title: Autoantigens act as tissue-specific chemoattractants.
abstract: We have investigated the chemoattractant properties of self-antigens associated with autoimmune diseases and solid tumors. Many autoantigens induced leukocyte migration, especially by immature dendritic cells (iDC) by interacting with various chemoattractant Gi-protein-coupled receptors (GiPCR). Our initial observation that myositis-associated autoantigens, histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, were chemotactic for CC chemokine receptor 5 (CCR5)- and CCR3-expressing leukocytes, while other nonautoantigenic aminoacyl-tRNA synthesases were not, suggested that only self-antigens capable of interacting with receptors on antigen-presenting cells were immunogenic. We next determined that self-antigens associated with autoimmune diseases, e.g., multiple sclerosis or experimental autoimmune encephalomyelitis, type I diabetes, scleroderma, systemic lupus erythematosus, autoimmune uveitis, or experimental autoimmune uveitis (EAU), were chemotactic for GiPCR expressed by iDC. The majority of autoantigens were DC chemoattractants at 10-100 ng/ml, but did not induce DC maturation until they reached 1000-fold higher concentrations. Interphotoreceptor retinoid-binding protein and retinal arrestin (S-antigen) are targets of autoantibodies in human uveitis and are chemotactic for CXC chemokine receptor 5 (CXCR5)- and/or CXCR3-expressing iDC. However, although S-antigen does not induce EAU in wild-type mice, it is nevertheless a chemoattractant for murine iDC. These unexpected observations suggested that the chemotactic activity of these tissue-specific self-antigens could be involved in promotion of tissue repair and restoration. Thus, the primary role of autoantigens may be to alert the immune system to danger signals from invaded and damaged tissues to facilitate repair, and autoimmune responses subsequently develop only in subjects with impaired immunoregulatory function.
authors.affiliation: National Cancer Institute-Frederick, Center for Cancer Research, Laboratory of Molecular Immunoregulation, MD 21702-1201, USA. Oppenhei@ncifcrf.gov
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: Hui Fang
authors.initials: HF
authors.lastname: Dong
authors.forename: Paul
authors.initials: P
authors.lastname: Plotz
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
authors.forename: Michelle
authors.initials: M
authors.lastname: Dykstra
authors.forename: Susan
authors.initials: S
authors.lastname: Pierce
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
authors.forename: Casey
authors.initials: C
authors.lastname: Carlos
authors.forename: Olivera
authors.initials: O
authors.lastname: Finn
authors.forename: Omanand
authors.initials: O
authors.lastname: Koul
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D002630:Chemotactic Factors / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D002630:Chemotactic Factors