Interphotoreceptor retinoid-binding protein (IRBP)-deficient C57BL/6 mice have enhanced immunological and immunopathogenic responses to IRBP and an altered recognition of IRBP epitopes.
Experimental autoimmune uveitis (EAU) and pinealitis (EAP) can be induced in susceptible mice by immunization with immunologically privileged retinal antigens. In the present study, we analyzed the immunologic and immunopathologic responses of mice deficient in the retinal autoantigen interphotoreceptor retinoid-binding protein (IRBP). The consequences of IRBP deficiency on the T-cell repertoire were also investigated. IRBP+/+, IRBP+/- and IRBP-/- mice on the C57BL/6 background were immunized with IRBP or with a pathogenic epitope, IRBP(1-20) peptide in adjuvant, and were evaluated for disease severity and immunological responses. C57BL/6 IRBP-/- mice were completely resistant to EAU and EAP, and had enhanced immunological responses to IRBP and to its pathogenic peptide 1-20, as compared to their IRBP+/+ counterparts. IRBP-/- mice exhibited an altered IRBP epitope recognition. T cell epitope mapping revealed a response to IRBP peptide 271-290 in IRBP-/- mice, that was absent in the wild type. Primed T cells of IRBP-/- mice transferred an exacerbated form of EAU to nai;ve wild type recipients. A gene-dose effect was evident in that C57BL/6 IRBP+/- mice, exhibited intermediate immunological responses and lower disease scores compared to wild type. We conclude that expression of IRBP in target tissues is a necessary prerequisite for disease induction, excluding other retinoid-binding or vision-related proteins as surrogate targets. Furthermore, endogenous expression of IRBP is directly responsible for lowering the threshold of susceptibility to uveitic disease.
Laboratory of Immunology, Section of Immunoregulation, National Institutes of Health, 10 Center Drive, 10/10N222, Bethesda, MD 20892-1857, USA
Dody
D
Avichezer
Gregory I
GI
Liou
Chi-Chao
CC
Chan
Giavonni M
GM
Lewis
Barbara
B
Wiggert
Larry A
LA
Donoso
John M
JM
Nickerson
Mary Alice
MA
Crawford
Rachel R
RR
Caspi
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005123:Eye / Q000473:pathology; D005136:Eye Proteins; D006579:Heterozygote; D006720:Homozygote; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007111:Immunity, Cellular / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D010870:Pineal Gland / Q000473:pathology; D012177:Retinol-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D013154:Spleen / Q000166:cytology; D014605:Uveitis / Q000276:immunology / Q000473:pathology; D014611:Vaccination; D000099214:Retinol-Binding Proteins, Interstitial
D018984:Epitopes, T-Lymphocyte; D005136:Eye Proteins; D007371:Interferon-gamma; D007376:Interleukin-2; D010446:Peptide Fragments; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial