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* National Cancer Institute-Frederick, Center for Cancer Research, Laboratory of Molecular Immunoregulation, and
Science Applications International Corporation-Frederick, Maryland;
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases,
National Eye Institute, Laboratory of Immunology, and
|| National Institute of Neurological Disorders and Stroke, Bethesda, Maryland;
¶ National Institute of Allergy and Infectious Diseases, Laboratory of Immunogenetics, Rockville, Maryland;
** Department of Immunology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pennsylvania; and
Shriver Center/University of Massachusetts Medical School, Waltham
1Correspondence: Laboratory of Molecular Immunoregulation, Building 560, Room 21-89A, National Cancer Institute, Frederick, MD 21702-1201. E-mail: Oppenhei{at}ncifcrf.gov
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.
Key Words: chemokines • tumor antigens • chemotaxis • migrations • dendritic cells
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