Differentially expressed genes in MHC-compatible rat strains that are susceptible or resistant to experimental autoimmune uveitis.
OBJECTIVE
Experimental autoimmune uveitis (EAU) is an established model for immune-mediated human uveitis. Although several genes from major histocompatibility complex (MHC) loci have been shown to play a role in uveitis, little is known about the role of non-MHC genes in the pathogenesis of EAU. Several non-MHC genes have been implicated in the pathogenesis of various autoimmune diseases. The primary objective of this study was to identify the non-MHC genes involved in the pathogenesis of EAU, to identify potential drug targets and possibly to target their protein products for immunotherapy.


METHODS
EAU was induced in the susceptible (Lewis; LEW) or resistant (Fischer 344; F344) rats that have identical MHC class II haplotype. Draining lymph node cells were obtained during the innate and adaptive phase of the immune response, and the pattern of gene expression was evaluated using microarray technology. Differentially expressed genes were validated at mRNA and protein levels using various methods.


RESULTS
Susceptibility to EAU was associated with an increased expression of numerous non-MHC genes such as Th1-type cytokines and chemokines, antiapoptotic factors, hormones, and neurotransmitters and a downregulation of selected adhesion molecules. In this study a combined genetic-genomic approach was used to identify different patterns of gene expression associated with the sensitization and effector phase of EAU pathogenesis.


CONCLUSIONS
The data demonstrate that the differential expression of several non-MHC genes is associated with the mechanism of uveitis.
Mattapallil
Mary J
MJ
Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Augello
Andrea
A
Cheadle
Chris
C
Teichberg
Diane
D
Becker
Kevin G
KG
Chan
Chi-Chao
CC
Mattapallil
Joseph J
JJ
Pennesi
Giuseppina
G
Caspi
Rachel R
RR
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D005802:Genes, MHC Class II / Q000502:physiology*; D008213:Lymphocyte Activation; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012177:Retinol-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D014605:Uveitis / Q000235:genetics* / Q000276:immunology; D000099214:Retinol-Binding Proteins, Interstitial
D000954:Antigens, Surface; D005136:Eye Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial