HLA-DR3 transgenic mice immunized with adenovirus encoding the thyrotropin receptor: T cell epitopes and functional analysis of the CD40 Graves' polymorphism

Pavel Pichurin, Nancy Pham, Chella S. David, Basil Rapoport, Sandra M. McLachlan

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The major histocompatibility (MHC) molecule HLA-DR3 is a susceptibility gene for Graves' disease (GD) in Caucasians. Mice lacking murine MHC and expressing human HLA-DR3 develop thyrotropin receptor (TSHR) antibodies and sometimes hyperthyroidism after vaccination with TSHR-DNA. MHC molecules present peptides processed from antigens to T cells. Therefore, we used DR3-transgenic mice to investigate recognition of TSHR ectodomain peptides. After immunization with TSHR A-subunit adenovirus (A-subunit-Ad) but not control-adenovirus (Control-Ad), splenocytes from DR3 mice responded to A-subunit protein in culture by producing interferon-γ (IFN-γ). When challenged with 29 overlapping TSHR peptides, splenocytes from A-subunit-Ad- or Control-Ad-immunized mice responded to several peptides. However, in splenocytes from A-subunit-Ad but not Control-Ad mice, a peptide containing TSHR residues 142-161 induced significantly more IFN-γ than the same splenocytes in medium alone. Immunized DR3 mice also permitted testing the TSHR-specific function of the CD40 single nucleotide polymorphism (C vs. T) associated with GD. Of three human DR3 human Epstein-Barr virus lines (EBVL), two had C in both alleles (CC) and one was CT. However, these EBVL presented peptides poorly and there was no difference between CC vs. CT EBVL in peptide presentation to splenocytes from immunized mice. A peptide corresponding to residues 145-163 is one of seven suggested to be important in GD based on HLA-binding affinities, T-epitope algorithms, and human studies. Consequently, as in human GD, TSHR amino acids 142-161 appear to include a major T cell epitope in HLA-DR3 transgenic mice immunized with A-subunit-Ad.

Original languageEnglish (US)
Pages (from-to)1221-1227
Number of pages7
JournalThyroid
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

Fingerprint

HLA-DR3 Antigen
Thyrotropin Receptors
T-Lymphocyte Epitopes
Adenoviridae
Transgenic Mice
Peptides
Graves Disease
Histocompatibility
Human Herpesvirus 4
Interferons
Protein Subunits
Hyperthyroidism
Single Nucleotide Polymorphism
Epitopes
Immunization
Vaccination
Alleles
T-Lymphocytes
Antigens
Amino Acids

ASJC Scopus subject areas

  • Endocrinology

Cite this

HLA-DR3 transgenic mice immunized with adenovirus encoding the thyrotropin receptor : T cell epitopes and functional analysis of the CD40 Graves' polymorphism. / Pichurin, Pavel; Pham, Nancy; David, Chella S.; Rapoport, Basil; McLachlan, Sandra M.

In: Thyroid, Vol. 16, No. 12, 01.12.2006, p. 1221-1227.

Research output: Contribution to journalArticle

Pichurin, Pavel ; Pham, Nancy ; David, Chella S. ; Rapoport, Basil ; McLachlan, Sandra M. / HLA-DR3 transgenic mice immunized with adenovirus encoding the thyrotropin receptor : T cell epitopes and functional analysis of the CD40 Graves' polymorphism. In: Thyroid. 2006 ; Vol. 16, No. 12. pp. 1221-1227.
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AB - The major histocompatibility (MHC) molecule HLA-DR3 is a susceptibility gene for Graves' disease (GD) in Caucasians. Mice lacking murine MHC and expressing human HLA-DR3 develop thyrotropin receptor (TSHR) antibodies and sometimes hyperthyroidism after vaccination with TSHR-DNA. MHC molecules present peptides processed from antigens to T cells. Therefore, we used DR3-transgenic mice to investigate recognition of TSHR ectodomain peptides. After immunization with TSHR A-subunit adenovirus (A-subunit-Ad) but not control-adenovirus (Control-Ad), splenocytes from DR3 mice responded to A-subunit protein in culture by producing interferon-γ (IFN-γ). When challenged with 29 overlapping TSHR peptides, splenocytes from A-subunit-Ad- or Control-Ad-immunized mice responded to several peptides. However, in splenocytes from A-subunit-Ad but not Control-Ad mice, a peptide containing TSHR residues 142-161 induced significantly more IFN-γ than the same splenocytes in medium alone. Immunized DR3 mice also permitted testing the TSHR-specific function of the CD40 single nucleotide polymorphism (C vs. T) associated with GD. Of three human DR3 human Epstein-Barr virus lines (EBVL), two had C in both alleles (CC) and one was CT. However, these EBVL presented peptides poorly and there was no difference between CC vs. CT EBVL in peptide presentation to splenocytes from immunized mice. A peptide corresponding to residues 145-163 is one of seven suggested to be important in GD based on HLA-binding affinities, T-epitope algorithms, and human studies. Consequently, as in human GD, TSHR amino acids 142-161 appear to include a major T cell epitope in HLA-DR3 transgenic mice immunized with A-subunit-Ad.

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