Human thyroglobulin peptide p2340 induces autoimmune thyroiditis in HLA-DR3 transgenic mice

Karras, Evangelos; Yang, Huan; Lymberi, Peggy; Christadoss, Premkumar

doi:10.1016/j.jaut.2005.02.002

Cited by 16 publications

(14 citation statements)

References 24 publications

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“…As H2E is homologous to human HLA-DR, the successful identification of mTg-derived peptides presented by an H2E class II molecule opens the possibility of comparing the roles of H2E and HLA-DR molecules in autoimmune thyroiditis. Interestingly, a 20-mer hTg peptide (p2340), which contains four N-terminal amino acids additional to a peptide (hTg2344) pathogenic in our A − E + strain [9], has been reported to bind to H2E k [27], as well as HLA-DR3 [28]. Similarly, we report here that an hTg-derived peptide, hTg179, weakly pathogenic in DR3-transgenic mice [13], is immunogenic in A − E + mice.…”

Section: Discussionsupporting

confidence: 65%

A novel H2A−E+ transgenic model susceptible to human but not mouse thyroglobulin-induced autoimmune thyroiditis: Identification of mouse pathogenic epitopes

Brown

McCormick

Brusic

et al. 2008

Cellular Immunology

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The A − E + transgenic mouse is highly susceptible to human thyroglobulin (hTg)-induced thyroiditis, but strongly tolerant to a challenge by mouse thyroglobulin (mTg), in stark contrast to traditionally susceptible strains, wherein mTg induces stronger thyroiditis. To identify mouse thyroid epitopes recognized by destructive, hTg-primed T cells, we selected the three hTg epitopes known to be presented by H2E b , as the basis for synthesizing potential mTg epitopes. One 15-mer peptide, mTg409, did prime T cells, elicit Ab, and induce thyroiditis. Moreover, cells primed with corresponding, pathogenic hTg410 cross-reacted with mTg409, and vice versa. mTg409 contained 4/4 anchor residues, similar to the corresponding hTg peptide. Based on this finding, a second mTg epitope, mTg179, was subsequently identified. These mTg autoepitopes, identified by using thyroiditogenic hTg epitopes, help to explain the severe thyroiditis seen in this novel A − E + transgenic model.

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Section: Discussionsupporting

confidence: 65%

A novel H2A−E+ transgenic model susceptible to human but not mouse thyroglobulin-induced autoimmune thyroiditis: Identification of mouse pathogenic epitopes

Brown

McCormick

Brusic

et al. 2008

Cellular Immunology

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“…Since then, work from several laboratories (19)(20)(21)(22)(23)(24)(25) has established the presence of 15 noniodinated but pathogenic Tg peptides, scattered throughout the Tg sequence ( Table 1). The majority of the determinants encompassed within these sites are recognized by CD4 þ and mouse MHC class II-restricted T cells; one was recognized by an MHC class I-restricted, cytotoxic T-cell (CTL) hybridoma (18); recently, four hTg peptides were described eliciting EAT in HLA-DR3-transgenic mice (21,26). Within the last group, of note are hTg peptides p2079, which elicits considerable EAT both directly and by adoptive transfer assays (21), and p2340 (23,26), which was originally shown to be a target of Tg-reactive Abs in patients with Graves' disease (27).…”

Section: Noniodinated But Pathogenic Tg Peptidesmentioning

confidence: 99%

“…The majority of the determinants encompassed within these sites are recognized by CD4 þ and mouse MHC class II-restricted T cells; one was recognized by an MHC class I-restricted, cytotoxic T-cell (CTL) hybridoma (18); recently, four hTg peptides were described eliciting EAT in HLA-DR3-transgenic mice (21,26). Within the last group, of note are hTg peptides p2079, which elicits considerable EAT both directly and by adoptive transfer assays (21), and p2340 (23,26), which was originally shown to be a target of Tg-reactive Abs in patients with Graves' disease (27). To a large extent, these findings reflected the bias of the screening approach; for example, since susceptibility to EAT is A k controlled, computerized algorithms were used to search for A k -binding, pathogenic Tg peptides.…”

Section: Noniodinated But Pathogenic Tg Peptidesmentioning

confidence: 99%

Recognition of Thyroglobulin by T Cells: The Role of Iodine

Carayanniotis

2007

Thyroid

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Among known autoantigens, thyroglobulin (Tg) is unique in its capacity to store iodine, an element provided in our daily diet. Evolutionary pressure has sculpted Tg into a large molecular scaffolding to allow organification of iodide and its incorporation into thyroid hormones. The increase in molecular size and the posttranslational modification by iodine had to exact immunological consequences. Over the last 15 years, numerous Tg peptides-targets of thyroiditogenic T cells-have been mapped, raising questions regarding the mechanisms that maintain or abrogate immune tolerance against this large autoantigen. This review summarizes the work in this area and discusses the role iodine may play in these processes.

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“…Our data describe two new thyroiditogenic Tg epitopes, p2369-2380 and p2439-2450, located near the cathepsin L cleavage sites 2388 and 2451, respectively. Interestingly, these epitopes are clustered close to known immunopathogenic Tg epitopes p2494-510 (16), p2495-503 and p2498-506 (34) in mTg and p2340-59 in human Tg (hTg) (35,36) at the C-terminal region of the large Tg molecule. Recent work by Jacobson et al (37) examining hTg digests by individual human cathepsins L, B, and D identified cleavage sites near the ones described by earlier work of Dunn et al (27) with rabbit Tg in 7 of 11 cases shown in Table I.…”

Section: Discussionmentioning

confidence: 83%

Identification of Pathogenic T Cell Epitopes Near Cathepsin Cleavage Sites in Thyroglobulin

Kolypetri

Jiang

Carayanniotis

2013

The Journal of Immunology

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Experimental autoimmune thyroiditis, induced in mice after challenge with thyroglobulin (Tg), is known to be under the genetic control of the H2Ak locus. Because cathepsins are known to influence proteolytic processing of Tg in vivo, we examined in this study whether putative H2Ak-binding Tg epitopes, located near cathepsin cleavage sites within mouse Tg, have immunopathogenic properties. Cathepsin L, B, and D cleavage sites in mouse Tg were predicted based on homology with known cathepsin cleavage sites in rabbit Tg. We used an algorithm-based approach to identify H2Ak-binding motifs within 20-aa residue segments adjacent to cathepsin cleavage sites, and five 12mer peptides encompassing these sequences were synthesized. Two of them, p2369 (aa 2369–2380) and p2439 (aa 2439–2450) were immunogenic, eliciting significant proliferative T cell responses using lymph node cells from peptide-primed mice and production of IL-2 and IFN-γ in recall assays in vitro. Both peptides induced experimental autoimmune thyroiditis upon direct challenge of CBA/J mice with peptide in CFA and by adoptive transfer of peptide-primed lymph node cells into naive recipient hosts, but neither peptide was characterized as dominant.

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Human thyroglobulin peptide p2340 induces autoimmune thyroiditis in HLA-DR3 transgenic mice

Cited by 16 publications

References 24 publications

A novel H2A−E+ transgenic model susceptible to human but not mouse thyroglobulin-induced autoimmune thyroiditis: Identification of mouse pathogenic epitopes

A novel H2A−E+ transgenic model susceptible to human but not mouse thyroglobulin-induced autoimmune thyroiditis: Identification of mouse pathogenic epitopes

Recognition of Thyroglobulin by T Cells: The Role of Iodine

Identification of Pathogenic T Cell Epitopes Near Cathepsin Cleavage Sites in Thyroglobulin

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