The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis.
Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.
Gandhi
Kaushal S
KS
Westmead Millennium Institute, University of Sydney, Sydney, Darcy Rd, New South Wales 2145, Australia.
McKay
Fiona C
FC
Cox
Mathew
M
Riveros
Carlos
C
Armstrong
Nicola
N
Heard
Robert N
RN
Vucic
Steve
S
Williams
David W
DW
Stankovich
Jim
J
Brown
Matthew
M
Danoy
Patrick
P
Stewart
Graeme J
GJ
Broadley
Simon
S
Moscato
Pablo
P
Lechner-Scott
Jeannette
J
Scott
Rodney J
RJ
Booth
David R
DR
D017951:Antigen Presentation / Q000235:genetics; D019013:CD40 Antigens / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D010085:Oxidative Phosphorylation; D012333:RNA, Messenger / Q000097:blood*; D013601:T-Lymphocytes / Q000378:metabolism*
D019013:CD40 Antigens; D012333:RNA, Messenger