Thyroglobulin peptides associate in vivo to HLA-DR in autoimmune thyroid glands.
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.
Muixí
Laia
L
Immunology Unit, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
Carrascal
Montserrat
M
Alvarez
Iñaki
I
Daura
Xavier
X
Martí
Mercè
M
Armengol
Maria Pilar
MP
Pinilla
Clemencia
C
Abian
Joaquín
J
Pujol-Borrell
Ricardo
R
Jaraquemada
Dolores
D
D000328:Adult; D000595:Amino Acid Sequence; D015551:Autoimmunity / Q000276:immunology*; D005260:Female; D006111:Graves Disease / Q000276:immunology / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D018448:Models, Immunological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D020539:Sequence Analysis, Protein; D013954:Thyroglobulin / Q000276:immunology* / Q000378:metabolism*; D013961:Thyroid Gland / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*
D006684:HLA-DR Antigens; D010446:Peptide Fragments; D013954:Thyroglobulin