Hdl Handle:
http://hdl.handle.net/10675.2/556
Title:
An Immunologically Privileged Retinal Antigen Elicits Tolerance
Authors:
Avichezer, Dody; Grajewski, Rafael S.; Chan, Chi-Chao ( 0000-0001-9460-8049 ) ; Mattapallil, Mary J.; Silver, Phyllis B.; Raber, James A.; Liou, Gregory I.; Wiggert, Barbara; Lewis, Giavonni M.; Donoso, Larry A.; Caspi, Rachel R. ( 0000-0002-7140-7671 )
Abstract:
Immunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25+ T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role.
Citation:
J Exp Med. 2003 Dec 1; 198(11):1665-1676
Issue Date:
1-Dec-2003
URI:
http://hdl.handle.net/10675.2/556
DOI:
10.1084/jem.20030413
PubMed ID:
14657219
PubMed Central ID:
PMC2194140
Type:
Article
ISSN:
1540-9538
Appears in Collections:
Department of Ophthalmology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorAvichezer, Dodyen_US
dc.contributor.authorGrajewski, Rafael S.en_US
dc.contributor.authorChan, Chi-Chaoen_US
dc.contributor.authorMattapallil, Mary J.en_US
dc.contributor.authorSilver, Phyllis B.en_US
dc.contributor.authorRaber, James A.en_US
dc.contributor.authorLiou, Gregory I.en_US
dc.contributor.authorWiggert, Barbaraen_US
dc.contributor.authorLewis, Giavonni M.en_US
dc.contributor.authorDonoso, Larry A.en_US
dc.contributor.authorCaspi, Rachel R.en_US
dc.date.accessioned2012-10-26T16:26:40Z-
dc.date.available2012-10-26T16:26:40Z-
dc.date.issued2003-12-1en_US
dc.identifier.citationJ Exp Med. 2003 Dec 1; 198(11):1665-1676en_US
dc.identifier.issn1540-9538en_US
dc.identifier.pmid14657219en_US
dc.identifier.doi10.1084/jem.20030413en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/556-
dc.description.abstractImmunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25+ T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role.en_US
dc.rightsCopyright © 2003, The Rockefeller University Pressen_US
dc.titleAn Immunologically Privileged Retinal Antigen Elicits Toleranceen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2194140en_US
dc.contributor.corporatenameDepartment of Ophthalmology-

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