Autoantigens signal through chemokine receptors: uveitis antigens induce CXCR3- and CXCR5-expressing lymphocytes and immature dendritic cells to migrate.
We tested the hypothesis that interaction between autoantigens and chemoattractant receptors may be an important step in the development of autoimmunity. The retinal autoantigens S-antigen (S-Ag) and interphotoreceptor retinoid binding protein (IRBP) can induce autoimmune uveitis in rodent models. We evaluated the chemotactic activity of S-Ag and IRBP and found that both induced migration of human and mouse immature dendritic cells (iDCs) and lymphocytes, but not neutrophils, monocytes, or mature DCs. Cross-desensitization studies and single-receptor transfected cells revealed that subfamily of alpha chemokine receptors CXCR5 and CXCR3 mediated the chemotactic effect of IRBP, while only CXCR3 was required for the chemotactic response to S-Ag. Examination of the relationships between chemoattraction and the ability to elicit pathology at the protein or peptide levels in the mouse uveitis model revealed dissociation of the capacity to induce uveitis, lymphocyte proliferation, and chemoattraction. These studies suggest that IRBP and S-Ag can initiate innate and, in sensitive individuals, adaptive immune response by attracting iDCs and T and B cells expressing CXCR3 and CXCR5.
Howard
O M Zack
OM
National Cancer Institute-Center for Cancer Research, Laboratory of Molecular Immunoregulation, Basic Research Program, Science Applications International Corporation, Frederick, MD, USA. howardz@mail.ncifcrf.gov
Dong
Hui Fang
HF
Su
Shao Bo
SB
Caspi
Rachel R
RR
Chen
Xin
X
Plotz
Paul
P
Oppenheim
Joost J
JJ
D019393:Arrestin / Q000502:physiology; D001324:Autoantigens / Q000502:physiology*; D015551:Autoimmunity; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology; D005136:Eye Proteins / Q000502:physiology; D006801:Humans; D007107:Immune System / Q000166:cytology*; D008214:Lymphocytes / Q000502:physiology; D054367:Receptors, CXCR3; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000502:physiology; D015398:Signal Transduction; D014605:Uveitis / Q000209:etiology / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
D019393:Arrestin; D001324:Autoantigens; D005136:Eye Proteins; D054367:Receptors, CXCR3; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C515187:CXCR3 protein, human; C095085:CXCR5 protein, human; C513179:CXCR5 protein, mouse; C515188:Cxcr3 protein, mouse