Cepharanthine blocks TSH receptor peptide presentation by HLA-DR3: Therapeutic implications to Graves' disease
Autor: | Cheuk Wun Li, Yaron Tomer, Erlinda Concepcion, Roman Osman, Francesca Menconi |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Models Molecular endocrine system endocrine system diseases Graves' disease T-Lymphocytes Immunology Epitopes T-Lymphocyte Peptide Peptide binding Mice Transgenic medicine.disease_cause Lymphocyte Activation Benzylisoquinolines Article Autoimmunity 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship 0302 clinical medicine HLA-DR3 Antigen medicine Cepharanthine Immunology and Allergy Animals Humans Amino Acid Sequence Receptor 030203 arthritis & rheumatology chemistry.chemical_classification Mice Knockout Antigen Presentation Receptors Thyrotropin medicine.disease Flow Cytometry Immunohistochemistry eye diseases Graves Disease Peptide Fragments 030104 developmental biology chemistry Hormone receptor Humanized mouse Cancer research Peptides hormones hormone substitutes and hormone antagonists Epitope Mapping Protein Binding |
Zdroj: | J Autoimmun |
ISSN: | 1095-9157 |
Popis: | We have previously identified a signature HLA-DR3 pocket variant, designated HLA-DRβ1-Arg74 that confers a high risk for Graves’ Disease (GD). In view of the key role of HLA-DRβ1-Arg74 in triggering GD we hypothesized that thyroid-stimulating hormone receptor (TSHR) peptides that bind to the HLA-DRβ1-Arg74 pocket with high affinity represent key pathogenic TSHR peptides triggering GD, and that blocking their presentation to CD4(+) T-cells can be used as a novel therapeutic approach in GD. There were several previous attempts to identify the major pathogenic TSHR peptide utilizing different methodologies, however the results were inconsistent and inconclusive. Therefore, the aim of our study was to use TSHR peptide binding affinity to HLA-DRβ1-Arg74 as a method to identify the key pathogenic TSHR peptides that trigger GD. Using virtual screening and ELISA and cellular binding assays we identified 2 TSHR peptides that bound with high affinity to HLA-DRβ1-Arg74 - TSHR.132 and TSHR.197. Peptide immunization studies in humanized DR3 mice showed that only TSHR.132, but not TSHR.197, induced autoreactive T-cell proliferation and cytokine responses. Next, we induced experimental autoimmune Graves’ disease (EAGD) in a novel BALB/c-DR3 humanized mouse model we created and confirmed TSHR.132 as a major DRβ1-Arg74 binding peptide triggering GD in our mouse model. Furthermore, we demonstrated that Cepharanthine, a compound we have previously identified as DRβ1-Arg74 blocker, could block the presentation and T-cell responses to TSHR.132 in the EAGD model. |
Databáze: | OpenAIRE |
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