experiments of Calder, Penhale & Irvine (1974) using this technique have shown that serum from patients with Hashimoto thyroiditis, when compared with serum from age and sex matched control subjects, causes a significant inhibition of LDA cytotoxicity. This data would again suggest that patients with Hashimoto thyroiditis possess circulating soluble immune complexes. As with the anticomplementary assay, however, this test gives no indication of the exact chemical nature of the immune complex and one can only hypothesize as to the nature of the antigenic component involved.

To summarize: evidence exists that in vitro K cells have a high cytotoxic potential. It is possible that in vivo these cells are actively involved in the production of thyroid cell damage in patients with autoinmune thyroid disease in one or other of two ways. First, in the target organ the coating of tissue with autoantibody will render them susceptible to K-cell-mediated lysis. Alternatively, the presence of immune complexes in antibody excess in thecirculation could activate quiescent K cells, giving them the specificity to destroy thyroid target cells. REFERENCES Calder E A (1974) Proceedings ofthe Royal Society ofMedicine 67, 502 Calder E A, MeLeman D & Irvine W J (1973) Clinical and Experimental Immunology 15, 467 Calder E A, Penhale W J, Banes E W & hrvine W J (1974) British MedicalJournal i, 30 Calder E A, Penhale W J & Irvine W J (1974) (in preparation) Calder E A, Penhale W J, MLeman D, Barnes E W & Irvine W J (1973) Clinical and Experimental Immunology 14, 153 Coombs R R A & Franks D (1969) Progress in Allergy 13, 174 Fahlri 0 & Hobbs J R (1972) Lancet ii, 403 JeweD D P & MacLennan I C M (1973) Clinical and Experimental Immunology 14, 219 MacLennan I C M (1972) Transplantation Reviews 13, 67 MacLennan I C M & Loewi G (1968) Nature (London) 219, 1069 Moiler E (1965) Science 147, 873 Moller G & Svehag S E (1972) Cell Immunology 4, 1-19 Mowbray J F, Hoffbrand A V. Holborow E J, Seah P P & Fry L (1973) Lancet i, 400 Perimann P & Holm G (1969) Advances in Immunology 11, 117 Perlmann P, Perlmann H & Miller-Eberhard H J (1973) International Archives ofAllergy and Applied Immunology 45,

12 Dr P Kendall-Taylor,1 Dr Susan M Diikis and Professor D S Munro (Clinical Endocrinology, Clinical Research Institute, The Royal Infirmary, Sheffield, S6 3DA)

Long-acting Thyroid Stimulator and Related Factors There is much circumstantial evidence that Graves' disease is an autoimmune disorder and that the hyperthyroidism may result from stimulation by thyroid-specific antibodies. This paper deals with two abnormal immunoglobulins, associated with the disease, which are of particular interest in this context: the long-acting thyroid stimulator (LATS), and the more recently discovered LATS protector, which may be a human-specific thyroid stimulator. Long-acting Thyroid Stimulator LATS is an IgG, which can be shown to stimulate the thyroid in man and experimental animals, the activity being associated with the Fab fragment and with the heavy chain. The LATS binds to a 4S protein, probably located in the plasma membrane in human thyroid homogenates and this binding can be reversed by acid elution or by treatment with thiocyanate, with recovery of the LATS activity.

LATS is usually detected by bioassay using its capacity to stimulate release of 1811 from prelabelled mouse thyroid glands as the index of activity. Although chemically and immunologically quite distinct, the actions of thyroidstimulating hormone and LATS on the thyroid are very similar and both are mediated by cyclic adenosine monophosphate; the only real difference appears to be the longer time course of action of LATS and this can be demonstrated in both in vivo and in vitro systems. For these reasons it was postulated that LATS is an autoantibody which interacts with and stimulates the human thyroid, so causing the hyperthyroidism of Graves' disease. However, it can only be detected in some, not all, patients with the disease so it is unlikely that LATS is the sole cause of the hyperthyroidism.

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LATS-protector In 1967 Adams & Kennedy reported an inhibitory effect of LATS-negative serum on the binding of LATS to human thyroid protein (HTP)- it protected LATS from neutralization by the binding protein. The interval that elapsed before this finding was confirmed in other

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'Present address: Wharfedale General Hospital. Otley, LS21 2LY

Ringertz B, Wmserman J, Packalen T L & Perlmann P (1971) International Archives ofAllergy and Applied Immunology

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It is clear then that LATS-protector is closely associated with Graves' disease. It interacts specifically with human thyroid tissue; unlike LATS it neither binds to, nor stimulates, the mouse thyroid.

6050-

U640 0seum

30

i 20

I0 Controld LATS

H

Fig 1 Release of 3'Ilfrom mouse thyroids maintained in organ culture (Brown & Munro 1967). Binding of LATS by HTP was inhibited by serum 1, indicating presence ofLATS-protector. Serum I did not contain detectable LA TS. Serum 2 contained neither LATS norLATS protector

laboratories is probably an indication of the importance of establishing suitable assay conditions. Fig 1 demonstrates, in a representative experiment, that the amount of HTP added should almost, but not entirely, neutralize the LATS activity. When the mixture of LATS+ HTP+serum 1 was assayed, thyroid stimulation resulted, indicating the presence of LATSprotector, whereas serum 2 did not contain demonstrable LATS-protector. The sensitivity of detection of LATS-protector is improved when the LATS negative serum is preincubated with HTP before the addition of LATS, but the temperature for preincubation is not critical.

Using this method, LATS-protector can be detected in unconcentrated serum from the majority of patients with Graves' disease (see Table 1) and is found in a much higher proportion than is LATS; it has been found in serum of patients receiving carbimazole. It has not been found in serum or in immunoglobulin concentrates from 32 normal subjects, in 14 patients with nontoxic nodular goitre or 12 with Hashimoto's disease, nor in 4 patients whose disease appears to have remitted. It is sometimes possible to demonstrate LATS-protector in serum which also contains LATS. Table I Patients with Graves' disease LATS Hyperthyroid - no treatment 6 2 Hyperthyroid - recurrent 5 Euthyroid - carbimazole

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Nega-

LATS-P tive 33 7 18 0 3 10

Total 46 20 18

61

84

10

Recent work has been directed to determining whether LATS-protector stimulates the human thyroid. Thyrotoxic LATS-negative Ig did not activate human thyroid adenycyclase whereas LATS did (Kendall-Taylor 1973) but, in contrast to this, Onaya et al. (1973) found that LATSnegative serum stimulated cyclic AMP accumulation in thyroid slices in vitro. They also found, as did Shishiba et al. (1973), an increase in colloid droplet formation. However, the most definitive evidence is the personal observation of Adams that injection of LATS-protector increased thyroid function of man in vivo (Adams et al. 1974).

The evidence strongly suggests that hyperthyroid serum contains an IgG distinct from, and perhaps additional to, LATS, which stimulates the human thyroid. This is probably the same as LATS-protector and might better be termed human-specific thyroid stimulator. REFERENCES Adams D D & Kennedy T H (1967) Journal of Clinical Endocrinology 27, 173 Adams D D et al. (1974) Journal of Clinical Endocrinology and Metabolism (in press) Brown J & Munro D S (196.7)Journal of Endocrinology 38, 439 Kendall-Taylor P (1973) British Medical Journal iii, 72 Onaya T, Masanobu K, Takahi Y & Ochi Y (1973) Journal of Clinical Endocrinology and Metabolism 36, 859 Shishiba Y, Shimizu T, Yoshimura S & Shizmne K (1973) Journal of Clinical Endocrinology and Metabolism 36, 517

Dr T Hjort and Dr S Husted

(Institute of Medical Microbiology, University ofAarhus, 8000 Aarhus C, Denmark)

Autoimmunity to Sperm Experience from animal experiments suggests that autoimmunity to spermatozoal antigens includes two main aspects: lesions in the spermproducing tissue in the testes and immune reactions affecting spermatozoa in the seminal plasma. However, in man the existence of a naturally occurring autoimmune orchitis has never been proved. Furthermore the role played by cell-mediated immunity has not been clarified, so that the discussion may be limited to the question of spermatozoal antibodies in serum and seminal plasma.

Long-acting thyroid stimulator and related factors.

252 Proc. roy. Soc. Med. Volume 68 April 1975 particular, the complement-fixing antibodies reacting with thyroid microsomal antigens. An alternative...
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