Pathogenic human thyroglobulin peptides in HLA-DR3 transgenic mouse model of autoimmune thyroiditis

Flynn, Jeffrey C.; McCormick, Daniel J.; Brusic, Vladimir; Wan, Qiang; Panos, John C.; Giraldo, Alvaro A.; David, Chella S.; Kong, Yi

doi:10.1016/j.cellimm.2004.07.002

Cited by 40 publications

(59 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, we can now confirm what the authors suggested, that is, that the peptide was likely a natural peptide generated in DR3 individuals (34), demonstrating that a computer algorithm can predict a peptide identical in size and sequence to a naturally processed peptide. It remains to be clarified whether DR51-Tg 726 -743 or any other DR-Tg complex expressed in human GD thyroids are also potentially pathogenic or related to the regulation of the autoimmune response.…”

Section: Discussionsupporting

confidence: 74%

“…EAT can also be induced by direct immunization with thyroiditogenic peptides, including some human Tg peptides (32,33). Although the pathological relevance of the Tg peptides that we have identified is not known, data from another group have demonstrated the pathogenicity of Tg 2098 -2112 in a DR3 transgenic model of Tg-induced EAT (34). A computerbased predicted set of 39 synthetic DR3-binding Tg peptides was screened against T cells from EAT ϩ DR3-transgenic mice, and only 4 could stimulate T cell responses.…”

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

Thyroglobulin Peptides Associate In Vivo to HLA-DR in Autoimmune Thyroid Glands

Muixí

Carrascal

Álvarez

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

Endocrine epithelial cells, targets of the autoimmune response in thyroid and other organ-specific autoimmune diseases, express HLA class II (HLA-II) molecules that are presumably involved in the maintenance and regulation of the in situ autoimmune response. HLA-II molecules thus expressed by thyroid cells have the “compact” conformation and are therefore expected to stably bind autologous peptides. Using a new approach to study in situ T cell responses without the characterization of self-reactive T cells and their specificity, we have identified natural HLA-DR-associated peptides in autoimmune organs that will allow finding peptide-specific T cells in situ. This study reports a first analysis of HLA-DR natural ligands from ex vivo Graves’ disease-affected thyroid tissue. Using mass spectrometry, we identified 162 autologous peptides from HLA-DR-expressing cells, including thyroid follicular cells, with some corresponding to predominant molecules of the thyroid colloid. Most interestingly, eight of the peptides were derived from a major autoantigen, thyroglobulin. In vitro binding identified HLA-DR3 as the allele to which one of these peptides likely associates in vivo. Computer modeling and bioinformatics analysis suggested other HLA-DR alleles for binding of other thyroglobulin peptides. Our data demonstrate that although the HLA-DR-associated peptide pool in autoimmune tissue mostly belongs to abundant ubiquitous proteins, peptides from autoantigens are also associated to HLA-DR in vivo and therefore may well be involved in the maintenance and the regulation of the autoimmune response.

show abstract

Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 88%

Thyroglobulin Peptides Associate In Vivo to HLA-DR in Autoimmune Thyroid Glands

Muixí

Carrascal

Álvarez

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…It remains to be determined whether the novel Tg-derived HLA-DR3-binding peptides identified in this study, as well as the previously identified thyroglobulin peptides (17), are immunodominant, subdominant, cryptic, or simply self-peptides. Importantly, of all the evaluated Tg-derived HLA-DR3-binding peptides, Tg.2098 is especially interesting as it was detected using our recombinant system, as well as by two other groups; the first group used thyroid tissues from patients with Graves disease (17), and the second group conducted peptide immunizations in mice (45). Hence, these data suggest that Tg.2098 could possibly play a role in the initiation of AITD.…”

Section: Discussionmentioning

confidence: 90%

Employing a Recombinant HLA-DR3 Expression System to Dissect Major Histocompatibility Complex II-Thyroglobulin Peptide Dynamism

Jacobson

Yang

Menconi

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Previously, we have shown that statistical synergism between amino acid variants in thyroglobulin (Tg) and specific HLA-DR3 pocket sequence signatures conferred a high risk for autoimmune thyroid disease (AITD). Therefore, we hypothesized that this statistical synergism mirrors a biochemical interaction between Tg peptides and HLA-DR3, which is key to the pathoetiology of AITD. To test this hypothesis, we designed a recombinant HLA-DR3 expression system that was used to express HLA-DR molecules harboring either AITD susceptibility or resistance DR pocket sequences. Next, we biochemically generated the potential Tg peptidic repertoire available to HLA-DR3 by separately treating 20 purified human thyroglobulin samples with cathepsins B, D, or L, lysosomal proteases that are involved in antigen processing and thyroid biology. Sequences of the cathepsingenerated peptides were then determined by matrix-assisted laser desorption ionization time-of-flight-mass spectroscopy, and algorithmic means were employed to identify putative AITD-susceptible HLA-DR3 binders. From four predicted peptides, we identified two novel peptides that bound strongly and specifically to both recombinant AITD-susceptible HLA-DR3 protein and HLA-DR3 molecules expressed on stably transfected cells. Intriguingly, the HLA-DR3-binding peptides we identified had a marked preference for the AITD-susceptibility DR signatures and not to those signatures that were AITD-protective. Structural analyses demonstrated the profound influence that the pocket signatures have on the interaction of HLA-DR molecules with Tg peptides. Our study suggests that interactions between Tg and discrete HLA-DR pocket signatures contribute to the initiation of AITD. The major histocompatibility complex (MHC)3 II molecule is intimately associated with the initiation of autoimmunity. Studies in several MHC II-associated autoimmune conditions, most notably type 1 diabetes, have now convincingly demonstrated that susceptibility to disease is caused by certain structural features of the MHC II peptide binding cleft that influence the display of immunogenic peptides (1-5). Similarly, we have shown that the autoimmune thyroid diseases (AITD), Graves disease (GD) and Hashimoto thyroiditis (HT), are strongly associated with unique HLA-DR peptide binding cleft sequences (6,30). Mechanistically, these pocket amino acid signatures could accommodate autoantigenic peptides derived from any of the thyroid-specific proteins, namely thyroglobulin (Tg), thyroid peroxidase, and thyrotropin receptor. Indeed, there exist data demonstrating that thyroglobulin, which constitutes 80% (8) of total thyroidal protein, is an important thyroidal target and participant in triggering AITD (reviewed in Ref. 9). Along a similar vein of thought, there is mounting evidence that suggests a role for polymorphisms in the thyrotropin receptor, the specific target of Graves disease, in the initiation of Graves hyperthyroidism (28).For the case of thyroid autoimmunity, the connection between MHC II susceptibility...

show abstract

“…Several previous studies by us and others (29,39,41) identified Tg.2098 as the major peptide triggering thyroid autoimmunity. In the present study we confirmed and extended these findings (29).…”

Section: Discussionmentioning

confidence: 99%

“…We showed that 87% of NOD-DR3 mice that developed EAT following immunization with whole hTg protein had significant T-cell proliferative and cytokine responses to Tg.2098, whereas responses to other hTg peptides that bound HLA-DR␤1-Arg74 were much weaker. Because mice were immunized with the entire hTg protein this suggested that Tg.2098 was generated from hTg by antigen-presenting cells in the mice and presented by HLA-DR3 (containing HLA-DR␤1-Arg74) to T-cells, generating a memory response to Tg.2098 (39,41).…”

Section: Discussionmentioning

confidence: 99%

Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis

Menconi

Osman

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

We previously showed that an HLA-DR variant containing arginine at position 74 of the DR␤1 chain (DR␤1-Arg74) is the specific HLA class II variant conferring risk for autoimmune thyroid diseases (AITD). We also identified 5 thyroglobulin (Tg) peptides that bound to DR␤1-Arg74. We hypothesized that blocking the binding of these peptides to DR␤1-Arg74 could block the continuous T-cell activation in thyroiditis needed to maintain the autoimmune response to the thyroid. The aim of the current study was to identify small molecules that can block T-cell activation by Tg peptides presented within DR␤1-Arg74 pockets. We screened a large and diverse library of compounds and identified one compound, cepharanthine that was able to block peptide binding to DR␤1-Arg74. We then showed that Tg.2098 is the dominant peptide when inducing experimental autoimmune thyroiditis (EAT) in NOD mice expressing human DR␤1-Arg74. Furthermore, cepharanthine blocked T-cell activation by thyroglobulin peptides, in particular Tg.2098 in mice that were induced with EAT. For the first time we identified a small molecule that can block Tg peptide binding and presentation to T-cells in autoimmune thyroiditis. If confirmed cepharanthine could potentially have a role in treating human AITD. Autoimmune thyroid diseases (AITD),2 Graves disease (GD), and Hashimoto thyroiditis (HT), are among the most common autoimmune disorders, afflicting up to 5% of the United States population (1). They are characterized by infiltration of the thyroid by lymphocytes reactive to thyroid antigens and production of thyroid-specific antibodies (2). Complex interaction of genetic susceptibility factors, environmental triggers, and epigenetic alterations leads to the breakdown of tolerance, resulting in AITD (3-5). Currently, there is no satisfactory therapy except for hormone replacement therapy in HT or thyroid suppression or ablation in GD (6 -10). To develop new therapies for AITD a better understanding of their etiology is needed. We have been studying the etiology of AITD using a reverse-genetics approach, i.e. dissecting the mechanisms causing disease through unbiased genetic screening studies. These studies led to the identification of a specific HLA-DR pocket sequence that is strongly associated with AITD (11). The presence of arginine at position 74 of the DR␤ chain renders the individual highly susceptible to AITD, whereas glutamine at position 74 is protective (12). These data were confirmed by other groups (13). The presence of DR␤1-Arg74 (from here on we refer to the HLA-DR3 containing arginine at position 74 as HLA-DR␤1-Arg74) results in a more positively charged P4 pocket. With this structural change in the pocket, the selectivity and binding of pathogenic peptides is affected, conferring higher risk for disease (12).Besides the HLA genes, two thyroid-specific genes, the thyroglobulin (Tg) and thyrotropin receptor (TSHR) genes also contribute to the etiology of AITD (2). Thyroglobulin is the most abundant thyroidal protein (14), and it is the precursor to ...

show abstract

Pathogenic human thyroglobulin peptides in HLA-DR3 transgenic mouse model of autoimmune thyroiditis

Cited by 40 publications

References 26 publications

Thyroglobulin Peptides Associate In Vivo to HLA-DR in Autoimmune Thyroid Glands

Thyroglobulin Peptides Associate In Vivo to HLA-DR in Autoimmune Thyroid Glands

Employing a Recombinant HLA-DR3 Expression System to Dissect Major Histocompatibility Complex II-Thyroglobulin Peptide Dynamism

Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis

Contact Info

Product

Resources

About