Pathogenicity of a human thyroglobulin peptide (2340–2359) in mice with high or low genetic susceptibility to thyroiditis

Hatzioannou, Aikaterini; Liakata, E; Karras, Evangelos; Thrasyvoulides, Apollon; Alevizaki, Maria; Lymberi, Peggy

doi:10.1111/j.1365-2567.2007.02645.x

Cited by 5 publications

(18 citation statements)

References 25 publications

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“…Other hTg peptides have also been identified as T-cell epitopes in AITD, including p2340 (a.a. 2340–2359) [33], p179 (a.a. 1790194), p2540 (a.a. 2540–2554), p2529 (a.a. 2529–2545) [34], and others [35]. However, all of these peptides were tested in EAT susceptible mice (e.g.…”

Section: Discussionmentioning

confidence: 99%

Tg.2098 is a major human thyroglobulin T-cell epitope

Menconi¹,

Huber²,

Osman³

et al. 2010

Journal of Autoimmunity

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An HLA-DR variant containing Arginine at position 74 of the DRβ1 chain confers a strong genetic susceptibility to autoimmune thyroid diseases (AITD), Graves' disease (GD) and Hashimoto's thyroiditis (HT), while Glutamine at position DRβ1-74 is protective. We hypothesized that the DRβ1-Arg74 variant is able to present pathogenic thyroglobulin (Tg) peptides to T-cells more efficiently, thereby triggering thyroid autoimmunity. Indeed, we have previously identified 4 human Tg (hTg) peptides that bind specifically to DRβ1-Arg74 with much weaker binding to the protective variant DRβ1-Gln74. The aim of our study was to examine in vivo whether an hTg peptide that binds strongly and specifically to DRβ1-Arg74 is capable of stimulating T-cells during the induction of thyroiditis in a "humanized" mouse expressing human DR3, and in patients positive for Tg antibodies. Sequencing of exon 2 of the DR transgene in the DR3-mice, null for endogenous MHC II molecules, confirmed that they expressed the disease associated DRβ1-Arg74 variant, thus making them an ideal in vivo model to test the presentation of hTg peptides by DRβ1-Arg74 HLA-DR. Induction of EAT in the DR3 mice lead to T-cell stimulation and proliferation to Tg.2098, a strong and specific DRβ1-Arg74 binder, while a non-binding control peptide, Tg.2766 did not induce this response. Moreover, Tg.2098 stimulated T-cells from 4 individuals who were positive for thyroglobulin antibodies, demonstrating that Tg.2098 is an immunogenic peptide capable of being presented in vivo and activating T-cells in EAT and AITD. Energetic analysis of the complex formed by Tg.2098 and DRβ-Arg74 has shown that the origin of the affinity was determined by residues 1, 7 and 9 in the peptide, while the selectivity of the peptide for the MHC was determined by the Asp in position 4. The disease-protective substitution R74Q, leads to reduction in affinity due to changes in local interaction with D4 as well as non-local interaction with other residues. The electrostatic potential on the surface of the DRβ-Arg74 -Tg.2098 complex has a unique signature which may be recognized by T-cell receptors leading to autoimmune thyroiditis. Taken together these findings suggest that Tg. 2098, a strong and specific binder to the disease associated HLA-DRβ-Arg74, is a major human Tcell epitope and participant in the pathoetiology of AITD.

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Section: Discussionmentioning

confidence: 99%

Tg.2098 is a major human thyroglobulin T-cell epitope

Menconi¹,

Huber²,

Osman³

et al. 2010

Journal of Autoimmunity

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“…We found it to be immunogenic in A ϩ E Ϫ and A ϩ E ϩ mice, and A b -restricted. Interestingly, an hTg-homologue of this peptide, p2340, was recently shown to be immunogenic and mildly pathogenic in H2 b mice (26). Because mTg2342 is presented in A bexpressing mice, it is likely that those p2340 (hTg peptide)-primed T cells responded to endogenously presented mTg2342 to induce thyroid destruction.…”

Section: Discussionmentioning

confidence: 99%

H2E-Derived Eα52-68 Peptide Presented by H2Ab Interferes with Clonal Deletion of Autoreactive T Cells in Autoimmune Thyroiditis

Brown

McCormick²,

David

et al. 2008

The Journal of Immunology

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Susceptibility and resistance to experimental autoimmune thyroiditis is encoded by MHC H2A genes. We reported that traditionally resistant B10 (H2b) mice permit thyroiditis induction with mouse thyroglobulin (mTg) after depleting regulatory T cells (Tregs), supporting Ab presentation to thyroiditogenic T cells. Yet, Eak transgenic mice, expressing Ab and normally absent Eb molecules (E+B10 mice), are susceptible to thyroiditis induction without Treg depletion. To explore the effect of Eb expression on mTg presentation by Ab, seven putative Ab-binding, 15–16-mer peptides were synthesized. Five were immunogenic for both B10 and E+B10 mice. The effect of Eb expression was tested by competition with an Eα52-68 peptide, because Eα52-68 occupies ∼15% of Ab molecules in E+B10 mice, binding with high affinity. Eα52-68 competitively reduced the proliferative response to mTg, mTg1677, and mTg2342 of lymph node cells primed to each Ag. Moreover, mTg1677 induced mild thyroiditis in Treg-depleted B10 mice, and in E+B10 mice without the need for Treg depletion. Eα52-68 competition with mTg-derived peptides may impede clonal deletion of pathogenic, mTg-specific T cells in the thymus.

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“…Proliferation assays of LNCs were performed as previously described . Briefly, 6‐ to 8‐week‐old female mice were immunized subcutaneously at both the tail base and the back with 100 nmol p2208, or with 75 μg hTg emulsified in complete Freund's adjuvant (CFA) (Sigma, St Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

“…Out of the 34 Tg peptides tested for pathogenic potential in HR strains, 17 were found to be thyroiditogenic. In contrast, only one of ten tested Tg peptides, the 20mer p2340 [amino acids (aa) 2340–2359)], was previously identified in our laboratory to induce EAT in LR strains . This peptide was pathogenic in LR strains C57BL/6 (H‐2 b ) and BALB/c (H‐2 d ) only via the adoptive transfer of syngeneic peptide‐primed LNCs and in HR strains SJL/J (H‐2 s ) and CBA/J (H‐2 k ) by direct challenge .…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, only one of ten tested Tg peptides, the 20mer p2340 [amino acids (aa) 2340–2359)], was previously identified in our laboratory to induce EAT in LR strains . This peptide was pathogenic in LR strains C57BL/6 (H‐2 b ) and BALB/c (H‐2 d ) only via the adoptive transfer of syngeneic peptide‐primed LNCs and in HR strains SJL/J (H‐2 s ) and CBA/J (H‐2 k ) by direct challenge . Identification of defined Tg peptides with pathogenic potential in LR mouse strains could facilitate studies of immunoregulation of EAT through the use of an expanded list of available hosts, such as recombinant inbred strains and knock‐in or knock‐out mice, currently available only in LR strain backgrounds.…”

Section: Introductionmentioning

confidence: 99%

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A novel pathogenic peptide of thyroglobulin (2208–2227) induces autoreactive T‐cell and B‐cell responses in both high and low responder mouse strains

2014

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Summary Experimental autoimmune thyroiditis (EAT) is commonly induced by thyroglobulin (Tg) or Tg peptides in mice genetically susceptible to thyroiditis. In the present study, we investigated the immunogenic and pathogenic potential of a novel 20mer human Tg peptide, p2208 (amino acids 2208–2227), in mouse strains classified as low (LR) or high (HR) responders in EAT. The peptide was selected for its content in overlapping binding motifs for MHC class II products, associated with either resistance (Ab), or susceptibility (As, Ek) to EAT. We therefore immunized LR BALB/c (H‐2d) and C57BL/6 (H‐2b) strains, as well as HR CBA/J (H‐2k) and SJL/J (H‐2s) mice with 100 nmol of p2208 in adjuvant and collected their sera, lymph nodes and thyroid glands for further analysis. The p2208 peptide was found to contain B‐cell and cryptic T‐cell epitope(s) in two of the four strains examined, one LR and one HR. Specifically, it elicited direct EAT in C57BL/6 mice (two of seven mice, infiltration index 1–3), as well as in SJL/J mice (two of six mice, infiltration index 1–2). Such an EAT model could provide insights into the immunoregulatory cascades taking place in resistant hosts.

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Pathogenicity of a human thyroglobulin peptide (2340–2359) in mice with high or low genetic susceptibility to thyroiditis

Cited by 5 publications

References 25 publications

Tg.2098 is a major human thyroglobulin T-cell epitope

Tg.2098 is a major human thyroglobulin T-cell epitope

H2E-Derived Eα52-68 Peptide Presented by H2Ab Interferes with Clonal Deletion of Autoreactive T Cells in Autoimmune Thyroiditis

A novel pathogenic peptide of thyroglobulin (2208–2227) induces autoreactive T‐cell and B‐cell responses in both high and low responder mouse strains

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