title: Immune dysregulation by the rheumatoid arthritis shared epitope.
abstract: Rheumatoid arthritis (RA) is closely associated with HLA-DRB1 alleles that code a five-amino acid sequence motif in positions 70-74 of the HLA-DRbeta-chain, called the shared epitope (SE). The mechanistic basis of SE-RA association is unknown. We recently found that the SE functions as an allele-specific signal-transducing ligand that activates an NO-mediated pathway in other cells. To better understand the role of the SE in the immune system, we examined its effect on T cell polarization in mice. In CD11c(+)CD8(+) dendritic cells (DCs), the SE inhibited the enzymatic activity of indoleamine 2,3 dioxygenase, a key enzyme in immune tolerance and T cell regulation, whereas in CD11c(+)CD8(-) DCs, the ligand activated robust production of IL-6. When SE-activated DCs were cocultured with CD4(+) T cells, the differentiation of Foxp3(+) T regulatory cells was suppressed, whereas Th17 cells were expanded. The polarizing effects could be seen with SE(+) synthetic peptides, but even more so when the SE was in its natural tridimensional conformation as part of HLA-DR tetrameric proteins. In vivo administration of the SE ligand resulted in a greater abundance of Th17 cells in the draining lymph nodes and increased IL-17 production by splenocytes. Thus, we conclude that the SE acts as a potent immune-stimulatory ligand that can polarize T cell differentiation toward Th17 cells, a T cell subset that was recently implicated in the pathogenesis of autoimmune diseases, including RA.
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Denise E
authors.initials: DE
authors.lastname: De Almeida
authors.forename: Song
authors.initials: S
authors.lastname: Ling
authors.forename: Xiujun
authors.initials: X
authors.lastname: Pi
authors.forename: Anne M
authors.initials: AM
authors.lastname: Hartmann-Scruggs
authors.forename: Paul
authors.initials: P
authors.lastname: Pumpens
authors.forename: Joseph
authors.initials: J
authors.lastname: Holoshitz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D016764:Cell Polarity / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000939:Epitopes / Q000378:metabolism / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000502:physiology; D006684:HLA-DR Antigens / Q000502:physiology*; D059811:HLA-DRB1 Chains; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006131:Growth Inhibitors; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D020381:Interleukin-17; D008024:Ligands