Exploiting genotypic differences to identify genes important for EAE development.
Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human autoimmune disease multiple sclerosis (MS) and is primarily driven by T helper type 1 (Th1) cells. Interleukin (IL)-12 and interferon (IFN)-gamma are important cytokines involved in the differentiation and amplification of Th1 cells, however mice deficient in either IFN-gamma or IL-12 still develop EAE. We have used microarray analysis of EAE-affected CNS tissues in wild-type, IFN-gamma -/- and IL-12 -/- animals to identify genes critical for development of EAE. Over 500 genes were regulated in at least one genotype and over 94 genes were regulated in all three. Of those, 17 were also upregulated in spleen during the disease. We show that a majority of the genes regulated in EAE are also regulated in diseased regions of human MS tissues. The genes in the pool of 94 are more likely to be found regulated in MS patients than the genes regulated in only one or two of the mouse strains suggesting that analyzing gene expression under these multiple genetic conditions may lead to better identification of the genes critical for disease development.
Jelinsky
Scott A
SA
Molecular Profiling and Biomarker Discover, Biological Technologies Department, Wyeth Research, 87 Cambridge Park Drive, Cambridge MA 02140, USA. sjelinsky@wyeth.com
Miyashiro
Joy S
JS
Saraf
Kathryn A
KA
Tunkey
Christopher
C
Reddy
Padma
P
Newcombe
Jia
J
Oestreicher
Judith L
JL
Brown
Eugene
E
Trepicchio
William L
WL
Leonard
John P
JP
Marusic
Suzana
S
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D007371:Interferon-gamma / Q000235:genetics*; D018664:Interleukin-12 / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D018417:Th1 Cells / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D018664:Interleukin-12; D007371:Interferon-gamma