Lepore, Alessio (2014) The chondroitin 6-sulfate oligosaccharide unit of human thyroglobulin promotes the induction of experimental autoimmune thyroiditis via CD44-mediated co-stimulation of murine Th1/Th17 cell differentiation. [Tesi di dottorato]
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Tesi Alessio Lepore PhD Molecular oncology and Endocrinology XXVI ciclo.pdf Download (11MB) | Anteprima |
| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | The chondroitin 6-sulfate oligosaccharide unit of human thyroglobulin promotes the induction of experimental autoimmune thyroiditis via CD44-mediated co-stimulation of murine Th1/Th17 cell differentiation |
| Autori: | Autore Email Lepore, Alessio alessiolep@gmail.com |
| Data: | 31 Marzo 2014 |
| Numero di pagine: | 94 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dipartimento: | Medicina Molecolare e Biotecnologie Mediche |
| Scuola di dottorato: | Medicina molecolare |
| Dottorato: | Oncologia ed endocrinologia molecolare |
| Ciclo di dottorato: | 26 |
| Coordinatore del Corso di dottorato: | nome email Santoro, Massimo masantor@unina.it |
| Tutor: | nome email Gentile, Fabrizio [non definito] |
| Data: | 31 Marzo 2014 |
| Numero di pagine: | 94 |
| Parole chiave: | Experimental autoimmune thyroiditis Chondroitin sulfate Thyroglobulin Costimulation CD44 T helper 17 cells |
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/04 - Patologia generale |
| Aree tematiche (7° programma Quadro): | SALUTE e TUTELA DEL CONSUMATORE > Biotecnologie, strumenti e tecnologie generiche per la salute umana |
| Depositato il: | 11 Apr 2014 10:24 |
| Ultima modifica: | 15 Lug 2015 01:02 |
| URI: | http://www.fedoa.unina.it/id/eprint/10022 |
Abstract
The data presented in this work document that the presence of a chondroitin 6-sulphate (CS) oligosaccharide unit linked to Ser2730 of human thyroglobulin (hTg) was associated with a marked increase of the immunopathogenicity of hTg in a model of murine experimental autoimmune thyroiditis (EAT) in CBA/J(H-2k) and SJL(H-2s) mice. When used to immunize CBA/J mice, CS-containing hTg (hTgCS) markedly enhanced, in comparison with CS-devoid hTgCS0, the infiltration of murine thyroids by mononuclear cells, the leak of thyroid hormones from thyroid epithelial cells into the bloodstream and the secondary proliferative and secretory responses of splenocytes and isolated CD4+ T cells to both hTgCS and hTgCS0 in vitro. These results indicated that the CS oligosaccharide unit of hTg is capable of enhancing markedly the primary sensitization of murine T cells to peptide epitopes shared between hTgCS and hTgCS0 and conserved between human and murine Tg. Moreover, the cytokine secretion patterns obtained with isolated murine CD4+ T cells indicated that the CS unit, both as a part of hTgCS and in the form of a purified, CS-containing nonapeptide isolated to homogeneity from hTgCS (hTgCSgp), was capable of enhancing the differentiation of Tg-reactive TH1 and TH17 cells. Furthermore, the response patterns of murine CD4+ T cells to hTgCS and hTgCSgp, also in relation with the responses to anti-CD3 and anti-CD28 antibodies, indicated that the CS unit of hTg did not behave as a pathogenic epitope in itself, but rather as an added co-stimulus for the differentiation of Tg-specific TH1 and TH17 cells, thereby promoting strongly thyroid disease. Finally, two-step cross-linking experiments and confocal microscopy of murine CD4+ T cells exposed to the purified hTgCS glycopeptide indicated that the CS oligosaccharide unit of hTg interacted specifically with CD44 of murine CD4+ T cells.
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