THYROIDVolume 11, Number 2, 2001Mary Ann Liebert, Inc.

Guest Editorial

Keeping Our Eyes Open

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IT IS EASY IN RESEARCH to follow the herd. When a new dis-covery is made, investigators are tempted to pursue the

phenomenon and may precipitate a stampede. Within thisflow and among the dust, it may be difficult to see whereone is going. Occasionally, however, some of the participantsemerge (or are ejected) at the periphery and have the abilityto look in other directions. The study by Marino et al. (1) inthe present issue demonstrating the presence of thyroglob-ulin (Tg) in Graves’ orbital tissue indicates that sometimesinvestigators with open eyes and clear vision can look backat the direction whence we came.

At the present time, the focus is on the thyrotropin re-ceptor (TSHR). The discovery more than 40 years ago of thy-roid-stimulating autoantibodies in Graves’ disease but rarelyin Hashimoto’s thyroiditis made such antibodies logical can-didates for the cause of Graves’ ophthalmopathy (GO). How-ever, the poor correlation between TSHR autoantibodies andGO, as well as the severe technical difficulties involved instudying autoantibody-TSHR interactions, slowed theprogress of the herd. Joseph Kriss had the insight and imag-ination to look beyond the prevailing concept and suggestedthat the GO was related to the presence in orbital tissue ofTg, a molecule not expected to be present outside the thy-roid gland. In a classic study, he demonstrated a mechanismby which Tg could reach the orbit. Radiolabeled Tg injectedinto Graves’ glands in vivo was detected by scanning inlymph nodes also known to be the destination of lymphaticflow from the orbit (2). He therefore established a directanatomical link between the thyroid and the eye. In the mo-lecular era, the surprising and exciting discovery of aminoacid analogy between portions of the Tg and acetyl-cholinesterase (present at high concentration in extraorbitalmuscles) strengthened interest in Tg as a GO-related au-toantigen (3). However, for a variety of reasons, includingthe inability to demonstrate a correlation between Tg au-toantibodies and GO, we entered a long period of searchingfor new autoantigens, presumably cross-reacting with a thy-roid antigen. Much progress has been made in this regard(4). The molecular cloning of the TSHR led to the develop-ment of new tools and reinvestigation of this antigen in GO,with the encouraging results available to date (for example,Valyasevi et al. [5]). The herd has now resumed its directionof 40 years ago.

In this light it is refreshing to read the report of Marino etal. (1). Whether or not their findings ultimately prove to beof significance in GO, their study looks beyond the dust ofthe stampede. By whichever route Tg is transported from thethyroid to the orbit (lymphatics or blood), this Tg is, in it-

self, insufficient to cause GO. In the absence of an immuneresponse to orbital Tg, as yet unproven, its presence couldsimply be an interesting epiphenomenon. Moreover, asMarino et al. (1) point out, Tg or Tg autoantibodies were un-detectable in the serum of two of their three patients in whomthey observed Tg in orbital tissue. This observation, togetherwith the known presence of tissue-infiltrating T cells in GO,leads them to suggest that any response to orbital Tg is likelyto be T-cell–mediated. Nevertheless, with appropriate cau-tion they express concern about the apparent absence of Tgautoantibodies even in a putative T-cell–mediated disease. Tcells are sometimes invoked as culprits when antibodies can-not be detected. Indeed, it is worth noting that the presenceof T cells in Graves’ thyroids, together with the difficulty indetecting TSHR autoantibodies by direct interaction withantigen, could have led to the argument that Graves’ hy-perthyroidism was caused by T cells. TSHR autoantibodies,present at very low concentrations, were only discovered be-cause of their thyroid stimulatory properties and their abil-ity to inhibit TSH binding, both very sensitive indirect as-says.

When Kriss was asked how his theory of an inflammatoryresponse to orbital Tg could withstand the fact that patientswith Hashimoto’s thyroiditis rarely develop ophthalmopa-thy despite the frequent presence of Tg autoantibodies, hisresponse was that the very high blood perfusion of theGraves’ thyroid, unlike in Hashimoto’s disease, increasedlymph flow carrying Tg to the orbit. But how can one thenexplain the presence of Tg in the orbits of the patients de-scribed by Marino et al. (1) all of whom were hypothyroidafter radioiodine therapy? As they clearly show, the orbitalTg in their patients is not synthesized locally but is of thy-roid origin. Radioiodine therapy could certainly release Tginto the lymphatics or bloodstream for transport to the or-bit. However, all patients had received radioiodine long be-fore their orbital tissue was obtained for study. Marino et al.(1) suggest that orbital Tg could persist for prolonged peri-ods of time. An alternative hypothesis is that disrupted thy-roid follicular architecture after radioiodine therapy couldlead to greater leakage of Tg into the lymphatics, perhapsaccelerated by TSHR autoantibody-driven hyperfunction ofsmall thyroid remnants. Other interesting questions raisedby the study include whether Tg is detected in tissue otherthan the orbit in patients with GO, and which molecules“trap” the Tg reaching extrathyroidal tissues? Could thismolecule be a heparan sulfate proteoglycan, along the linesof the authors’ previous work (6)?

Overall, it now seems well established that Tg is present

in orbital tissue of patients with severe GO. However,whether or not Tg is directly related to GO or is an epiphe-nomenon remains an open question. The absence of de-tectable Tg or Tg autoantibodies in serum is not, in our opin-ion, conclusive evidence against a role for Tg in this process.Nevertheless, we would be surprised if Tg turns out to bethe key antigen in GO. Regardless of the pathophysiologicalsignificance of orbital Tg in Graves’ eye disease, the work ofMarino et al. (1) teaches us that we must always keep oureyes open.

References

1. Marino M, Lisi S, Pinchera A, Mazzi B, Latrofa F, Sellari-Franceschini S, McCluskey RT, Chiovato L 2001 Identificationof thyroglobulin in orbital tissues of patients with thyroid as-sociated ophthalmopathy. Thyroid 11:177–185.

2. Kriss JP 1970 Radioisotopic thyrolymphography in patientswith Graves’ disease. J Clin Endocrinol Metab 40:872–875.

3. Ludgate M, Dong Q, Dreyfus PA, Zakut H, Taylor P, VassartG, Soreq H 1989 Definition, at the molecular level, of a thy-roglobulin—acetylcholinesterase shared epitope: Study of its

pathophysiological significance in patients with Graves’ Oph-thalmopathy. Autoimmunity 3:167–176.

4. Gunji K, Kubota S, Swanson J, Kiljanski J, Bednarczuk T, Wengrowicz S, Salvi M, Wall JR 1998 Role of the eye musclesin thyroid eye disease: Identification of the principal auto-antigens [published erratum appears in Thyroid 1998;8:1079].Thyroid 8:553–556.

5. Valyasevi RW, Erickson DZ, Harteneck DA, Dutton CM,Heufelder AE, Jyonouchi SC, Bahn RS 1999 Differentiation ofhuman orbital preadipocyte fibroblasts induces expression offunctional thyrotropin receptor. J Clin Endocrinol Metab 84:2557–2562.

6. Marino M, Andrews D, McCluskey RT 2000 Binding of ratthyroglobulin to heparan sulfate proteoglycans. Thyroid 10:551–559.

Address reprint requests to:Basil Rapoport, M.B., Ch.B. and Sandra M. McLachlan, Ph.D.

Autoimmune Disease UnitCedars Sinai Research Institute and U.C.L.A.

School of MedicineLos Angeles, CA 90048

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