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
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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