Autoantigenic HCgp39 epitopes are presented by the HLA-DM-dependent presentation pathway in human B cells.
It is hypothesized that autoimmune diseases manifest when tolerance to self-Ags fails. One possible mechanism to break tolerance is presentation of self-Ag in an altered form. Most Ags are presented by APCs via the traditional presentation pathway that includes "epitope editing" by intracellular HLA-DM, a molecule that selects for stable MHC-peptide complexes. We were interested in testing the hypothesis that autoreactive MHC-peptide complexes may reach the cell surface by an alternate pathway without being edited by HLA-DM. We selected a cartilage autoantigen human cartilage glycoprotein 39 to which T cell responses are observed in rheumatoid arthritis (RA) patients and some DR(*)04 healthy subjects. RA is genetically associated with certain DRB1 alleles, including DRB1(*)0401 but closely related allele DRB1(*)0402 is either neutral or mildly protective with respect to RA. We generated human B lymphoblastoid cell line cells expressing DR(*)0401 or DR(*)0402 in the presence or absence of intracellular HLA-DM and assessed their ability to present a candidate autoantigen, human cartilage glycoprotein 39. Our results show that the presence of intracellular HLA-DM is critical for presentation of this autoantigen to CD4(+) T cell hybridomas generated from DR(*)04-transgenic mice. Presentation of an autoantigen by the traditional HLA-DM-dependent pathway has implications for Ag presentation events in RA.
Patil
N S
NS
Department of Pediatric Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. namrata@stanford.edu
Hall
F C
FC
Drover
S
S
Spurrell
D R
DR
Bos
E
E
Cope
A P
AP
Sonderstrup
G
G
Mellins
E D
ED
D054392:Adipokines; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001324:Autoantigens / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002358:Cartilage, Articular / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D000071451:Chitinase-3-Like Protein 1; D018985:Epitopes, B-Lymphocyte / Q000378:metabolism*; D006023:Glycoproteins / Q000276:immunology* / Q000378:metabolism; D006681:HLA-D Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D006825:Hybridomas; D037102:Lectins; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D054392:Adipokines; D001324:Autoantigens; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D018985:Epitopes, B-Lymphocyte; D006023:Glycoproteins; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; C553506:HLA-DRB1*04:02 antigen; D037102:Lectins; D010446:Peptide Fragments