Clinical Endocrinology (1 979) 1 1, 59-68.

EVIDENCE FOR THYROID ANTIGEN-REACTIVE T LYMPHOCYTES I N F I L T R A T I N G T H E T H Y R O I D G L A N D IN GRAVES’ DISEASE T . H. T O T T E R M A N , L. C. A N D E R S S O N A N D P . H A Y R Y

Transplantation Laboratoiy, Fourth Department of Surgery, University of Helsinki, Finland (Received 15 September 1978; revised 29 November 1978; accepted 5 December 1978)

SUMMARY

We have investigated the relative distribution and some in vitro functions of thyroidinfiltrating immunocompetent cells obtained at fine-needle aspiration biopsy in twelve patients with Graves’ disease and thirteen patients with Hashimoto’s thyroiditis. In both disorders the predominant (5749%) thyroid-infiltrating cell was a small lymphocyte. Significant numbers of plasma cells (10%) were seen only in Hashimoto’s thyroiditis. Mononuclear phagocytes (monocytes plus macrophages) were present in similar numbers (12-18%) in both disorders. In both Graves’ and Hashimoto’s disease there was a relative reduction of (thymus-dependent) lymphocytes in the thyroid gland as compared t o the blood. Blood and thyroid-infiltrating T lymphocytes were tested for in vitro cell-mediated immunity (CMI) t o thyroid antigen in the leucocyte migration inhibition test (LMT). CMI was readily demonstrated in the blood of most patients with Graves’ and Hashimoto’s disease. When the thyroid-infiltrating lymphocytes were tested for CMI in the LMT, only the infiltrating cells from patients with Graves’ disease displayed CMI, whereas the thyroidinfiltrating lymphocytes in Hashimoto’s disease were negative. Fractionation of the immunocompetent cells demonstrated that the thyroid antigen-induced LMT response of blood and thyroid-infiltrating lymphocytes in Graves’ disease is a T lymphocytedependent phenomenon. Most attempts to investigate the role of thyroid antigen-directed cell-mediated immunity (CMI) in human autoimmune thyroid disease have hitherto involved the study of cellular and humoral elements of the peripheral blood. Several recent studies have indicated normal relative and absolute numbers of circulating thymus-dependent (T) and bursaequivalent (B) lymphocytes in patients with Graves’ and Hashimoto’s disease (Calder & Irvine, 1975). Buchanan et al. (1958) first presented evidence for CMI to thyroid homogenate in Hashimoto patients using skin tests. This was confirmed by Sdborg & Halberg (1968) who applied the leucocyte migration inhibition test (LMT) of Sbborg & Bendixen (1967) as an in vitro test for CMI. Lamki et al. (1973) demonstrated positive LMTs t o thyroid antigens in patients Correspondence: T . 11. Totterman, M.D., Wallenberg Laboratory, Dept. of Tumour Biology, University of Uppsala, P.O.Box 562, S-751 22 Uppsala, Sweden.

03004664/1979/00104059$02.00

0 1979 Blackwell Scientific Publications

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T. H. Totterman et al.

with Graves’ disease. Several later studies have confirmed the presence of anti-thyroid CMI in the blood of patients with thyroid disorders expressing humoral autoimmunity (Calder & Irvine, 1975) although negative results have also been reported (Matsui et al., 1977). In Hashimoto’s and Graves’ disease the thyroid gland is infiltrated with lymphocytes (frequently organized as germinal centres) along with plasma cells and macrophages ( N h e et al., 1972; Bonnyns et al., 1972), and the two disorders may coexist in the same gland (Bonnyns et al., 1972). Very little is known about the subclass distribution and possible pathogenic role o f thyroid-infiltrating immunocompetent cells in human autoimmune thyroid disease, We have recently developed methods which allow morphological identification of different subclass marker-carrying lymphocytes from very small cell samples (Ranki et al., 1976). Using thyroid fine-needle aspiration biopsy we have demonstrated a relative enrichment of B lymphocytes in the thyroid gland of patients with juvenile autoimmune thyroiditis (Totterman et al., 1977), Hashimoto’s thyroiditis (Totterman, 1978) and Graves’ disease (Totterman, 1978). In subacute thyroiditis (de Quervain) the thyroid gland was invaded almost exclusively by T lymphocytes (Totterman, 1978; Totterman et al., 1978). When thyroid-infiltrating lymphocytes were tested for CMI t o thyroid antigen in the LMT, positive responses were observed in all patients with subacute thyroiditis (Totterman et al., 1978) but not in patients with juvenile autoimmune thyroiditis (Totterman et al., 1977). In the present study we have tested the ability of thyroid-infiltrating T lymphocytes t o express antithyroid CMI in patients with Graves’ disease and Hashimoto’s thyroiditis. It was found that T lymphocytes infiltrating the gland in Graves’ disease exhibit a far stronger inhibitory effect upon migration of autologous leucocytes than d o blood T cells. In Hashimoto’s thyroiditis the thyroid-infiltrating T cells seem t o be negative in this respect. MATERIALS AND METHODS

Patients and controls Twelve patients with Graves’ disease (mean age 3 7 ; range 18-64) were studied. The dirlgnosis was based on clinical symptoms and signs according t o Lamberg et al. (1969) as well as on established laboratory findings indicating hyperthyroidism. At the time of testing, eight patients were hyperthyroid and four were euthyroid on treatment with carbimazole. All patients had a diffuse goitre. Thirteen cases o f Hashimoto’s thyroiditis (mean age 41; range 20-67) were studied. They all fulfilled the following diagnostic criteria (Nbve et al., 1972): abundant lymphocytes and Hurthle cells in fine-needle biopsy, a firm goitre and significantly elevated thyroid autoantibody titres, i.e., anti-thyroglobulin antibodies 2 1/25 000 (Roitt & Doniach, 1958) and/or anti-microsomal antibodies 2 1/10’ (Perrin & Bubel, 1974). All were euthyroid on substitution therapy with thyroxine. Twenty healthy persons from the laboratory staff showing no signs or symptoms of thyroid disease served as controls in the LMT (see below). Collection and preparation of thyroid-infiltrating lymphocytes A fine-needle aspiration biopsy was performed on both thyroid lobes of the patients using a 0.7 mm in outer diameter needle. Part of the aspirate was immediately spread onto microscope slides for MayGruenwald-Giemsa and histochemical staining (see below). The rest was diluted in 3 ml of a medium consisting of phosphate-buffered saline (pH 7.2) with 0.55% bovine serum albumin, preservative-free heparin (1 2.5 IU/ml) and 2.5 mM Hepes buffer

T Lymphocytes iiz Graves’ disease

61

(Sigma Co., USA). The degree of blood contamination was calculated from the thyroid and blood smears as follows: lymphocytes/polymorphonuclear leucocytes in thyroid aspirate Index of blood contamination (IC)= lymphocytes/polymorphonuclear leucocytes in blood Biopsies with an IC less than 3.0 were not considered representative (Totterman et al., 1977). The mononuclear white cells were separated from erythrocytes and thyroid parenchymal cells by density centrifugation over Ficoll-Isopaque (Ficoll-Paque, Pharmacia, Sweden) according to Bdyum (1968). It has previously been shown that no subclass-specific cell losses take place during this purification (Totterman et al., 1977). The yield was 0.3-4.0 X lo6 of infiltrating mononuclear cells per patient.

Identification of T lymphocytes T cells were quantitated histochemically from smears of blood and thyroid aspirate by their acid a-naphthyl acetate esterase (ANAE) activity (Ranki et al., 1976). Leucocyte migration inhibition test (LMT) The LMT of Sdborg & Bendixen (1967) was slightly modified as described previously (Makinen et al., 1977), and used as an in vitro test for CMI. Thyroid homogenate of Graves’ disease goitre obtained at operation was used as antigen in a concentration of 360 pg of protein per ml of culture medium. A similarly prepared human uterine smooth muscle homogenate (obtained at operation for myomata) served as control antigen in the LMT and was used in a concentration of 400 jg/ml. The optimal concentrations of the antigens were determined in the following way (Bendixen et al., 1976): thyroid patients and healthy subjects were tested simultaneously in the LMT with increasing concentrations of antigen. The dose of antigen giving the greatest difference in migration index (see below) between patients and controls without inhibiting the leucocyte migration of the controls (the highest ‘nontoxic’ antigen concentration) was chosen for further experiments. The migration areas were measured by planimetry, and the results calculated as follows: mean area of migration with antigen

x 100

Migration index (MI) % = mean area of migration without antigen

When LMT’s were performed with thyroid-infiltrating lymphocytes, the small cell yield necessitated mixing of infiltrating lymphocytes with autologous blood leucocytes at ratios 1:6, 1:12, 1:20, 1:50, and 1:lOO. The control migration without antigen was performed with mixtures containing the highest proportion of thyroid-infiltrating lymphocytes indicated.

Depletion of T lymphocytes in the LMT The role of T lymphocytes in the antigen-induced leucocyte migration inhibition was investigated by removing the T cells from the leucocyte suspension prior to the LMT in the following way: The defibrinated blood (Makinen er al., 1977) was centrifuged over Ficoll-

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T. H . T o t t e m a n et al.

lsopaque and the lymphocytes were collected from the interface. The bottom fraction was mixed with an equal volume of Macrodex@ (Dextran, Leiras Inc., Finland), and sedimented for 60 min at -I-37°C. The supernatant consisted of granulocytes with a few monocytes. Half of the lymphocytes were then rosetted with 2-amino-ethyl-isothiouronium bromidehydrobromide-treated sheep red blood cells (AET-SRBC) according t o Pellegrino et al. (1 975) and centrifuged over Ficoll-Isopaque. The non-AET-SRBC-rosette forming lymphocytes (non-T lymphocytes) were recovered from the interface. Finally, the non-depleted and T cell-depleted lymphocyte suspensions were added to equal parts of the granulocyte suspension and the two cell mixtures tested separately in the LMT. Thyroid-infiltrating lymphocytes were depleted of T cells in a similar way by centrifugation of the AET-SRBC-rosetted cell suspension over Ficoll-lsopaque in siliconized 5 ml glass tubes. RESULTS

Distribution of major cell types in thyroid fine-needle aspirates Representative thyroid fine-needle aspirates were obtained in twelve patients with Graves’ disease and thirteen cases of Hashimoto’s thyroiditis (Table 1). The mean degree of blood contamination, as determined b y the IC, was higher in Graves’ disease than in Hashimoto’s disease. The predominatinginfiltratingcell in both disorders was a small lymphocyte, whereas in Hashimoto’s thyroiditis also substantial numbers of plasma cells were detected. Monocytes and macrophages were found in both disorders in approximately equal numbers. In six patients with Graves’ disease and four patients with Hashimoto’s thyroiditis the cell yield at thyroid biopsy was sufficient for further studies. Distribution of ANAE marker-carrying ( T ) lymphocytes in blood and thyroid infiltrate iri Graves’and Hashimoto ’s disease In both Graves’ and Hashimoto’s disease a significantly lower number of thyroid-infiltrating lymphocytes expressed the ANAE T cell marker as compared t o blood lymphocytes (Table 2). The non-T lymphocytes infiltrating the thyroid gland in these disorders are mostly B cells (Totterman, 1978). LMT with blood and thyroid-infiltrating lymphocytes As shown in Table 3 , blood leucocytes of five out o f six patients with Graves’ disease and three of four patients with Hashimoto’s thyroiditis displayed a positive CMI t o thyroid antigen in the LMT, i.e., the MI was below the normal control limit (87%, i.e., mean MI for the controls minus 2 X S.D.). When blood leucocytes from the same patients were tested for CMI against smooth muscle antigen (not shown), the MI was always above the normal control limit for that antigen (93%). Thyroid-infiltrating lymphocytes were tested for CMI t o thyroid antigen in the LMT by mixing them at increasing ratios with autologous peripheral blood leucocytes (Table 3). In all six patients with Graves’ disease a stronger antigen-induced inhibition of leucocyte migration was seen when thyroid-infiltrating lymphocytes were added t o blood leucocytes as compared to that with blood leucocytes alone. This difference was significant (p < 0.001) at a ratio of 1 :SO.Even when the LMT with blood leucocytes was negative for CMI (case 2), the addition of 1 % thyroid-infiltratinglymphocytes resulted in a significant inhibition. There was a dose-dependent relationship between the MI and the amount of added thyroid-infiltrating lymphocytes. When thyroid-infiltratinglymphocytes from the four patients with Hashimoto’s

Graves’ disease Hashimoto’s disease 12 13

Number of biopsies 8.0 32.1

15 i I 1+5

59 51 t

t

13 12

Lymphocytes

of blood contamination; mean Mean values t SD

* IC = index

3.2 10.3

**

t

f

IC*

Thyroid parenchymal ceUs

f

SD

1 . O i 1.5 lot6

Plasma cells

12 i I 18 f 9

Monocytes and macrophages

% Cells per category* *

1 3 t 10 8 i 7

Granulocytes

Table 1. Distribution of the major cell types in thyroid fine-needle aspiration biopsies from patients with Graves’ disease and Hashimoto’s thyroiditis

n

e

2 n

Q

2:

2=

Q

s.

n h

1

$ k

3-

’h

Y

+3

T. H. Totterinan et a1

64

Table 2. Relative proportions of ANAE-positive (T) lymphocytes in the blood and thyroid inflammatory infiltrates of patients with Graves’ disease and Hashirnoto’s thyroiditis ANAE-positive lymphocytes (%)

IC * Graves’ disease Mean f SD (n = 6) P* * Hashirno to’s thyroiditis Mean f SD (n = 4)

Thy r oi d infiltrate

Blood

8.2 f 2.1

12

f

6

38

f

9

31

+

11

< 0.001 IS

17.0 f 4.2

f

8

P* *

< 0.001

* IC = index of blood contamination. * * P-value for difference in means compared by

the paired t-test

Table 3. Thyroid antigen-induced leucocyte migration inhibition by thyroidinfiltrating lymphocytes in Graves’ disease and Hashimoto’s thyroiditis Migration index (%)*

Disease Graves’ disease

Patient

Blood leucocy tes only

73

1 2 3

93

80 69 83 84

4

5 6 Mean

i

SD (n = 6)

80

f

1:lOO

1:50

67 83 61

50 40 47 36 59 38

n.d.** n.d. n.d. 45

9

f

1 :6 --

1:20

1:12

32 31

n.d. n.d. n.d. n.d. n.d. n.d.

l1.d.

74

78

91 n.d. n.d.

n.d. n.d. n.d.

96 n.d. n.d. n.d.

n.d. n.d. n.d. n.d.

I1.d. I1 . d . n.d 1l.d. I1.d.

9

< 0.001

Pt Hashimo to’s thyroiditis

Thyroid-infiltrating lymphocytes: autologous blood leucocytes

1

2 3 4

Mean i SD (n = 4)

75 83

n.d.

86

79 96

89

n.d. n.d.

98 88

76 81tl

Controls Mean f SD (n = 20)

90

< 0.01

Pt 93

f

3

* ltalicised figure = positive in the LMT * * n.d. = not done t P-value for difference in means as compared by

the paired t-test.

f

9

T Lymphocytes in Graves’ disease

65

Table 4 . T lymphocytc dependence of the thyroid antigen-induced leucocyte migration inhibition by blood and thyroid-infiltrating lymphocytes in Graves’ disease Migration index* Thyroid-infiltrating lymphocytes* *

Blood leucocytes

All cells Patient 1 4

5 6 7 8 9 10

Mean i SD PP

After T cell depletion

73 69 83 84 86 70 66 72

IS

_c

n.d.f 91 97 n.d. 91 102 93 95 96

8

_c

4

< 0.002

All cells Patient

After T cell depletion

50 36 59 38

75 62 89 81

n.d. n.d. n.d. n.d.

n.d. n.d. n.d. n.d.

4 6 + 11

7 7 t 11

< 0.01

* ltalicised figure = positive in the LMT. ** Thyroid-infiltrating

lymphocytes were indirectly tested by inixing them with autologous blood leucocytes at a ratio of 1:50. t n.d. = not done P P-value for differences in means compared by the paired 1-test. Only complete pairs of data tested.

disease were tested in an identical manner, n o further inhibition of blood leucocyte migration was obtained. In fact, there was a ‘dilution’ effect on the blood LMT response in every occasion. The very small number of available thyroid-infiltrating cells did not allow their testing for CMI against smooth muscle antigen.

T lymphocyte dependence of the LMT response with blood and thyroid-infiltrating cells In order t o study the T lymphocyte dependence of the thyroid antigen-induced inhibition in the LMT the T cells were removed from the leucocyte suspension prior to the assay. When blood leucocytes from six patients with Graves’ disease were depleted of T lymphocytes, the LMT response turned negative in every case (Table 4). The difference in mean MI before (75 f 8%) and after (96 4%) T cell depletion was statistically significant (P< 0.002). Removal of T lymphocytes from the thyroid-infiltrating lymphocyte population prior t o assay was possible in four cases (Table 4). This procedure completely abolished the ability of thyroid-infiltrating cells t o increase the LMT response of autologous blood leucocytes.

*

DISCUSSION In Hashimoto’s thyroiditis the predominant thyroid-infiltrating immunocompetent cell was a small lymphocyte, whereas the monocyte-macrophage population was less conspicuous.

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T. H. Totterman et al.

About equal proportions of T and non-T (B) lymphocytes were seen, indicating a role for both major lymphocyte subclasses in the pathogenesis of the disease. This confirms our results in two earlier communications (Totterman et al., 1977, Totterman, 1978). In accordance with our observations in juvenile autoimmune thyroiditis (Totterman er al., 1977), the thyroid-infiltrating T cells of Hashimoto patients were unable to respond to thyroid antigen in the LMT. This observation was somewhat unexpected, since thyroglobulin (Tg)-binding T lymphocytes, albeit in small numbers, were earlier demonstrated in the thyroid infiltrates of patients with Hashimoto’s disease (Totterman, 1978). This indicates that in chronic autoimmune thyroiditis the Tg-binding T cells in the thyroid infiltrates d o not display in v i m detectable reactivity t o thyroid antigen. It is possible that this lack of reactivity is caused by an excess of antigen (tolerance). Alternatively, the in situ effector cells might be controlled by some suppressor cell population (Waldmann & Broder, 1977). We have earlier demonstrated a considerably increased frequency of Tg-binding lymphocytes in the gland of Hashimot0 patients as compared to blood (Totterman, 1978). This accumulation of receptor specificity within the gland argues against the possibility that the thyroid-infiltrating lymphocytes are merely ‘passive bystanders’, secondarily trapped in the thyroid after some unknown traumatic mechanism. The striking accumulation of Tg-binding non-T lymphocytes (probahly B cells; Bankhurst et al., 1973) plus the finding of mature plasma cells in the gland of Hashimoto patients suggests an intra-thyroidal synthesis of autoantibodies. In accordance with this is the report of Clinton & Weigle (1972) who showed an accumulation of anti-Tg antibody-synthesizing cells in the thyroid gland of rabbits immunized with bovine Tg. If such a synthesis takes place in man, then cells with Fc-receptors for immunoglobulin G (K cells) could well be mainly responsible for the destruction of antibody-coated (Rnedo et al.. 1976) thyroid parenchymal cells. In Graves’ disease lymphocytes predominated over monocytes and macrophages in the thyroid aspirates, and almost no plasma cells were observed. There was a relative accumulation of non-T cells in the thyroid infiltrate similar to that observed in an earlier study (Totterman, 1978). We have previously shown that in Graves’ disease there are high frequencies of Tg-binding non-T and T lymphocytes within the gland as compared with blood levels (Totterman, 1978). Thus similar immunocompetent cells seem to accumulate in the gland both in Graves’ disease and chronic autoimmune thyroiditis, with one important exception: the thyroid-infiltrating lymphocytes from all patients with Graves’ disease tested displayed a strong CMI to thyroid antigen in the LMT. Thus the thyroid infiltrate in Graves’ disease contains T lymphocytes that have the capacity to respond (at least in v i m ) to thyroid antigen(s) by releasing lymphokines. The release of different lymphokines in situ could attract inflammatory cells with resultant nonspecific damage of thyroid tissues. However, the more specialized functions of these autoantigen-reactive T cells remain t o be established, since it is not known exactly which T lymphocyte subpopulation(s) release(s) the leucocyte migration inhibition factor. Studies in mice indicate that killer T cells are possibly not responsible for this phenomenon (Brondz et al., 1978). There is evidence indicating that at least helper T cells (which augment antibody synthesis) can bind soluble antigens (Basten et al., 1971; Kontiainen & Andersson, 1975). Tg-binding T cells within the thyroid in Graves’ and Hashimoto’s disease possibly belong t o this functional T cell subpopulation. ACKNOWLEDGEMENTS

We are grateful to Professor B.-A. Lamberg and Dr. A. Gordin for their help with the patient

T Lymphocytes in Graves' disease

67

material. This study was supported by grants from Finska Lakaresallskapet, The Sigrid Juselius Foundation, and h a k e Pharmaceuticals, Helsinki, Finland.

REFERENCES BANKHURST, A.D., TORRIGIANI, G. & ALLISON, A.C. (1973) Lymphocytes binding human thyroglobulin in healthy people and its relevance t o tolerance for autoantigens. Lancet, i, 226-230. BASTEN, A., MILLER, J.F.A.P., SPRENT, J. & PYE, J . (1971) Specific inactivation of thymusderived (TI and non-thymus (B) lymphocytes by '*sI-labelled antigens. Nature New Biology, 231, 104106. BENDIXEN, G., BENDTZEN, J.E., CLAUSEN, J.E., KJAER, M. & SQBORG, M. (1976) Human leukocyte migration inhibition. Scandinavian Journal of Immunology. Suppl. 5 , 175-184. BONNYNS, M., VANHAELST, L., DELESPESSE, G., BASTENIE, P.A. & ERMANS, A.M. (1972) In Thyroiditis and Thyroid Function, (eds P. A. Bastenie & A. M. Ermans). Pergamon Press, Oxford. BQYUM, A. (1968) Separation of lymphocytes from blood and bone marrow. Scandinavian Journal of Clinical and Laboratory Investigation, 21, Suppl. 97, 77-89. BRONDZ, B.D., SUSLOV, A.P. & EGOROVA, S.C. (1978) Comparative study of cytotoxic T-lymphocytes and producers of the macrophage migration inhibition factor (MIF) in the H-2 system. Scandinavian Journd of Immunology, 8,109-1 18. BUCHANAN, W.W., ANDERSSON, J.R., GOUDIE, R.W. & GRAY, K.T. (1958) A skin test in thyroid disease. Lancet, u,928-93 1 . CALDER, E.A. & IRVINE, W.J. (1975) Cell-mediated immunity and immune comulexes in thvroid disease. Clinics in Endocrinology and Metabolism. 4, 287-3 18. CLINTON, B.A. & WEIGLE, W.O. (1972) Cellular events during the induction of experimental thyroiditis in the rabbit. JournalofExperimentalMedicine, 136, 1605-1615. KONTIAINEN, S. & ANDERSSON, L.C. (1975) Antigen-binding T cells as helper cells. Separation of helper cells by immune rosette formation. Journal of Experimental Medicine, 142, 1035-1039. LAMBERG, B.-A., GORDIN, A., VIHERKOSKI, M . & KJIST, G. (1969) Long-acting thyroid stimulator (LATS) in toxic nodular goitre, toxic adenorna and Graves' disease. Acta Endocrinologia /Copenh.), 62,199-204. LAMKI, L., ROW, V.V. & VOLPE, R. (1973) Cell-mediated immunity in Graves' disease and in Hashimoto's thyroiditis as shown by the demonstration of migration inhibition factor (MIF). Journal of Clinical Endocrinology and Metabolism. 36, 358-364. MATSUI, Y.,BEALL, G.N., CHOPRA, I.J., SOLOMON, D.H., KRUGER, S. & BEALL, M. (1977) Assays for antigenstimulated lymphocyte-derived migration enhancement and inhibition factors from patients with thyroid diseases and their relatives. Acta Endocrinologica, 86, 733-741. MAKINEN, T., TOTTERMAN, T.H., GORDIN, A. & WEBER, T.H. (1977) Migration inhibition factor and the blood clotting system: effects of defibrination, heparin and thrombin. Clinical and Expen'mentallmmunology, 29, 181-186. NEVE, P., ERMANS, A.M. & BASTENIE, P.A. (1972) In Thyroiditis and Thyroid Function, (eds P. A. Bastenie & A. M. Ermans). Pergamon Press, Oxford. PELLECRINO, M.A., FERRONE, S., DIERICH, M.P. & REISFELD, R.A. (1975) Enhancement of sheep red blood cell human lymphocyte rosette formation by the sulfhydryl compound 2-amino ethylisothiouronium bromide. Clinical Immunology and Immunopathology, 3, 3 24-3 33. PERRIN, J. & BUBEL, M.A. (1974) Assessment of a haemagglutination test of thyroid microsomal antibody. Medical Laboratory Technology, 31,205-211. PINEDO, C . , MUL, N.A.J. & BALLIEUX, R.E. (1976) In vitro adherence of nonsensitized cells t o antibodycoated thyroid tissue in autoimmune thyroiditis. Clinical Immunology and Immunopathology, 5,6-11. RANKI, A., TOTTERMAN, T.H. & HAYRY, P. (1976) Identification of resting human T and B lymphocytes by acid a-naphthyl acetate esterase staining combined with rosette formation with Staphylococcus aureus strain Cowan I. Scandinavian Journal of Immunology, 5 , 1129-1 138. ROITT, I.M.& DONIACH, D. (1958) Human autoimmune thyroiditis: serological studies. Lancet, ii, 1027-1 032.

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SqBORC, M. & BENDIXEN, G. (1967) Human lymphocyte migration as a parameter of hypersensitivity. Acta Medica Scandinavica. 181,247-256. SBBORG, M. & HALRERG, P. ( 1 968) Cellular hypersensitivity in Hashimoto’s thyroiditis. Acta Medica Scandinavica, 183, 101-105. TOTTERMAN. T.H. (1978) Distribution of T-, 9- and thyroglobulin-binding lymphocytes infiltrating the gland in Craves’ disease, Hashimoto’s thyroiditis, and de Quervain’s thyroiditis. clinical Immunology and Immunopathology. 10, 270-277. TOTTERMAN, T.H., MAENPAA, J . , GORDIN, A., MAKINEN,T., TASKINEN, E., ANDERSSON, L.c., & HAY RY, P. (1 977) Blood and thyroid-infiltrating lymphocyte subclasses in juvenile autoimmune thyroiditis. Clinical and Experimental Immunology, 30, 193-199. TOTTERMAN, T.H., GORDIN, A., HAYRY, P. & ANDERSSON, L.C. (1978) Accumulation of thyroid antigen-reactive T lymphocytes in the gland of patients with subacute thyroiditis. Clinical and Experimental Immunology. 32,153-158. WALDMANN, T.A. & BRODER, S. (1977) Suppressor cells in the regulation of the immune response. I n Progress in Clinical Immunology Vol. 3 , (ed. R. S. Schwartz). Grune & Stratton, New York.

Evidence for thyroid antigen-reactive T lymphocytes infiltrating the thyroid gland in Graves' disease.

Clinical Endocrinology (1 979) 1 1, 59-68. EVIDENCE FOR THYROID ANTIGEN-REACTIVE T LYMPHOCYTES I N F I L T R A T I N G T H E T H Y R O I D G L A N D...
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