title: An HLA-DRB1-coded signal transduction ligand facilitates inflammatory arthritis: a new mechanism of autoimmunity.
abstract: Particular alleles of HLA contribute to disease susceptibility and severity in many autoimmune conditions, but the mechanisms underlying these associations are often unknown. In this study, we demonstrate that the shared epitope (SE), an HLA-DRB1-coded sequence motif that is the single most significant genetic risk factor for erosive rheumatoid arthritis, acts as a signal transduction ligand that potently activates osteoclastogenesis, both in vitro and in vivo. The SE enhanced the production of several pro-osteoclastogenic factors and facilitated osteoclast (OC) differentiation in mouse and human cells in vitro. Transgenic mice expressing a human HLA-DRB1 allele that code the SE motif demonstrated markedly higher propensity for osteoclastogenesis and enhanced bone degradation capacity ex vivo. In addition, the SE enhanced the differentiation of Th17 cells expressing the receptor activator for NF-κB ligand. When the two agents were combined, IL-17 and the SE enhanced OC differentiation synergistically. When administered in vivo to mice with collagen-induced arthritis, the SE ligand significantly increased arthritis severity, synovial tissue OC abundance, and bone erosion. Thus, the SE contributes to arthritis severity by activating an OC-mediated bone-destructive pathway. These findings suggest that besides determining the target specificity of autoimmune responses, HLA molecules may influence disease outcomes by shaping the pathogenic consequences of such responses.
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. jholo@umich.edu
authors.forename: Joseph
authors.initials: J
authors.lastname: Holoshitz
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Fu
authors.forename: Jeena
authors.initials: J
authors.lastname: Joseph
authors.forename: Song
authors.initials: S
authors.lastname: Ling
authors.forename: Alessandro
authors.initials: A
authors.lastname: Colletta
authors.forename: Prannda
authors.initials: P
authors.lastname: Sharma
authors.forename: Dana
authors.initials: D
authors.lastname: Begun
authors.forename: Steven
authors.initials: S
authors.lastname: Goldstein
authors.forename: Russell
authors.initials: R
authors.lastname: Taichman
mesh_terms: D000483:Alleles; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D059811:HLA-DRB1 Chains; D018836:Inflammation Mediators; D008024:Ligands