The Journal of Experimental Medicine
Randox clinical diagnostic solutions
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published 1 December 2003. doi:10.1084/jem.20030413
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Avichezer, D.
Right arrow Articles by Caspi, R. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Avichezer, D.
Right arrow Articles by Caspi, R. R.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
© The Rockefeller University Press, 0022-1007/2003/12/1665 $8.00
The Journal of Experimental Medicine, Volume 198, Number 11, 1665-1676

An Immunologically Privileged Retinal Antigen Elicits Tolerance : Major Role for Central Selection Mechanisms



Dody Avichezer1, Rafael S. Grajewski1, Chi-Chao Chan1, Mary J. Mattapallil1, Phyllis B. Silver1, James A. Raber2, Gregory I. Liou4, Barbara Wiggert3, Giavonni M. Lewis1, Larry A. Donoso5, and Rachel R. Caspi1

1 Laboratory of Immunology, National Eye Institute, National Institutes of Health (NIH), Bethesda, MD 20892
2 Veterinary Resources Section, National Eye Institute, National Institutes of Health (NIH), Bethesda, MD 20892
3 Laboratory of Cell and Molecular Biology, National Eye Institute, National Institutes of Health (NIH), Bethesda, MD 20892
4 Department of Ophthalmology, Medical College of Georgia, Augusta, GA 30912
5 Wills Eye Hospital, Philadelphia, PA 19107

Address correspondence to Rachel R. Caspi, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Dr., 10/10N222, Bethesda, MD 20892. Phone: (301) 435-4555; Fax: (301) 402-0485; email: rcaspi{at}helix.nih.gov

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.

Key Words: gene knockout mice • interphotoreceptor retinoid-binding protein • thymic selection • uveitis • autoimmunity

Abbreviations used in this paper: ACAID, anterior chamber–associated immune deviation; CFA, complete Freund's adjuvant; DTH, delayed type hypersensitivity; EAU, experimental autoimmune uveoretinitis; IRBP, interphotoreceptor retinoid-binding protein; KO, knockout; PLP, proteolipid protein; rIRBP, recombinant repeat 1 of human IRBP; S-Ag, retinal soluble antigen.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS