V. V. Row

Biological activity of lymphocytotoxic antibodies in Graves’ disease and Hashimoto’s thyroiditis

Sera of 48 patients with Graves’ disease (GD) and 23 with Hashimoto’s thyroiditis (HT) were tested for lymphocytotoxic (LCT), granulocytotoxic (GCT) and monocytotoxic (MCT) activity. In GD, 12 patients (25%) had cold-reacting LCT and 13 patients (27%) had warm-reacting LCT. LCT were cytotoxic to both B and T cells but the majority of sera with cold-reacting LCT and eluates from lymphocytes were more cytotoxic to B lymphocytes. Warm-reacting LCT were directed exclusively against B cells. LCT did not correlate with peripheral lymphocyte counts, antithyroglobulin or antimicrosomal antibodies, sex, age, pregnancies, thyroid status or medication. However the mean duration of the disease was 15 months in LCT positive group and 55 months in LCT negative group (p < 0.01). Weak GCT were found in 8 of 35 sera (23%). Six of 33 sera (18%) contained cold-reacting MCT and 9 (27%) had warm-reacting MCT. Some cytotoxins were directed against several types of cells as evidenced by cytotoxicity of eluates from lymphocytes against PMN and/or monocytes. Of 23 patients with HT, 11 (48%) had cold-reacting LCT. None had warm-reacting LCT. Sera and eluates from lymphocytes showed predominant cytotoxicity toward B cells. No correlation to the presence of antibodies, sex, age, pregnancies, thyroid status or medication was detected. Four of 23 sera had weak cold-reacting GCT, 5 had cold-reacting MCT which killed on average 31 % of monocytes and 4 had weak warm-reacting MCT. Twelve of 22 sera from GD and HT had cytotoxic activity against thyroid cells (TCT). TCT correlated with LCT at p < 0.05. Eluates from lymphocytes had TCT activity but the supernatants devoid of LCT activity retained TCT as well. Thus the identity of LCT and TCT cannot be proven at the present time. None of 4 tested sera reacted with glycolipids. Although the clinical significance of cytotoxins is unknown, their presence in the early stages of GD may mean that their production is altered by either the natural course of the disease or by therapy. Cytotoxins should be taken into consideration while investigating immunologic abnormalities in thyroid diseases.

Sensitization of T lymphocytes to thyroid antigen in autoimmune thyroid disease as demonstrated by the monocyte procoagulant activity test

Monocyte procoagulant activity (PCA) production has been reported to have a close relation to cell-mediated immunity (CMI), and the collaboration of T lymphocytes is necessary to induce PCA. Antigen-specific sensitization of lymphocytes in patients with Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) has been demonstrated by means of the production of cell-bound PCA by monocytes following antigen stimulation of whole peripheral blood mononuclear cells (PBM). These cells, obtained from both normal subjects and patients with autoimmune thyroid diseases, produced significant amounts of PCA with non-specific lectin, concanavalin A (Con A) stimulation; however, there was no significant difference between the two groups, suggesting that Con A stimulated T cells induced monocyte PCA nonspecifically. Peripheral mononuclear cells from patients with autoimmune thyroid diseases produced significantly greater amounts of PCA than PBM from normal subjects when stimulated with solubilized and IgG-free thyroid antigen. On the other hand, liver antigen did not induce significant amounts of PCA production in PBM from either normal subjects or patients. Significantly larger amounts of PCA were produced by PBM from patients following thyroid antigen stimulation than with liver antigen stimulation. Although monocytes were the major source of PCA, T cells were necessary to induce PCA in monocytes with thyroid antigen and Con A stimulation. Elimination of lymphocyte subsets in PBM from patients by negative selection (using monoclonal antibodies and complement) suggested that the collaboration of T lymphocytes, especially helper/inducer (T4+) T cells, was necessary to produce PCA with thyroid antigen stimulation. These data provide evidence that patients with autoimmune thyroid disease have sensitized T (helper/inducer) lymphocytes to thyroid antigen, which can induce monocyte PCA with thyroid antigen stimulation.

ANTIGEN-SPECIFIC SUPPRESSOR CELL FUNCTION AND AUTOIMMUNE DISEASES

compared these with the clinical presentation (table). Amongst these, 188 cases of intraduct carcinoma were found, in 42 of which there was no definite evidence of invasion. Of these 42, 16 were associated with a breast lump alone, 11 with Paget’s disease (2 also with a lump), and 15 with a nipple discharge which was bloodstained in only 11 (7 with a palpable lump). The majority (62%) of cases of intra duct carcinoma in situ were therefore detected by association,with Paget’s disease or nipple discharge. Moreover, in both these groups of patients there was a high ratio of in-situ to invasive tumours whereas in-situ carcinoma without invasion is rare

IMMUNOMODULATORY EFFECT OF THE TREATMENT OF GRAVES’DISEASE ON ANTIGEN‐SPECIFIC MONOCYTE PROCOAGULANT ACTIVITY PRODUCTION

The monocyte procoagulant activity (PCA) production assay has been shown to be a good parameter of cell‐mediated immunity. We have studied antigen‐specific PCA production in peripheral blood mononuclear cells from patients with Graves’disease to determine the effect of the treatment on the cell‐mediated immune response. Peripheral blood mononuclear cells from patients with untreated or relapsed Graves’disease produced significantly greater PCA with thyroid antigen stimulation than those from normal subjects. Patients both on antithyroid drugs in the hyperthyroid state and within 3 months post‐131I therapy also produced significantly larger amount of PCA than normal subjects. However, there was no significant difference in PCA production with thyroid antigen stimulation between normal subjects and patients on anti‐thyroid drugs in the euthyroid state, or patients over 3 months post‐131I therapy. The ratio of positive to negative PCA production in patients on anti‐thyroid drugs in the euthyroid state or over 3 months post‐131I therapy was significantly lower than in untreated or relapsed Graves’disease patients. Mononuclear cells from patients on propylthiouracil responded to propylthiouracil in vitro by production of PCA. Cells from normal subjects, untreated Graves’disease patients, or patients with Hashimotos thyroiditis did not produce PCA with propylthiouracil stimulation. Mononuclear cells from patients who were on propylthiouracil for more than 3 months produced greater PCA than those on the drug for less than 3 months, suggesting sensitization of lymphocytes to propylthiouracil during the course of treatment. However, after 131I therapy, they gradually became unresponsive to propylthiouracil. This study has shown that the activity of the antigen‐specific response assessed by PCA production in mononuclear cells from Graves’disease patients declined after treatment, suggesting that the treatment exerted immunomodulatory effects.