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The Journal of Immunology, 2002, 168: 5907-5911.
Copyright © 2002 by The American Association of Immunologists

Enhanced Iodination of Thyroglobulin Facilitates Processing and Presentation of a Cryptic Pathogenic Peptide1

Yang D. Dai, Varada P. Rao and George Carayanniotis2

Division of Endocrinology, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Increased iodine intake has been associated with the development of experimental autoimmune thyroiditis (EAT), but the biological basis for this association remains poorly understood. One hypothesis has been that enhanced incorporation of iodine in thyroglobulin (Tg) promotes the generation of pathogenic T cell determinants. In this study we sought to test this by using the pathogenic nondominant As-binding Tg peptides p2495 and p2694 as model Ags. SJL mice challenged with highly iodinated Tg (I-Tg) developed EAT of higher severity than Tg-primed controls, and lymph node cells (LNC) from I-Tg-primed hosts showed a higher proliferation in response to I-Tg in vitro than Tg-primed LNC reacting to Tg. Interestingly, I-Tg-primed LNC proliferated strongly in vitro against p2495, but not p2694, indicating efficient and selective priming with p2495 following processing of I-Tg in vivo. Tg-primed LNC did not respond to either peptide. Similarly, the p2495-specific, IL-2-secreting T cell hybridoma clone 5E8 was activated when I-Tg-pulsed, but not Tg-pulsed, splenocytes were used as APC, whereas the p2694-specific T cell hybridoma clone 6E10 remained unresponsive to splenic APC pulsed with Tg or I-Tg. The selective in vitro generation of p2495 was observed in macrophages or dendritic cells, but not in B cells, suggesting differential processing of I-Tg among various APC. These data demonstrate that enhanced iodination of Tg facilitates the selective processing and presentation of a cryptic pathogenic peptide in vivo or in vitro and suggest a mechanism that can at least in part account for the association of high iodine intake and the development of EAT.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Increased iodine (I) ingestion has been shown to promote induction of autoimmune thyroiditis in humans (1, 2, 3, 4, 5) and experimental animals such as chicken (6, 7), rats (8, 9, 10, 11, 12), hamsters (13), and mice (14). The mechanisms underlying this association remain poorly understood. One attractive theory has been that enhanced I intake increases the immunogenicity of thyroglobulin (Tg),3 precipitating an autoimmune response. This is a plausible explanation given that 1) I is organified within Tg, whose main metabolic role is the formation of the hormones thyroxine (T4) and tri-iodothyronine via intramolecular coupling of specific iodotyrosyls (15); 2) Tg is the largest autoantigen known, inducing experimental autoimmune thyroiditis (EAT) in several species (16); and 3) highly iodinated Tg (I-Tg) demonstrates enhanced immunogenicity (17) or altered antigenicity (18) at the serological level.

Tg-induced EAT, which serves as a model for Hashimoto’s thyroiditis in humans, is, nevertheless, considered to be a T cell-mediated disease (16) and the question of whether or how incorporation of I into Tg promotes generation of Tg-specific autoreactive T cells has not been adequately investigated. Four of the five known pathogenic Tg peptides do not contain I atoms or T4 residues (19, 20). Furthermore, studies using peptide analogs that encompass hormonogenic, i.e., T4-containing, sites of Tg have clearly shown that these epitopes are generated even after processing of normal Tg and that the presence of I atoms per se does not render a peptide immunogenic (21, 22, 23). In contrast, processing of noniodinated Tg does not generate the T4-containing pathogenic peptide (2549–2560) in vitro (24), suggesting that a minimal amount of Tg iodination is required for the generation of some Tg T cell epitopes.

In this study we have examined whether transition of normal Tg to a highly iodinated form (I-Tg), i.e., a shift from 15–20 I atoms to 55–70 I atoms/monomeric subunit, would enhance its immunopathogenicity in mouse EAT. The availability and prior characterization of two nondominant, As-binding, pathogenic Tg peptides, 2495–2511 (p2495) and 2694–2711 (p2694), in our laboratory (25, 26) has allowed us to test the hypothesis that processing of I-Tg, but not Tg, leads to generation of cryptic pathogenic determinants. Such a mechanism might partly account for the association of high I intake and autoimmune thyroiditis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and Ags

Female SJL/J mice (6–8 wk old) were purchased from The Jackson Laboratory (Bar Harbor, ME). Tg was purified from frozen thyroid glands of outbred ICR mice (Bioproducts for Science, Indianapolis, IN), as previously described (27). The mouse Tg peptides 2495–2511 (Ac-GLINRAKAVKQFEESQG-NH2; p2495) and 2694–2711 (Ac-C(acm)SFWSKYIQTLKDADGAK-NH2; p2694) with the -SH group of the N-terminal Cys blocked by acetamide were synthesized and purified commercially (Alberta Peptide Institute, Edmonton, Canada). Amino acid coordinates of peptides were assigned according to the Tg sequence described by Kim et al. (28), and they do not include the leader sequence.

Tissue culture media and cell lines

Assays were performed in complete DMEM (Life Technologies, Burlington, Canada) supplemented with 10% FBS (Bioproducts for Science), 20 mM HEPES buffer, 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin (all from Life Technologies), and 5 x 10-5 M 2-ME (Sigma-Aldrich, St. Louis, MO). The IL-2-dependent cell line CTLL (29) was obtained from American Type Culture Collection (Manassas, VA). The H-2As-restricted, IL-2-secreting T cell hybridomas 5E8 and 6E10 reactive with p2495 and p2694, respectively, were generated as previously described (25). Dendritic cells (DC) were generated from bone marrow progenitors as previously described (30). Briefly, bone marrow cells from femurs and tibias were cultured in 24-well plates (106 cells/ml/well) with 1000 U/ml rGM-CSF (BD PharMingen, San Diego, CA). Every 2 days, 75% of the medium was replaced with fresh medium containing GM-CSF, and on day 6 the proliferating immature DC were dislodged gently and subsequently cultured in petri dishes (107 cells/ml) in complete medium containing GM-CSF. After 24 h the nonadherent mature DC were collected for further study. Enrichment for B cells was performed by C'-mediated cytotoxicity of RBC-depleted spleen cells using a mixture of mAbs specific for Thy1.2 (30-H12), Mac-1 (M1/70.15.11.5.HL), and DC (33D1; American Type Culture Collection) and rabbit serum complement (Serotec, Oxford, U.K.). Following separation on Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden), >90% of the surviving cells expressed the B cell-specific marker Lyb.8.2 by FACS analysis. The splenic macrophage-enriched population was prepared using an overnight adherence procedure (31). Briefly, RBC-depleted splenocytes in DMEM (107 cells/ml) were incubated for 90 min at 37°C in 60-mm plastic dishes. Nonadherent cells were discarded, the dishes were gently rinsed, and complete medium was replaced. After an 18-h culture, the nonadherent cells were discarded, and adherent cells were detached by incubating the plate with 0.25% trypsin (Life Technologies) in complete DMEM for 10 min at room temperature.

Determination of I content in Tg

Iodination of Tg was performed by the Iodogen method according to the manufacturer’s instructions (Pierce, Rockford, IL), and free I was separated from Tg by exhaustive dialysis. The I content in Tg samples was determined by a modified nonincinerative method (32, 33) based on the catalytic activity of I in the ceric (Ce)-arsenite (As) reaction. The reduction of Ce(IV) to Ce(III) by As(III) leads to a decoloration of yellow Ce ion to colorless cerious ion, a process that can be followed spectrophotometrically. Construction of standard curves was performed using known concentrations of T4 (Sigma-Aldrich) dissolved in 99 vol absolute methanol and 1 vol 30% ammonium hydroxide.

T cell activation assays

Mice were immunized s.c. with 100 µg Tg or I-Tg in 100 µl CFA emulsion (with Mycobacterium butyricum; Difco, Detroit, MI), and 9–12 days later inguinal, brachial, and axillary lymph node cells (LNC) were tested for 96 h in Ag-specific recall assays in 200-µl microcultures (4–6 x 105 cells/well). During the last 24 h 1 µCi [3H]thymidine (DuPont, Markham, Ontario, Canada) was added to each well. Cell harvesting and counting of the incorporated radioactivity were performed as previously described (25). The stimulation index is defined as cpm in the presence of Ag/cpm in the absence of Ag. Activation of peptide-specific T cell hybridomas was monitored by mixing Ag, 105 T cells, and various numbers of APC for 24 h, and assessing the IL-2 content in the culture supernatant as previously described (27).

Induction of EAT

Mice were immunized s.c. with 100 µg Tg or I-Tg emulsified in CFA. Two weeks later they were boosted with 50 µg of the same Ag in IFA (Difco). EAT was assessed by histological examination of the thyroids 4 wk after the initial immunization. Mononuclear cell infiltration was scored as follows: 0.5 = interstitial accumulation of cells between two or three follicles; 1 = one or two foci of cells at least the size of one follicle; 2 = extensive infiltration (10–40% of the total area); 3 = extensive infiltration (40–80% of the total area); and 4 = extensive infiltration (>80% of the total area). Statistical differences in EAT severity between mouse groups were determined by the nonparametric Mann-Whitney U test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Preparation of I-Tg

The I content in the I-Tg preparations was assessed by a modified (32), nonincinerative, colorimetric method (33) based on the catalytic function of I in the reduction of the yellow Ce ion Ce(IV) to the colorless cerious ion Ce(III) by As(III). Using T4 as a standard in the assay, it was confirmed that the initial change in absorbance was proportional to the amount of T4 over the range of 120–960 pmol (Fig. 1GoA). By extrapolation, normal mouse Tg was shown to contain 15–20 I atoms, and this content increased to a plateau of ~70 I atoms/molecule over a 20-min incubation period with Iodogen (Fig. 1GoB). Maximally iodinated Tg (>60 I atoms/monomeric subunit) was used in all subsequent work.



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  		FIGURE 1. I determination in Tg preparations. A, Reduction of absorbance at 410 nm in the first 60 s of the I-catalyzed Ce-As reaction as a function of T4 added. B, I content in Tg iodinated over various time periods by the Iodogen method, as extrapolated from A. Sixteen micrograms of the Tg sample was used for I determination (1 mol T4 contains 4 mol I).

 
Iodination enhances the immunopathogenicity of Tg

To examine whether iodination of Tg promotes its pathogenicity, SJL/J mice (six mice per group) were immunized with Tg or I-Tg in CFA on day 0 and boosted with the respective Ag in IFA on day 14. Thyroids were collected on day 28 for histological examination of EAT development. In two experiments, I-Tg-challenged groups developed severe EAT (infiltration index (I.I.), >=3; Table IGo) and exhibited significantly higher mean I.I. (expt. 1, 2.8 vs 1.3; expt. 2, 3.8 vs 2.0) than those in the Tg-primed groups. In total, 6 of 12 SJL mice challenged with I-Tg in both experiments presented with complete destruction of the thyroid gland architecture (I.I., 4; Fig. 2Go), whereas this degree of EAT severity was not observed in any of the 12 Tg-challenged mice tested.


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  		Table I. EAT induction in SJL mice following challenge with normal or highly iodinated Tg1

 


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  		FIGURE 2. Representative histological appearance of thyroids following challenge of SJL mice with Tg or I-Tg as described in Materials and Methods. A, Normal thyroid. B, Extensive mononuclear cell infiltration of the thyroid covering 40–80% of the area (I.I. = 3). C, Complete destruction of the thyroid gland architecture by a massive infiltrate (I.I. = 4). Under the described experimental conditions only mice that received I-Tg presented with an I.I. of 4. Magnification, x100.

 
To examine whether the increased pathogenicity of I-Tg correlates with its immunogenicity, SJL/J mice were challenged s.c. with 100 µg Tg or I-Tg emulsified in CFA, and the Ag-specific in vitro responses of primed LNC were determined 9–11 days later. LNC from Tg-primed mice did not proliferate strongly against Tg or I-Tg (Fig. 3GoA). In contrast, LNC from I-Tg-primed mice responded vigorously against I-Tg, and to some extent to Tg, in vitro. No responses were detected against highly iodinated OVA (data not shown), indicating recognition of determinants restricted to I-Tg. These data suggested that modification of Tg by I rendered this molecule highly immunogenic at the T cell level.



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  		FIGURE 3. I-Tg is highly immunogenic and promotes induction of p2495-specific T cells in vivo. Proliferative in vitro responses of LNC from SJL mice (two mice per group) against Tg preparations (A; 167 µg/ml) or Tg peptides (B; 20 µg/ml) 10 days after challenge with 100 µg of either Tg or I-Tg emulsified in CFA. [3H]Thymidine was added during the last 24 h of a 96-h culture. Each value represents average of triplicate wells. The data are representative of two independent experiments.

 
Enhanced iodination of Tg promotes generation of the cryptic pathogenic peptide p2495

The enhanced immunopathogenicity of I-Tg vs Tg could be explained via at least two distinct mechanisms that are not mutually exclusive. First, iodination might facilitate generation of cryptic T cell epitopes that are shared with normal Tg, but are formed only after processing of I-Tg in APC. Second, iodination might lead to formation of new I-modified T cell epitopes that do not exist in normal Tg. We proceeded to seek evidence for the first mechanism because of the availability and prior characterization of the cryptic Tg peptides p2495 and p2694 in our laboratory (19, 25, 26). These peptides are immunogenic and cause EAT but are not normally generated following processing of Tg in vivo or in vitro.

SJL/J mice were again immunized with Tg or I-Tg in CFA, and 9 days later the draining LNC were tested in recall proliferative assays against p2495 or p2694 in vitro. Neither peptide could stimulate the Tg-primed LNC to proliferate, in accordance with their cryptic nature (Fig. 3GoB). Surprisingly, however, p2495, but not p2694, induced significant proliferation of I-Tg-primed LNC. This finding supported the view that iodination of Tg promotes selective generation of pathogenic peptides such as p2495. To confirm this at the clonal T cell level we used the CD4+, As-restricted 5E8 and 6E10 T cell hybridoma clones that secrete IL-2 upon recognition of p2495 and p2694, respectively (Fig. 4Go, A and B). Freshly isolated SJL spleen cells, used as APC, were incubated with 5E8 or 6E10 T cells and varying concentrations of Tg, I-Tg, or I-OVA. I-Tg strongly activated the p2495-specific 5E8 clone within the 0.1–1 µM range (Fig. 4GoC), whereas equimolar amounts of normal Tg were not stimulatory. Similarly, I-OVA did not elicit a response up to 3.5 µM, excluding the possibility that the high I content in the antigenic preparation mediated a nonspecific activation of the T cells. In addition, Tg subjected to the iodination process, but in the absence of I, did not activate the 5E8 clone (data not shown), suggesting that Tg is not degraded by this treatment in a manner that obviates the need for processing. In contrast, the p2694-specific 6E10 clone was not activated with either Tg or I-Tg, (Fig. 4GoD), while it responded strongly to equimolar amounts of free p2694 (Fig. 4GoB). These data confirmed that enhanced iodination of Tg promoted the selective processing and presentation of the cryptic pathogenic peptide p2495 in APC.



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  		FIGURE 4. Enhanced presentation of p2495 following processing of I-Tg in vitro. IL-2 release following activation of H-2As-restricted T cell hybridoma clones 5E8 (p2495-specific) and 6E10 (p2694-specific) cultured with SJL splenocytes (5 x 105 cells/well) in the presence of serial dilutions of free peptide (A and B) or Tg preparations or OVA (C and D).

 
Generation of p2495 following processing of I-Tg in macrophages and DC

We next examined whether the selective generation of p2495 could be observed only after processing of I-Tg in certain APC subsets. Splenic resting B cells were isolated by complement-mediated depletion of T cells and accessory cells using anti-Thy1.1, anti-MAC-1, and anti-DC mAbs. Splenic macrophages were enriched by plastic adherence. Mature DC were obtained by culturing bone marrow progenitors in the presence of GM-CSF. The various APC populations were mixed at a 1:1 ratio with 5E8 or 6E10 T cells in the presence of 1 µM Tg and I-Tg, using equimolar amounts of free p2495, p2694, and I-OVA as controls. As shown in Fig. 5Go, none of the APC populations could generate p2495 or p2694 following processing of normal Tg, as indicated by the lack of activation of the peptide-specific T cell clones. In contrast, processing of I-Tg in macrophages or DC, but not B cells, allowed generation of p2495 and activation of the 5E8 clone (Fig. 5Go, A, C, and E). This was a selective process because p2694 was not generated in any APC under identical conditions of culture (Fig. 5Go, B, D, and F). These findings demonstrated that enhanced iodination of Tg promotes selective generation of p2495 in specific APC subsets, such as macrophages and DC, which are potent stimulators of naive T cells.



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  		FIGURE 5. Efficient generation of p2495 following processing of I-Tg in macrophages and DC. IL-2 release following activation of the 5E8 (p2495-specific) and 6E10 (p2694-specific) clones cultured at a 1:1 ratio with splenic macrophages (A and B), bone marrow-derived DC (C and D), and splenic B cells (E and F) in the presence of 1 µM of the Ags shown. The data are representative of three independent experiments; *, not done.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Tg plays a central role in thyroid function and pathology because of its capacity 1) to store available I, 2) to act as a matrix for the formation and storage of thyroid hormones, and 3) to encompass epitopes that activate thyroid-infiltrating T cells (16, 19, 20). In this study we provide evidence that increased iodination of normal Tg renders the molecule highly immunogenic via at least one distinct mechanism: the enhanced generation of noniodinated, cryptic, pathogenic T cell determinants, such as p2495, in APC. Because the structure (34) and proteolytic degradation (35, 36) of Tg are known to be affected by its I content, the present findings can be best explained by an I-mediated modification of Tg substrate sites resulting in altered I-Tg processing in APC compared with that of normal Tg. This hypothesis can account for the observed selective changes in the hierarchy (37) of T cell epitopes in I-Tg, manifested by the generation of p2495, which changes from cryptic (26) to dominant, and by the apparent lack of effect on the formation of p2694, which remains nondominant (25). The same hypothesis can also account for the differential capacity of various APC (macrophages and DC vs B cells) to process a given peptide due to their diverse protease contents (38). Because circulating Tg is poorly iodinated (39, 40), peptides such as p2495 would not be normally generated in extrathyroidal sites, but, once formed, they could elicit strong autoreactive T cell responses, as it is unlikely that immune mechanisms of peripheral tolerance would be pre-established against cryptic epitopes. This consideration deserves further merit in view of the fact that to date all known pathogenic T cell epitopes in Tg have been characterized as nondominant (19). Our results are analogous to those of Griem et al. (41), who showed that alteration of bovine RNase A by the metal ion Au(III) leads to sensitization of T cells specific for cryptic peptides. Thus, iodination of Tg can be included in the list of known post-translational modifications of autoantigens that promote the generation of pathogenic T cell epitopes in autoimmune diseases (42).

Processing of I-Tg could also generate novel, I-modified T cell determinants containing iodotyrosyls or enhance the production of T cell epitopes that encompass hormonogenic sites. While there is no evidence as yet for the former mechanism, the peptide 2549–2560 containing T4 at position 2553 (T42553) is known to activate pathogenic CD4+ T cells that recognize I atoms, because they cannot be activated by a thyronine-containing (T02553) analog that lacks I (21, 22, 23, 43). If there is increased production of T42553 during the processing of I-Tg vs Tg, it could potentiate the generation of Tg-reactive, EAT-inducing T cells. However, the contribution of hormonogenic regions to the enhanced immunopathogenicity of I-Tg is probably minimal, because most T4-containing peptides are weakly antigenic or devoid of immunogenicity (20).

High I intake may promote the iodination of Tg, but it can also precipitate a number of other pathogenetic cascades related to I toxicity. High doses of I can cause necrosis of hyperplastic thyroid glands of normal animals (13, 44) or human thyroid follicles in vitro (45). This initial thyroid cell injury may be an important prerequisite for the subsequent development of autoimmune thyroiditis in goitrous nonobese diabetic mice (46), obese strain chickens (44), or humans with preexisting goiters (3, 5, 47, 48). In addition, I can exhibit pleiotropic effects by influencing processes that interfere with immune function. These include inhibition of IFN-{gamma}-induced class II expression on rat (FRLT-5), but not human, thyroid cells (49), increased inducibility of the 72-kDa heat shock protein in cultured human thyrocytes (50), and enhancement of IgG production in pokeweed mitogen-stimulated human peripheral blood lymphocytes in vitro (51).

Our findings are in agreement with studies reporting an essential role of I for Tg recognition by human T cells (52). Presentation of cryptic I-Tg peptides on professional APC such as DC would lead to activation of resting autoreactive T cells that can subsequently act as effector cells in autoimmune thyroiditis and/or as Th cells in the concomitant Ab response against thyroid Ags. In conjunction with the available TCR repertoire, the host MHC haplotype would dictate, via determinant selection, the relative contribution of each peptide in the disease process. This hypothesis would explain why only certain individuals develop autoimmune thyroiditis after high I intake (16) or why they occasionally present with enhanced B cell autoreactivity to Tg without overt symptoms of thyroiditis (53). The validity of this hypothesis will be further tested following the discovery of additional pathogenic T cell epitopes in Tg.


   Acknowledgments
 
We thank Judy Foote and Howard Gladney for their expert help with the histology work.


   Footnotes
 
1 This work was supported by a grant from the Canadian Institutes of Health Research and Ph.D. fellowships from the Memorial University of Newfoundland (to Y.D.D. and V.P.R.). Back

2 Address correspondence and reprint requests to Dr. George Carayanniotis, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland A1B 3V6, Canada. E-mail address: gcarayan{at}mun.ca Back

3 Abbreviations used in this paper: Tg, thyroglobulin; As, arsenite; EAT, experimental autoimmune thyroiditis; Ce, ceric; DC, dendritic cell; I.I., infiltration index; I-Tg, iodinated Tg; LNC, lymph node cell; T4, thyroxine. Back

Received for publication October 9, 2001. Accepted for publication March 22, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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