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1.
J Immunol ; 173(3): 1699-710, 2004 Aug 01.
Article in English | MEDLINE | ID: mdl-15265899

ABSTRACT

HLA-B27 transgenic rats and strains of HLA-B27-transgenic beta(2)-microglobulin (beta(2)m)-deficient mice develop a multisystem inflammatory disease affecting the joints, skin, and bowel with strong similarity to human spondyloarthritis. We show that HLA-B27 transgenic mice and rats express HC10-reactive, beta(2)m-free HLA-B27 homodimers (B27(2)) and multimers, both intracellularly and at the cell surface of leukocytes, including rat dendritic cells. Fluorescent-labeled tetrameric complexes of HLA-B27 homodimers (B27(2) tetramers) bind to populations of lymphocytes, monocytes, and dendritic cells. The murine (and probably rat) paired Ig-like receptors (PIRs) are ligands for B27(2). Thus, B27(2) tetramers stain RBL cells transfected with murine activating PIR-A4 and inhibitory PIR-B receptors. Murine PIR-A and -B can be immunoprecipitated from the RAW264.7 macrophage cell line, and murine PIR-A can be immunoprecipitated from the J774.A1 line using B27(2). B27(2) tetramer staining corresponds to the distribution of PIR expression on lymphoid and myeloid cells and on murine macrophage cell lines. B27(2) can induce TNF-alpha release from the J774.A1 macrophage cell line. The binding of B27(2) to PIR is inhibited by HC10, an mAb that ameliorates arthritis in HLA-B27(+) beta(2)m(-/-) mice. The expression and PIR recognition of B27(2) could explain the pathogenesis of rodent spondyloarthritis.


Subject(s)
Disease Models, Animal , HLA-B27 Antigen/immunology , Receptors, Immunologic/immunology , Spondylarthritis/immunology , Animals , Animals, Genetically Modified , Antibodies, Monoclonal/immunology , Biopolymers , Biotinylation , Cell Line/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Dimerization , HLA-B27 Antigen/chemistry , HLA-B27 Antigen/genetics , HLA-B27 Antigen/metabolism , Ligands , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Knockout , Mice, Transgenic , Precipitin Tests , Protein Binding , Rats , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Recombinant Fusion Proteins/immunology , Recombinant Fusion Proteins/metabolism , Spondylarthritis/genetics , Spondylitis, Ankylosing/genetics , Spondylitis, Ankylosing/immunology , Transfection , Tumor Necrosis Factor-alpha/metabolism , beta 2-Microglobulin/deficiency , beta 2-Microglobulin/genetics
2.
Eur J Immunol ; 33(3): 748-59, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12616495

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.


Subject(s)
Endosomes/metabolism , HLA-B27 Antigen/metabolism , Lymphocytes/metabolism , Protozoan Proteins , Antiporters/physiology , Brefeldin A/pharmacology , Cell Line , Cysteine/physiology , Dimerization , Glycoproteins/metabolism , HLA-B27 Antigen/chemistry , Humans , Immunoglobulins/physiology , Membrane Transport Proteins , Phosphoproteins/metabolism
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