Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.
Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.
Lock
Christopher
C
Department of Neurology and Neurological Sciences, Beckman Center, Stanford University, Stanford, California, USA.
Hermans
Guy
G
Pedotti
Rosetta
R
Brendolan
Andrea
A
Schadt
Eric
E
Garren
Hideki
H
Langer-Gould
Annette
A
Strober
Samuel
S
Cannella
Barbara
B
Allard
John
J
Klonowski
Paul
P
Austin
Angela
A
Lad
Nagin
N
Kaminski
Naftali
N
Galli
Stephen J
SJ
Oksenberg
Jorge R
JR
Raine
Cedric S
CS
Heller
Renu
R
Steinman
Lawrence
L
D000208:Acute Disease; D000818:Animals; D001344:Autopsy; D002908:Chronic Disease; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000473:pathology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics*; D020381:Interleukin-17 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011961:Receptors, Fc / Q000502:physiology; D015203:Reproducibility of Results; D014158:Transcription, Genetic
D020381:Interleukin-17; D015850:Interleukin-6; D011961:Receptors, Fc; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma