Effector T cells driving monophasic vs. relapsing/remitting experimental autoimmune uveitis show unique pathway signatures.
Mol Immunol, 2010/11-2010/12;48(1-3):272-80.
von Toerne C[1], Sieg C, Kaufmann U, Diedrichs-Möhring M, Nelson PJ, Wildner G
Affiliations
PMID: 20727594DOI: 10.1016/j.molimm.2010.07.017
Impact factor: 4.174
Abstract
Autoimmune diseases often show a relapsing-remitting course. Here we describe characteristics of the autoreactive T cell response in the Lewis rat model of experimental autoimmune uveitis (EAU), a model for the clinical heterogeneity seen in human uveitis. Depending on the autoantigen used, the experimental disease course can be either monophasic or relapsing/remitting. This appears to be dictated by subtle differences in the T cell effector phenotype elicited. Using transcriptomic profiling and pathway analysis, the molecular basis for the monophasic vs. relapsing/remitting effector T cell phenotype was investigated. CD4+ T cell lines specific for peptide R14 derived from interphotoreceptor retinoid-binding protein (IRBP), which mediate the relapsing disease, were compared to the monophasic disease-inducing lines responding to retinal S-antigen peptide PDSAg. Expression profiles from T cell lines representing each specificity were analyzed using Affymetrix microarrays. Differential gene expression was confirmed and extended by quantitative PCR and verified on the protein level. A set of genes was uniquely upregulated in the R14-specific T cells. Gene ontology analysis demonstrated that these genes were linked to regulatory pathways associated with antigen presentation, lymphocyte activation, regulation of apoptosis and WNT/Hedgehog signaling. R14-specific T cells were further demonstrated to have prolonged survival in vivo, and a Th1-dominated cytokine profile, while the PDSAg-specific T cells lines were more Th17-prone. Our findings suggest that the nature of specific antigens leads to subtle programming of the effector phenotype underlying recurrent inflammation.
MeSH terms
Animals; Arrestin; Autoantigens; Autoimmune Diseases; Cell Separation; Cytokines; Disease Models, Animal; Female; Flow Cytometry; Gene Expression Profiling; Male; Oligonucleotide Array Sequence Analysis; Rats; Rats, Inbred Lew; Retinol-Binding Proteins; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; T-Lymphocytes; Uveitis
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