title: Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling.
abstract: The MHC class I allele HLA-B27 is very strongly associated with development of autoimmune spondyloarthritis, although the disease mechanism remains unknown. Class I molecules classically associate in the endoplasmic reticulum (ER) with beta2-microglobulin (beta(2)m) and antigenic peptides for cell surface expression and presentation to T cells. We have previously shown that HLA-B27 is capable of forming beta(2)m-free disulfide-bonded homodimers in vitro. Here we show that HLA-B27 forms disulfide-bonded homodimers in vivo by two distinct pathways. HLA-B27 homodimers form in the ER but appear unable to egress to the cell surface in human cells. Cell surface HLA-B27 homodimers are abundantly expressed in a variety of lymphoid cell lines. Experiments with inhibitors indicate that HLA-B27 homodimers can arise from cell-surface heterodimers via an endosome-dependent recycling pathway. HLA-B27 homodimer expression on the cell surface of 721.220 is dependent on the unpaired cysteine(67) and is inhibited by restoration of tapasin function or by incubation with peptides that bind strongly to HLA-B27 heterodimers. Cell surface expressed HLA-B27 homodimers are likely to be immunologically reactive ligands for NK family immunoreceptors and, hence, could play a pathogenic role in spondyloarthritis.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, Great Britain. lucy.bird@imm.ox.ac.uk
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Bird
authors.forename: Chen Au
authors.initials: CA
authors.lastname: Peh
authors.forename: Simon
authors.initials: S
authors.lastname: Kollnberger
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: Paul
authors.initials: P
authors.lastname: Bowness
mesh_terms: D017920:Antiporters / Q000502:physiology; D020126:Brefeldin A / Q000494:pharmacology; D002460:Cell Line; D003545:Cysteine / Q000502:physiology; D019281:Dimerization; D011992:Endosomes / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology; D008214:Lymphocytes / Q000378:metabolism*; D026901:Membrane Transport Proteins; D010750:Phosphoproteins / Q000378:metabolism; D015800:Protozoan Proteins
chemical_list: D017920:Antiporters; D006023:Glycoproteins; C118853:HC-10 protein, Cryptosporidium parvum; D015796:HLA-B27 Antigen; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D015800:Protozoan Proteins; C107762:tapasin; D020126:Brefeldin A; D003545:Cysteine