Thyroid autoimmunity Brian R. Champion,

Anne Cooke and David C. Rayner

Glaxo Inc., Research Triangle Park, North Carolina, USA, University of Cambridge, and University of Alberta, Edmonton, Canada

Antigenic

structure

genes for three and

the

remains

a major

major thyroid

in thyroid

thyrotropin

receptor-were

for antibody

and T cells have been reported

addition,

new evidence thyroid

for selective

immunology.

thyroglobulin,

epitopes in human

sequenced

thyroid

in the

UK

The

peroxidase

late 1980’s,

and

within the last year. In

V gene segments

use of T-cell receptor

infiltrates may point the way to specific immunotherapy.

Current

Opinion

in Immunology

1992, 4:77&778

peptides. The cloning and sequencing of thyroglobulin [ 51 and TPO autoantibodies [ 61 from thyroidal lymphocytes of patients with Hashimoto’s thyroiditis and Graves’ disease, respectively, have also been described. Specific properties of the thyroid autoantigens are discussed individually in recent reviews [ 7-121.

Introduction The major human thyroid autoimmune diseases - Hashimoto’s thyroiditis, primary autoimmune hypothyroidism and Graves’disease - are characterized by reactivity to self thyroid antigens, which may be expressed as destruc five inflammatory autoimmunity [ 1?? ] or anti-receptor autoimmunity. While this clinical. link provides the impetus for research in thyroid immunology, animal models continue to increase in sophistication: in addition to ‘clas sical’ experimental autoimmune thyroiditis (RAT) produced by thyroglobulin immunization, a novel form of RAT produced by immunization with thyroid peroxidase has been developed [2]. Monoclonal antibodies to the thyroid stimulating hormone (TSH) receptor, with stimulatory and blocking activity, have been produced in mice by an anti-idiotypic strategy [3*]. A new model of spontaneous thyroid autoimmunity in the non-obese diabetic (NOD) mouse has also been described by Bernard et al.

Thyroglobulin

Thyroglobulin is a 66OkD homodimeric glycoprotein which functions as the thyroid prohormone: within the thyroglobulin molecule, thyroxine and triiodothyronine are generated by the TPO-catalysed iodination and coupling of specific hormonogenic tyrosines.

Thyroglobulin

autoantibodies

Murine monoclonal antibodies raised against human thyroglobulin have been used by several groups to define epitopes recognized by autoantibodies in the sera of patients with autoimmune thyroid diseases. Recent studies with human thyroglobulin expression libraries, fusion proteins and synthetic peptides indicate that a dominant selfepitope(s) lies in the central (non-hormonogenie) region of the thyroglobulin molecule [13,14*,15]. The tertiary structure of thyroglobulin is not known, but recognition by antibody suggests that this region is probably exposed on the surface of the native thyroglobulin molecule. Not all thyroglobulin autoantibodies recognize linear epitopes: one study of four human monoclonal autoantibodies derived from lymphocytes from the thyroid of patients with Hashimoto’s thyroiditis showed that they recognize native thyroglobulin only [ 161. Although thyroglobulin autoantibody has an undefined, and probably limited, pathogenic role, recognition of this central determinant by autoantibodies in patients with Sjogren’s

[4*1.

In this review, we discuss the structure of the major thyroid autoantigens and current work in the cellular immunology of thyroid autoimmunity, as well as potential approaches to specific immunotherapy in thyroid disease.

Thyroid

focus

antigens -

Cambridge,

autoantigens

The recent molecular cloning of genes for the three principal thyroid antigens - thyroglobulin, thyroid peroxidase (TPO, the ‘microsomal antigen’) and the TSH receptor-has had a major impact on our understanding of their autoantigenicity. It is now relatively straightforward to define T-cell and linear B-cell epitopes through the use of recombinant antigen fragments or synthetic

Abbreviations EAT*xperimental IFN-interferon;

autoimmune IL-interleukin;

TGF-transforming

thyroiditis; ICAMintercellular MHC-major growth

factor;

Th-T

complex;

helper; TNLtumor

TSH-thyroid

770

adhesion molecule;

histocompatibility

stimulating

@ Current Biology Ltd MN

HM-human

NO&non-obese

necrosis factor; hormone.

0952-7915

leukocyte-associated diabetic;

TPO-thyroid

TCR-T-cell peroxidase;

antigen; receptor;

Thyroid

syndrome appears to correlate with the severity of thyroid lesions [ 171.

Thyroglobulin-reactive

T cells

A major recent development has been the demonstration that iodinated determinants on thyroglobulin are responsible for pathogen&y in the EAT model. In previous work [ 181, we described two independently-derived murine (CBA&a; H-2k) T-cell clones that could recognize normal, but not thyroxine-deficient, thyroglobulin. Using synthetic thyroxine-containing peptides (corresponding to the four hormonogenic domains of thyroglobulin), both these clones were shown to recognize (although somewhat differently) a nonamer peptide containing the hormonogenic site at position 2553 [l!?]. A thyroxine residue at position 2553 was essential for recognition: replacement of thyroxine with its precursor residue Tyr (or any other amino acid) produced a non-stimulatory sequence. The pathological relevance of this epitope was suggested by the ability of thyroid cells expressing MHC class II molecules to activate one of the T-cell clones. Subsequent in vivo work confirmed this: T cells that reacted with the peptide (generated by animal priming and in vitro restimulation) were highly effective at inducing thyroiditis on transfer to naive recipients [ 20**]. Experiments in H-29 and H-2S strains indicate that thyroglobulin iodination is required for induction of thyroiditis in these strains as well, but that the pathogenic determinant(s) are different (DC Rayner, unpublished data). A possible non-iodinated epitope is suggested by recent work from Texier et al. [21], who localized a 40-residue sequence (from a central, non-hormonogenic region of the thyroglobulin molecule), which was recognized by a thyroglobulin-reactive murine cytotoxic T cell hybridoma. A peptide corresponding to this sequence could induce minimal thyroid inflammation in mice. In the Obese strain chicken model, iodination also appears to play a critical role in the development of spontaneous autoimmune thyroid disease [ 22.01. Treatment with compounds that interfere with thyroidal iodine metabolism, beginning in ovo, was effective in blocking development of thyroiditis and thyroid autoantibodies. Moreover, adoptive transfer of Obese strain spleen cells, into MHC-matched recipients of another strain, produced thyroiditis only in iodide-supplemented (and not iodide-depleted) recipients. This suggests that tissue expression of an iodinated determinant may be necessary for pathogenic lymphocytes to localize in the thyroid. In human populations, epidemiological evidence (reviewed in 1231) has long suggested a similar link between dietary iodine and thyroid autoimmune disease. A recent report of anti-thyroglobulin and anti-thyroid membrane autoantibodies, in children given iodine prophylaxis after the Chernobyl disaster, supports this association [24]. Whether T-cell recognition of iodinated thyroglobulin epitopes is the basis of these observations remains an attractive but untested hypothesis.

autoimmunity

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Cooke and Rayner

We have speculated previously [ 18,19-] that tolerance to iodinated (or thyroxine-containing) epitopes may not be effectively established, because circulating thyroglobulin is known to be poorly iodinated. Results from a recent in vitro study of thyroid epithelial cell polarity are consistent with this idea. Productive thyroglobulin iodination was found to occur exclusively at the apical (follicular luminal) pole of the cell, whereas about 10% of thyroglobulin secretion (presumably non-iodinated molecules) took place through the basal side [ 25.1.

Thyroid

peroxidase

TPO is a membrane-bound haemoprotein enzyme of molecular weight 105 kD that catalyses thyroid hormone biosynthesis. TPO has been known for several years to be identical with the microsomal antigen, recognized by complement-fixing autoantibodies from thyroid autoim~ mune patients.

TPO autoantibodies

Although TPO is glycosylated, carbohydrate residues appear to play no role in its autoantigenicity [ 26,271. Epitope mapping studies indicate that the autoantibody response to TPO is heterogeneous, and recognizes at least two domains of the molecule [28,29,30*,31*], Screening of TPO fragment cDNA expression libraries with murine monoclonal anti-TPO antibodies [30-l or autoantibodies from a patient with Hashimoto’s thyroiditis [31*] indicate the presence of epitopes at positions 59G622 and 713-721. Some TPO antibodies appear to have the ability to block the catalytic function of the enzyme, but whether this has any role as a pathogenic mechanism in thyroid disease remains unresolved. Kohno et al. [Q] found that TPO autoantibodies from chronic thyroiditis patients are able to block enzyme activity (and thus differ from the TPO antibodies, which may occur in the absence of disease). In contrast, other investigators have found no evidence for such an inhibitory effect [28]. Similarly, the question of whether TPO and thyroglobulin contain cross~reac~ tive epitopes for autoantibody [ 331 remains controversial [ 341. The solution to these arguments may lie in technical differences used by the different investigators.

JPO-reactive

J cells

Experimental autoimmune thyroiditis can be induced in C57BL/6 (Hm2b) mice by immunization with purified porcine TPO in Freund’s complete aduvant, or by adoptive transfer of sensitized T cells. One of the pathogenic T-cell epitopes (comprising residues 774-788) has been defined through a combination of classical biochemical methods, and analysis of synthetic peptides based on the cDNA sequence of porcine TPO [35**]. Two studies reporting human T-cell autoreactiviv to TPO have been reported recently. Using synthetic pep tides representing I6 regions of the TPO molecule (selected through predictive algorithms), Tandon et a/.

771

772

Autoimmunity

1361 defined three sequences (comprising amino acids 415-432, 439-457 and 463-481) which stimulated peripheral blood T cells of 23-37% of patients with Graves’ disease or autoimmune hypothyroidism. Some other peptides appeared to be stimulatory in individual patients. Dayan et ul. [37**] used an antigen-independent cloning approach to isolate T-cell clones from the thyroid of a single patient with Graves’ disease. Nearly half the clones isolated reacted with TPO, and these showed marked heterogeneity in their responses to synthetic peptides. Two epitopes (comprising residues 535-551 and 6326451, which were recognized by a number of clones, were restricted by different HL4 class II molecules. It is impossible to predict from such studies in humans which, if any, of these epitopes (and their corresponding T cells) mediate pathogenesis.

Thyroid stimulating hormone

The TSH receptor is coupled to the G protein and shows high sequence homology with the lutropin receptor. It is synthesized as a 90 kD precursor glycoprotein which appears to be cleaved to form an extracellular TSH-binding a-subunit; the a-subunit is linked to a P-subunit, which consists of transmembrane and cytoplasmic domains, by disulphide bonds [ 10,11,31*,38,39]. Patients with Graves’ disease have stimulatoty autoantibodies directed at the TSH receptor, whereas those with primaty autoimmune hypothyroidism (primary autoimmune myxedema) have autoantibodies which block TSH binding to the receptor but are non-stimulatoty. Both direct binding studies and functional analyses (using cells transfected with chimeric receptors) indicate that TSH, stimulatoty autoantibodies, and blocking autoantibodies all bind to different sites on the receptor [ 40*~,41-44,45°]. Although one study found that thyroidstimulating autoantibodies failed to recognize linear epitopes [31*], others have found recognition of peptide sequences corresponding to positions 352-366 [43], 333-343 [44], and S-165 [42]. This discrepancy suggests that (like many antibodies) TSH receptor autoantibocies have a high afhnity for conformational epitopes but can recognize linear sequences in some assay systems. Blocking autoantibodies also appear to recognize conformational epitopes, indicated by the observation that Tyr 385 and the sequence comprising residues 295-306 are important for recognition [ 40**]. Site-directed mutagenesis of the extracellular domain of the rat TSH receptor, followed by expression in Cos-7 cells, has shown that Thr 40 is important for the action of thyroid-stimulating autoantibodies, but not TSH [40**]. Functional studies of thyroid epithelial cells have shown that in addition to activating adenyl cyclase to raise intracellular CAMP, stimulatory autoantibodies also elevate mRNA levels for thyroglobulin and TPO [46] and the c-myc and c-fos oncogene products [47,48]. These autoantibodies activate phospholipase A2 [49], but unlike TSH, do not appear to activate phospholipase C [50*]. One of the more interesting recent observations in this area is the finding that a I61 base pair region of the gene

encoding the TSH receptor is homologous with the gene encoding the HIV regulatoty protein Nef [ 51**]. A rabbit antibody to a peptide representing part of this TSH receptor sequence showed cross-reactivity with recombinant Nef protein; sera from patients with Graves’ disease also appear to recognize Nef weakly. These findings have sparked speculation on retroviral involvement in the pathogenesis of Graves’ disease. T-cell reactivity with the TSH receptor has not been reported, although it has been suggested that some T-cell clones that react with autologous thyroid epithelial cells may recognize the TSH receptor. The availability of recombinant TSH receptor fragments and synthetic peptides should permit direct examination of this question.

64 kD membrane antigen Recent work has shown that autoantibodies from some patients with autoimmune thyroid disease and ophthal mopathy recognize a novel 64kD autoantigen on thyroid cell membranes [52,53**]. This molecule has no known homology with other proteins (and should not be confused with the diabetes-associated 64 kD autoantigen, glutamic acid decarboxylase). The antigen is expressed in thyroid and extraocular muscle, and is recognized by sera from some, but not all, patients with thyroid autoimmune disease.

Cellular

mechanisms

T cell-thyroid

epithelial cell interactions

MHC class II expression and antigen presentation Thyroid epithelial cells can interact directly with both MHC class I restricted and class II restricted T cells. In the latter case, expression of MHC class II molecules by thyroid cells is induced by a T-cell cytokine, interferon (IFN)=y, with an enhancing effect of tumor necrosis factor (TNF)-a; reciprocally, these thyroid cells can present antigen to MHC class II restricted T cells in vitro [ 19.1. Moreover, in a murine model, pre-exposure to IFN-y is sufficient to evoke intlammatory destruction of grafted syngeneic thyroid tissue [54]. Nonetheless, the role of different antigen-presenting cell populations in the inductive phase of spontaneous thyroid&is remains unclear. The topic of direct autoantigen presentation by thyroid follicular cells has been reviewed recently [1*,55].

Adhesion

molecules

Contact between leukocytes and thyroid epithelial cells is necessary for antigen presentation and for some cellular effector mechanisms. Work from Wall’s group has shown that binding between human thyroid cells and autologous T lymphocytes is enhanced by pre-exposure of the thyroid cells to IFN-y [ 56 1. The mechanism is likely to involve thyroid cell induction of adhesion molecules, such as intercellular adhesion molecule (ICAM)-l (CD54),

Thyroid

which can be induced (at least in vitro) by IFN-)I, interleukin (IL)-1 p and TNF-cl [57,58,59-l. Parenthetically, IL-I and TNF-cr. are synthesized by thyroid epithelial cells [60,6I], raising the possibility of autocrine control of adhesion and other properties regulated by these cytokines. Other adhesion molecules that appear to be expressed constitutively on thyroid cells include the neural cell adhesion molecule (CD56) [62] and lymphocyte function associated antigen-3 (CD581 [58].

T-cell

receptor

V gene heterogeneity

work from Davies’ laboratory [63**] indicates that the usage of T-cell receptor (TCR) Vcr genes by autoimmune thyroid-infiltrating T cells from patients with Graves’ disease and Hashimoto’s thyroiditis is about threefold less diverse than that of peripheral blood T cells from these patients. Similar restriction (of both Vu and VP gene usage) has been observed in inbred models which respond to defined epitopese.g. the PL/J mouse response to the amino-terminal peptide of myelin basic protein. However, in human disease, with multiple antigens and selfepitopes, this result is remarkable. No comparable restriction in VP gene usage was observed in thyroids from these patients [64=*], and how VCLlimitation correlates with antigen specificity is not known. It is possible that it develops as a result of prolonged exposure to a relatively weak amplifying stimulus. T cells with an autologous mixed lymphocyte reaction type specificity are present in thyroid infiltrates, and these cells may show restricted V-gene heterogeneity. An alternative hypothesis postulates a Va-specific tissue superantigen, but this does not easily explain the different spectrum of Vcl usage by different patients. The use of V gene segments by y6 TCR+ T cells is uncharacterized, although these cells have been implicated as possible effecters in thyroid autoimmunity [65]. New

Approaches

to immunotherapy

in thyroid

disease Antigen-based

strategies

In high-responder mouse strains, preinjection of soluble thyroglobulin protects against development of EAT following subsequent thyroglobulin immunization. Thyroglobulin that lacks thyroxine is as elfective a tolerogen as normal thyroglobulin, suggesting that the tolerogenic determinant(s) are different from those which induce the disease (DC Rayner, unpublished data). This observation fits well with the linding that TSH stimulation of the level of circulating thyroglobulin-which is poorly iodinatedis also capable of inducing tolerance [66]. The circulating pool of thyroglobulin may in fact function normally to inhibit the development of thyroid autoreactivity. Tolerization with soluble thyroglobulin depends CD4+ T cells [66,67], although its subcellular basis undefined. In foreign antigen models, administration soluble proteins enhances a type2 T helper (Th2)

on is of re-

autoimmunity

Champion,

Cooke and Rayner

sponse at the expense of the type 1 T helper (Thl ) response [68,69], but the role of this mechanism in rem sponses to thyroglobulin is not clear. It is possible that this ‘redirection’ may be mediated by cytokines (such as IL-10 or transforming growth factor (TGF)-P), although the appropriate in viuo experiments have not yet been performed. Whether EAT is primarily Thl-dependent is open to argument: disease is transferable by R-2-secret ing T cells [ 19**], but aggravated by blockade of the IL-2 receptor [70]. In addition, these methods have not yet been applied to other thyroid antigens, such as TPO. Nonetheless, it is possible that tolerization to one au toantigen may cover others through ‘bystander’ suppress sion [71]. A different approach to specific tolerance is through administration of antigen in conjunction with anti-CD4 antibody. In the murine EAT model, injection of antiCD4 monoclonal antibody prevents both thyroiditis and the autoantibody response following immunization with thyroglobulin and adjuvant, and this protection is transferable (PR Hutchings, IM Roitt, A Cooke, unpublished data).

Cytokine-based

strategies

Some recombinant cytokines can suppress autoimmune responses, and may conceivably provide an alternative approach to immunotherapy of autoimmune diseases. For example, TGF-P mediates in vivo oral tolerance to myelin basic protein [72]. In the thyroid system, TGF-P suppresses in vitro proliferation of thyroidal T cells from patients with Graves’ disease in response to lectin, IL2 or autologous thyroid cells and has a direct inhibitory effect on autoantigen expression and MHC class II molecule expression by thyroid epithelial cells [73]. The effects of cytokine therapy may not be simple, and the ever-present risk of exacerbating the disease process may limit their therapeutic application. Observations using IL-1 in vivo provide one example: in diabetes-prone BB rats, low-dose (0.4 l.rg/kg/d) H-1 0 delayed and diminished the development of sponta neous autoimmune diabetes. However, at a higher dose (8.0 ugkg/d), diabetes was accelerated and the severity of insulitis and lymphocytic thyroiditis were considerably increased [74]. Similarly, in a murine EAT model, culture of thyroglobulinsensitized spleen cells in the presence of IL2 receptor antibody augmented the development of thyroiditis on adoptive transfer, although this treatment might intuitively have been anticipated to have been protective [70].

TCR-based

strategies

‘Vaccination’ of animals with radiation-attenuated T cells has been shown to prevent experimental thyroiditis, through induction of both anti-idiotypic antibody and suppressor T cells [75,76], In a continuation of this line of work, Charreire’s group has recently described a monoclonal anti-idiotypic antibody, specific for TCR from an MHC class I restricted thyroglobulin-specific cy

773

774

Autoimmunitv

totoxic T cell hybridoma, which is able to protect against development of murine EAT when given parenterally before immunization [77*]. Analogous antibodies directed against specific V regions are protective in experimental myelin autoimmunity, and this may be a potential approach to immunotherapy in situations, such as human thyroid disease [63**,64**] in which TCR V gene usage is limited. Nevertheless, the different range of V region usage in different individuals may limit the practicality of this strategy. A related approach is through the use of methods directed against MHC molecules, using either blocking antibody 1781 or peptides. In experimental disease, the identification of pathogenic epitopes may be the first step in the design of competitive antagonist peptides; altematively, the known MHC associations may permit synthesis of peptides that bind h4HC but do not necessarily resemble autoantigen. Such approaches would ideally cover reactivity to cryptic or subdominant epitopes which may evolve after initial damage [79].

Conclusion

2.

COSTAGLIOLAS, RUF J, DURAND-GORDEM-J, CARAYONP: MonoclouaI Antiidiotypic Antibodies Interact with the 93 Kilodakon Thyrotropin Receptor and Exhibit Heterogeneous Biological Activities. Endocrinology 191, 128:155%1562. The authors immunized mice with monoclonal anti-TSH antibodies in order to derive ten monoclonal anti-idiotypic antibodies with anti-receptor specificity. Four of these functioned as thyroid-stimulating antibodies and five as blocking antibodies, determined by an in vitro membrane adenyl cyclase assay. The antibodies produced only limited (1.5. to 2-fold) stimulation or inhibition of adenyl cyclase activity in comparison with baseline levels. Nonetheless, such reagents may conceivably be a step towards an animal model of anti-TSH receptor autoimmunity

3. .

4. .

BERNARD NF, ERTIIGF, MARGOLESE H: High Incidence of Thyroiditls and Anti-thyroid AutoantibodIes in NOD Mice. Diabetes 1992, 41:4G46. An association between autoimmune diabetes and thyroiditis exists in humans and BB rats; this paper reports a high frequency of thyroidi~ tis (77% at > 180 days of age) in the authors’ colony of NOD mice. Thyroid disease was age-dependent, occurred in both sexes, and was accompanied by autoantibodies to unidentified thyroid membrane antigens 5.

Recent progress in thyroid immunology is proceeding on two main fronts, and we will close with some comments on future directions. The fir& area of intense activity is the structure of the thyroid autoantigens. The following are among the key questions that remain to be resolved: firstly, the reactivity of human thyroidal lymphocytes to iodinated determinants on thyroglobulin; secondly, recognition sequences used by autoimmune T and B cells in spontaneous autoimmune models; and thirdly, the relationship of V-gene usage to T-cell specificity. The second research front is in the area of specific biological therapy, where essentially all work to date has focused on immunoprophylaxis. Effective protocols that will work in established or relapsing disease (and particularly in spontaneous models) would be welcome, although they are certainly still some years away. Whether specific immunotherapy will have any advantage over conventional treatment in clinical thyroid disease is another matter entirely. However, this approach holds promise for immune-mediated diseases with no effective therapy, and in developing these protocols, thyroid-based models will continue to be valuable prototypes of organspecific autoimmunity.

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10.

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12.

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13.

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1. WEETMANAP: Autoimmune Thyroiditis: Predisposition and . Pathogenesis. Clin Endocrinol 1992, 36:307-323. A current and extensively referenced review, focusing on human Hashimoto’s disease and primary autoimmune hypothyroidism from the standpoint of immunopathogenesis.

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acterized by a Monoclonal Antibody. J Endocrinol 1992, 15:25-30. 14. .

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Thyroid Four of 15 murine monoclonal antibodies to human thyroglobulin recognized low molecular weight protease~digestion products of thyroglobulin. These same antibodies were able to detect thyroglobulin fragments in human thyroglobulin expression cDNA libraries. Suhcloning of immunoreactive expression clones localized the epitope fo a 102.amino acid sequence (corresponding to residues 1149-1250). Studies with human autoantibodies indicated that this was a dominant self-epitope. 15.

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Champion,

autoimmunity

Cooke and Rayner

thyroiditis and thyroglobulin autoantibodies which normally develop in these animals within weeks of hatching. Transfer of lymphocytes from the Obese strain into the related Cornell strain (which only develops a late, mild thyroiditis) only induced thyroiditis in recipients which were supplemented with iodine. 23.

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2-t.

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17.

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CHAMPION BR, PAGEKR, PARISHN, RAYNERDC, DAWEK, BrswtiHUGHES G, COOKE A, GEYSEN M, Ron~ IM: Identification of a Thyroxine-containing Self-epitope of Thyroglohulin which Triggers Thyroid Autoreactive T Cells. J Exp Med 1991, 174363-370. Synthetic thyroxine-containing peptides representing the four major hormonogenic sites of thyroglobulin were used to define the epitopic specificity of two autoreactive murine thyroglobulin-specific Tcell hybridomas. Both were found to recognize the nonamer sequence Asp-Asp-thyroxine-Ala-Ser.Phe-Ser-Arg-Ala (representing the hormono~ genie site at position 2553) as the minimal epitope, with thyroxine as an essential component. Syngeneic thyroid cells expressing MHC class II molecules were able to activate one of the T-cell hybridomas in the absence of added peptide. This is the first precise def&ion of a self-thyroglobulin T-cell epitope. Since thyroxine biosynthesis depends in part on available iodine, these findings suggest a possible mechanism linking iodine intake, thyroglobulin antigenicity, and autoimmune thyroid disease. 19. ..

20. ..

HUTCHINGS PR, COOKE A, DAWEK, CHAMPION BR, GEYSEN M, VALERIOR, Rorrr IM: A Thyroxine-containing Peptide Can Induce Murine Experimental Autoimmune Thyroiditis. J Exp Med 1992, 175:869+72. The thyroxine-containing self-epitope, which wz identified recently [IS**], was shown to be very effective at priming T cells in uivo for transfer of thyroid&is to naive recipients (using CBA/J; H-2k mice). It was also able to reactivate mouse thyroglobulin-primed T cells, indicat ing that this hormonogenic site is at least one of the pathogenic T-cell epitopes for murine thyroiditis in H-2k mice.

21.

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S, CI~VBARE

M, MAIIC~IP

J. CHABALX

0. Long-term Iodination of Thyroglobulin by Porcine Thyroid Cells Cultured in Porous-bottomed Culture Chambers: Regulation by Thyrotropin. J Endocrind 1991, 128:51-61, By culturing porcine thyroid epithelial celIs as a monolayer on porous membranes, polarized cells were obtained for analysis of thyroglobulin iodination and secretion at the apical and basal sides of the ceils. Thy~ roglohulin iodination only took place at the apical pole of the cell, hut some thyroglobulin secretion (10% of the total) occurred at the basal pole.

P, RAP~PORT B: DeterminaFINKER, SETO P, RUF J, CARAYON tion at the Molecular Level of a B cell Epitope on Thyroid Peroxidase Likely To Be Associated with Autoimmune Thyroid Disease. J Clin Endocrinol Metab 1991, 73:919-921. A murine monoclonal antibody to human TPO, the reactivity of which is blocked by autoantibodies from patients with autoimmune thyroid diseases, recognized TPO fragments expressed in a human TPO cDNA library Sequencing of 18 reactive clones localized this linear self epitope to the nine amino acids representing residues 713-721 of the TPO molecule. 30. .

LIBERT F, LULZA’I’~M, DIN~AK’C, I’ VA%RT G: Thyroperoxidase, but not the Thyrotropin Receptor, Contains Sequential Epitopes Recognized by Autoantibodies in Recombinant Peptides Expressed in the pUEX Vector. J Clin Endcu-inoi Metub 1991, 73:857X360. Screening of human TPO fragments expressed as recombinant o-galactosidase fusion proteins with autoantibodies present in serum from a patient with Hashimoto’s thyroiditis led to the definition of two linear seK-epitopes of the TPO molecule (comprising residues 59&622 and 710-722). Similar approaches to define TSH receptor autoantibodies (stimulatory or blocking) failed to define any linear self epitopes.

31. .

32.

KOHNO Y, YAMACUCHIF, SAITO K, NIIMI H, NISHIKA~AT. T: Anti-thyroid Peroxidase Antibodies in Sera from Healthy Subjects and from Patients with Chronic Thyroiditis: Differences in the Ability to Inhibit Thyroid Peroxidtie Activities. Clin Eq Immunol 1991, 85:459-463. HOSOYA

775

776

Autoimmunihr 33.

RUFJ, FERRANDM, DURANDE-GORDE JM, CARAYONP: Immunoputication and Characterization of Thyroid Autoantibodies with Dual Specificity for ThyrogIobulin and Thyroperoxidase. Aufooimmunity 1992, 1 I:179188

34.

HENRY M, ZANELLIE, MAIXHIERYY: Anti-human Thyroid Peroxidase and Anti-human ThyroglobuIin Antibodies Present No Cross-reactivity on Recombinant Peptides. Clin Exp Immunol 1991, 86:47%482.

KOTANIT, UMEKI K, YAGIHA~HIS, HIRAI K, OHTAKIS: Identilication of Tbyroiditogenic Epitopc on Porcine Thyroid Peroxidase for C57BL/6 Mice. J Immunoll992, 148:20842089. An epitope of porcine TPO, which was recognized by primed lymph node cells and was able to induce thyroiditis in C57BV6 (H-2b) mice, was defined by a combination of analyses of CNBr fragments of TPO and synthetic peptides. The 15.amino acid sequence GPAQITCTPRGWDSP (in the one letter amino acid code), representing residues 774-788 of porcine TPO, stimulated proliferation of primed lymph node cells and induced thyroidltis in mice. These observations represent the first definition of a pathogenic TPO epitope which is presumably (although not yet proven to be) recognized within murine TPO by self.reactive T cells. 35. ..

36.

TANDON N, FREEMANM, WEETMANAP: T celI Responses to Synthetic Thyroid Peroxidase Peptides in Autoimmune Thyroid Disease. Clin Exp Immunol 1991, 86:5&O.

DAYANCM, IQNDEI M, CORCORANAE, GRUBECK-LOEBENSTEIN B, JAMESRF, RAPOPORTB, FELDMANNM: Autoantigen Recognition by Thyroid-infiltrating T Cells in Graves’ Disease. Proc Nut1 Acad Sci USA 1991, 88:7415-7419. A large panel of T-cell clones was obtained from the thyroid of a patient with Graves’ disease by an antigen-independent cloning protocol (which used stimulation with anti-CD3 antibodies). Analysis of their reactivities fo known thyroid antigens revealed that nearly half recognized human TPO. The epitope specificities of the TPO-reactive clones apt pearcd to be heterogeneous, based on their reactivity with synthetic TPO peptides which were predicted fo bear T-cell epitopes. A number of clones recognized residues 535-551 and 63245, in association with diierent MHC class II molecules. 37. ..

38.

39.

on TSH Receptor/LH-CG Receptor Chimeras than Either TSH or Immunoglobulins from Idiopathic Myxedema Patients. Biochem Biophys Res Commun 1991, 179:7&77. 43.

GS, JONESCA, ALIAWAY GP, TAKAI0, DESAI RK, SEETAKAMLZU T, KOHN LD, PRABHAKARBS: Prokaryotic Expression of the Thyrotropin Receptor and Identification of an Immunogenic Region of the Protein Using Synthetic Peptides. Biocbem Biopbys Res Commun 1991, 179~31~326.

44

MORI T, SUGAWA H, PIRAPHATD~STT, INOUE D, ENOMOTO T, IMUFL4 H: A Synthetic Oligopeptide Derived from Human Thyrotropin Receptor Sequence Binds to Graves’ Immunoglobulin and Inhibits Thyroid Stimulating Antibody Activity but Lacks Interactions with TSH. Biocbem Biopkys Res Commun 1991, 178:165-172.

r5. .

NAGAYAMA Y, WADSWOKTH HL, Russo D, CHAZENBAUCGD, RA~OPORTB: Binding Domains of Stimulatory and Inhibitory

Thyrotropin (TSH) Receptor Autoantibodies Determined with Chimeric TSH-Lutropin/Chorionic Gonadotropin Receptors. J Clin Invest 1991, 88:336340. Three chimeric receptors (with high-affinity TSH binding properties) were made between TSH receptor and the lutropin/chorionic gonadotropin receptor; these were used to compare the capacity of TSH and stimulatoly autoantibodies to evoke CAMP responses in transfected cells. The results showed that TSH, stimulatoly autoantibodies and blocking autoantibodies bind differently fo the TSH receptor. 46.

Receptor: Regulation of Adenylate Cyclase Activity, Thyroglobulin and Thyroid Peroxidase mRNA Levels in primary Cultures of Graves’ Thyroid Tissue. Clin Exp Immunoll991, 86:6165. 47.

48.

Russo D, NAGAYAMA Y, CHAZENBALK GD, WADSWORTH HL, RAPOPORTB: Role of Amino Acids 261-418 in Proteolytic Cleavage of the Extracellular Region of the Human Thyrotropin Receptor. Endocrinology 1992, 130:2135-2138.

49.

KOSUGI S, BAN T, AKAMIZUE T, KOHN LD: Identification of Separate Determinants on the Thyrotropin Receptor Reactive with Graves’ Thyroid-stimulating Antibodies and with Thyroid-stimulating Blocking Antibodies in Idiopathic Myxedemz These Determinants have no Homologous Sequence on Gonadotropin Receptors. Mol Endocrinol 1992, 6:168-180. TSH receptor constructs with mutations in different regions were compared with wild-type receptor (using transfected Cos-7 cells), for their ability to mediate elevations in CAMP levels in response to TSH and stimulatory TSH receptor autoantibodies. Thr 40 was critical for the activity of stimulatory autoantibodies, but not TSH or blocking antibodies. Effects of blocking antibodies were also analyzed and shown to be dependent on residues 295-306 and Tyr 385. 41.

KOSUGI S, BAN T, AKAMIZUT, KOHN ID: Site-directed Mutagenesis of a Portion of the Extracellular Domain of the Rat Thyrotropin Receptor Important in Autoimmune Thyroid Disease and Nonhomologous with Gonadotropin Receptors. Relationship of Functional and Immunogenic Domains. J Biol Cbem 1991, 266:1941%19418.

42.

TAHARAK, BAN T, MINEGISHIT, KOHN LD: Imrnunoglobulins from Graves’ Disease Patients Interact with Different Sites

HATABu H, KASAGI K, 1111~Y, NOSAKA T, MISAKI T, HIDAKA A, TOKUDA Y, ENW K, MORI T, LEE K, ET AL.:Induction of

c-fos and c-nzyc mRNA Expression by ImmunoglobuIin G from Patients with Graves’ Disease in Thyrotropin-depcndent Rat Thyroid CelI Line (FRTLS). Clin Endocrinol 1991, 34:349-356.

LOOSFELT H, PICHON C, JOLIVET A, MISRAHI M, CAILLQU B, Jmous M, VANNIERB, MILGROM E: Two-subunit Structure of the Human Thyrotropin Receptor. Proc Nut1 Acud Sci USA 1992, 89~3765-3769.

40. ..

COLLISON KS, BANGA JP, BARNETT PS, HUNG GC, MCGREC~R AM: Autoantibody Stimulation of the Human Thyrotropin

HUBER GK,

SAFIR~TEIN R,

NEIJFELD D,

DAVIES TF:

Thy

rotropin Receptor Autoantibodies Induce Human Thyroid CelI Growth and c-fos Activation. J Clin Endocrinol Metab 1991, 72:1142-1147. DI CERBO A, DI GIROLAMO M, GUARDABMSOV, DE FIUPPIS V, CORDA D: Immunoglobulins from Graves’ Patients Stimulate

PhospholipaseA2 in FRTLS Thyroid Cells. J Clin Endocrinol Metab 1992, 74:585-592. 50. .

LKIRE~VT E, VAN SANDEJ, LUDGATEM, CORVLAIN B, ROCMANSP, DUMONT JE, M~CKEL J: Unlike Thyrotropin, Thyroid-stimulat-

ing Antibodies do not Activate Phospholipase C in Human Thyroid Slices. J Clin Invest 1991, 87:1634-1642. Although both TSH and stimulatoly autoantibodies trigger CAMP responses in thyroid cells, this paper provides evidence of a different post~receptor response to the two ligands. These findings may be relevant to the pathological effects of stimu1atoIy autoantibodies in Graves’ disease. 51.

B~JRCH HB,

NAGY EV, LLJKESYG,

CAI WY,

WARTOFSKY L,

BURMAN KD: Nucleotide and Amino Acid Homology Between the Human Thyrotropin Receptor and the HIV-l nef Protein: Identification and Functional Analysis. B&hem Biopbys Res Commun 1991, 181:49%505. This paper reports an intriguing homology between a I61 base pair region of the gene encoding the TSH receptor and the gene encoding the HIV protein Nef; antibodies recognizing the product of this sequence in the TSH receptor can cross-react with Nef. ..

52.

KENDLER DL, ROOTMAN J, HUBER GK, DAVIES TF: A 64kDa

Membrane Antigen Is a Recurrent

Epitope

for Natural

Thyroid Autoantibodies in Patients with Graves’ Thyroid and Ophthalmic Diseases. Clin Endocrinol (Oxf) 1991, 35:539-547. I%NC Q, LUDGATE M, VA.SSART G: Cloning and Sequencing of a Novel 64kDa Autoantigen Recognized by Patients with Autoimmune Thyroid Disease. J Clin Endocrinol Metah 1991, 72:1375-1381. This paper describes the cloning and sequencing of a new 64 kD aw toantigen expressed in the human thyroid and in extraocular muscle. The full length cDNA has the potential to encode a product comprising 572 amino acids, with a predicted size of 63kD and no apparent homology with other known protein molecules. The recombinant protein was recognized by sera from approximately seven out of 34 patients with autoimmune thyroid diseases; recognition of this autoantigen may provide a link between the thyroiditis and ophthalmopathy of Graves’ disease.

53. ..

54.

FROHMAN M, FRANCFOKT JW, C~WNG

tion of Thyroid 146:2227-2234. 55.

Isografts

Exposed

C: T-dependent Destructo IFNy. J Immunol1991.

FELDMANN M, DAYAN C, RAPOPORT B, LQNDEI M: T Cell Activation and Antigen Presentation in Human Thyroid Autoim 1992, 5 (Supplement A):115121. munity. J Autoimmuniry

56.

FUKAUWA H, HIROMATXI Y, BERNARD N, SALVI M, WALL JR: Binding of Peripheral Blood and Thyroidal T Lymphocytes to Thyroid Cell Monolayers: Possible Role of ‘Homing-like’ Receptors in the Pathogenesis of Thyroid Autoimmunity. Autoimmunily 1991, 10:181-188.

57.

WEETMAN AP,

COHEN SB,

MAKG~BA

MW,

BORYSIE~ICZ

LK: Ex-

TOLOSA E,

ROURA C,

MARTI M,

BELFIORE A,

59. .

TOLOSA E, ROURA C, CAXUFAMO SANMARTI A,

SALIN.U I, 0~101s

DAClESTF, M..,,WN A, CONCEI’CION ES, (;R&\TS 1’. LUiAT >. BEN NI’N A: Evidence for Selective Accumulation of Intrathyroidal T Lymphocytes in Human Autoimmune Thyroid Disease Based on T Ceil Receptor V Gene I’sage J Clin hrwt 1992, 891157-162. An extension of the preceding study [63-l, rhk paper sho\~c~cl n stricted VU gene usage (mean, four out of 18 gene families) but esscn ttally unrestricted VP usage (mean 14.4 out of 19) in lymphoc~es from the thyroids of patients with autoimmune disorders. Possible explana~ tions may include. (a) autoantigen specific expansion; (h) expansion 01 autoreactive lymphoq-tes (autologous mixed lymphoqte reaction t)pc) expressing MHC class II molecules; and (c) amplification by a \‘wse lectwe superantigen. Data linking Va usage to specificity is awaited wth Interest. . .

65.

Fez-SALA

M,

ZHENG

61.

ZHENG

62.

63.

RQH, ABNF( E, CHU CQ, FIELD M, GRLJBECK-LOEBENSTEIN B, MAINI RN, FELDMANN M: Detection of Interleukin-6 and Interleukin-1 Production in Human Thyroid Epithelial Ceils by Non-radioactive In Situ Hybridization and Immunohistochemical Methods. Clin Exp Immunol 1991, 83:314-319. RQH, ABNEY ER, CHU CQ, FIELD M, MAINIRN, LAMB JR, FELDMANN M: Detection of In Viuo Production of Tumour Necrosis Factor-alpha by Human Thyroid Epithelial Cells. Immunology 1992, 75~456462.

66.

DAVIES TF, MARTIN A, CONCEPCION ES, GRAVES P, COHEN L, BEN NUN A:

HI~AKAY, K.WVCDA T, ICHII~~~ K, T\X\KI MASAI K: Decreases in c*p T Cell Receptor Negative T Cells and CD8 Cells, and an Increase in CD4+CD8+ Cells in Active Hashimoto’s Clirz Exp Immunol 1992, Disease and Subacute Thyroiditis. 87z44-49. AMIYO

MATSUZ~KA

KONG

YM,

N,

F, FUKATA S, KLIMA K,

GIRALW

AA,

WAI~MANN

H,

COHB~ID

SP,

FULLER

BE: Resistance to Experimental Autoimmune Thyroiditis: L3T4’ Cells as Mediators of Both Thyroglobulin and TSHinduced Suppression. Clin Immunol Immurzoputhol 1989. 51:3%54. 67.

68.

PARISHNM, ROITT IM, C~~KF A: Phenotypic Characteristics of Cells Involved in Induced Suppression to Murine Experimental Autoimmune Thyroiditis. Ew .I Immu?lol 1988, 18:1463-1467. DE

WIT

D,

AHKAMO~ICZ

VAN

MECHFLFN

D,

GOLDMAN M,

M,

R~FIA~~T

BAZIN Ii,

M,

FICIXIKEDO

AC.

LJRRAII\I J,

IEO C). The Injection of Deaggregated Gamma Globulins in Adult Mice Induces Antigen-specific Unresponsiveness of T Helper Type 1 but not Type 2 Lymphocytes. .I EXI, .Llcd 1992. 175:%14.

69.

BI!RSTEINHJ, SHEACM, A~rrksAK: Aqueous Antigens Induce In Vivo Tolerance Selectively in IL-2. and IFN-y-producing (Thl) Cells. J Immunol 1992, 148:3687-3691.

70.

BRALEY~MULIZEN H,

St-IARp GC, BIC~L JT, KYIUAKO~M: Induction of Severe Granulomatous Experimental Autoimmune Thyroiditis in Mice by Effector Cells Activated in the Presence of Anti-interleukin 2 Receptor Antibody. .I E.q .Mc,d 1991, 173:89%912.

71.

MILER

72.

MILLERA, LIDEK0, ROBEUS AB, SPORNMB, WEINEH HL: Suppressor T Cells Generated by Oral Tolerization to Myelin Basic Protein Suppress Both In Vitro and In Vito Immune Responses by the Release of Transforming Growth Factor p after Antigen-specific Triggering. Proc Nat/ Acad Sci i’SA 1992, 89:421-425.

73.

WIDDER

MIGITA K, EGUCHIK, KAWAKAMI A, IDAH, FUKUDA T, KURATA A, ISHIAKAWA N, ITO K, NAGATAKI S: Detection of Leu-19 (CD56) Antigen on Human Thyroid Epithelial Cells by an Immuno1991, 72:246249. histochemical Method. Immunology

Evidence of Limited Variability of Antigen Receptors on Intrathyroidal T Cells in Autoimmune Thyroid Disease. N En@ J Med 1991, 325:23%244. TCR u-chain cDNA transcript were amplified by the poiymerase chain reaction for analysis of Va usage: lymphocytes from the thyroids of nine . .

IV&WI Y,

PUJOL-BORRELL:

Expression of Intercelhdar Adhesion Molecule-l in Thyroid FoUicular Cells in Autoimmune, Non-autoimmune and Neoplastic Diseases of the Thyroid Gland: Discordance with HLA J Autoimmunity 1992, 5:107-118. A companion paper to 1581, this study compared the expression of class I and II HIA molecules and ICAM- in human thyroid epitheIiaI cells. Although levels of these proteins are induced in parallel by cytokines (IFN-y and TNF-a) in vitro, expression of ICAMl was disproportionately low in thyroid cells from Graves’ disease thyroids in comparison with high levels of HLA expression. This suggests the existence of other mechanisms which differentially regulate expression of these molecules in t&o. 60.

COHEN WL,

H,

M, MAFZI M, LUCAS-MARTIN A, G,

Cooke and Rayner

64.

PUJOL-BORRELL R:

Induction of Intercellular Adhesion Molecule-l but not of Lymphocyte Function-associated Antigen-3 in Thyroid Follicular Cells. J Autoimmuni& 1992, 5:11F135.

Champion,

patients with Graves’ disease and Hashimoto’s thyroiditis expressed a mean of five (out of 18) different Va gene families, in contrast with 1’ expressed by lymphocytes from the peripheral blood of these patients. Although the pattern of Vx use varied between patients, this finding raises the possibility of V region directed immunotherapy in autoim mune diseases.

pression of an Intracellular Adhesion Molecule, ICAM-1, by Human Thyroid Cells. J Endocrinol 1989, 122:185-191. 58.

autoimmunity

A, LI~XX0, Werxxc IIL. Antigen-driven Bystander Sup pression after Oral Administration of Antigen. ./ Ex~ .I!& 1991, 174:701&708.

J,

L~EBEN~TEIN L~EBENSTEIN

I&WINCER R, NIEIXIU

K,

WILFIN(; B, G~ssr.

A, A,

TR~EB

K,

PIRICH

K,

SPITZAUEH S, GRLXLCK-

B: The Immunoregulatory Intluence of Transforming Growth Factor p in Thyroid Autoimmunity: TGF p Inhibits Autoreactivity in Graves’ Disease. J Autoimmun~ti~ 1991, 4689-701.

777

778

Autoimmunitv

74.

VERTREES S, WILSONCA, UBUNGENR, WILSON D, BASKIN IX, TOIVOLA B, JACOBS C, BOLM N, BAKER P, LERNMARK A:

Interleukin-1 p Regulation of Islet and Thyroid Autoimmu1991, 4717-732. nity in the BB Rat. J Autoimmunity 75.

ROUBATY C, BEDINC, CHARREIREJ: Prevention of Experimental Autoimmune Thyroiditis Through the Anti-idiotypic Network. J Immunol 1990, 144:2167-2172.

76.

FLYNNJC, KONG Y-CM: In Viuo Evidence for CD4+ and CDS+ Suppressor T Cells in Vaccination-induced Suppression of Murine Experimental Autoimmune Thyroiditis. Clin Immunol Immunopatbo11991, 60:484494.

77. .

TEXIERB, BEDINC, ROUBATYC, BREZINC, CHARREIRE J: Protec-

tion from Experimental Autoimmune Thyroiditis Conferred by a MonoclonaI Antibody to T CeII Receptor from a Cytotoxic Hybridoma Specific for ThyrogIobuIIn. J Immunol 1992, 148:439-444. Immunization of CBA/J mice with a thyrogIobuIin-specific MHC class I restricted T ceII hybridoma, HTC2, mm previously shown by Charreire’s

group [75] to protect against EAT. This study reports the derivation of a monoclonal anti-idiotypic antibody spectic for HTC2 TCR, which specilicaliy inhibits cytotoxicity by HTC,, precipitates clonotypic TCRs, and protects against EAT when given before immunization with a tqptic fragment of thyroglobulin. 78.

VL~DUTIIJAO, STEINMANL: Inhibition of Experimental Autoimmune Thyroiditis in Mice by Anti-I-A Antibodies. Cell Immunoi 1987, 109:16!+180.

79.

LEHMANN PV, FORSTHUBER T, MILLER A, SERCARZ EE: Spreading of T-cell Immunity to Cryptic Determinants of an Autoantigen. Nature 1992, 358:155-157.

BR Champion, Department angle Park, North Carolina

of Immunology, 27709, USA.

A Cooke, Division of Immunology, Department of Cambridge, Cambridge CB2 lQP, UK. DC Rayner, Department T6G 2R7, Canada.

of Pathology,

Glaxo Inc., Research of Pathology,

Tri-

University

University of Alberta, Edmonton

Thyroid autoimmunity.

Antigenic structure remains a major focus in thyroid immunology. The genes for three major thyroid antigens--thyroglobulin, thyroid peroxidase and the...
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