Studies on Long-Acting Thyroid Stimulator (LATS) as Immunoglobulin

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LATS 1, 2) which was found in the sera of patients with Graves'disease may play an important role in pathogenesis of the disease. Recently, it has been suggested that the LATS might possibly be an antibody to thyroid3). In the present paper, we describe our data relating the hypothesis. (A) Association of LATS activity with IgG 4) . (1) Isolation of LATS. LATS present in the serum of patients with Graves' disease was separated by means of column chromatography. More than a half of the original LATS activity, which was determined by Mckenzie's bioassay 2) , appeared in an unabsorbed fraction obtained when the serum passed initially through a DEAE-Sephadex column (0.02M sodium phosphate buffer, pH 6.6). Average specific LATS activity (LATS activity/protein concentration) of this fraction was thus 6 times that of the original serum. The protein in this fraction was identified by immunoelectrophoresis as IgG. When this fraction was passed through a carboxymethyl cellulose (CM-C) column, the specific LATS activity was relatively higher in the slowereluting fractions, thus the highest specific activity in one of the fractions was 30-40 times that of the original serum. These CM-C fractions formed a single IgG precipitin arc with different electrophoretic mobilities on immunoelectrophoresis. (2) Neutralization of LATS by anti-IgG 4) . LATS activity in IgG fractions was specifically neutralized by anti-IgG serum and not by anti-IgA or anti-IgM serum.(B) LATS production by lymphocyte culture 5) . Peripheral lymphocytes separated from leucocytes obtained from the patients with Graves' disease or normal subjects were cultivated with or without phytohemagglutinin (PHA) for 5 days at 37°C. Following the culture of lymphocytes with PHA, more than 80% of the cells were transformed into "blast cells" and a 14C-amino acid was incorporated into the IgG fraction in the medium with culture. Significant LATS-like activity was detected in the culture media obtained when lymphocytes from the patients with Graves'disease were cultivated with PHA. Neither LATS-nor TSH-like activity was detected in the control culture media; i. e. 1) When lymphocytes from patients with Graves'disease were cultivated without PHA, 2) When lymphocytes from normal subjects were cultivated with or without PHA, 3) When the medium containing no lymphocytes was incubated with or without PHA. The LATS-like activity in the medium with culture was identified as LATS by the following findings: 1) When various doses of the medium with culture were assayed, LATS type responses were observed, and an approximately linear relationship was obtained between the injected dose and response. 2) The greatest portion of the activity was found in the IgG fraction which was separated by DEAE-Sephadex chromatography. 3) The activity was mostly neutralized with anti-IgG serum. From these findings, it seems reasonable to suggest that LATS originates from antibody-forming tissues in Graves'disease. (C) Other findings relating to the hypothesis that LATS is an antibody. (1) Oral glucocorticoid therapy resulted in a marked fall in plasma LATS concentration3). A similar result was obtained and, in addition, a significant decrease of LATS was observed following administration of 6-MP (20mg/day). (2) Concentration of immunoglobulins (IgG, IgA and IgM) in the sera of the patients with Graves' disease remained within the normal range. There was no relationship between the concentration of immunoglobulins and LATS.(D) Efforts to isolate antigen (s) to LATS. (1) No difference in incorporation to mouse organs was observed between 131I-LATS IgG and 125I-normal IgG. (2) No correlation was observed between LATS activity and titer of anti-thyroid antibodies (TRC, CF and cytotoxic factor).
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Studies on Long-Acting Thyroid Stimulator (LATS) as Immunoglobulin

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