Transcriptional characteristics of CD4+ T cells in multiple sclerosis: relative lack of suppressive populations in blood.
BACKGROUND
Multiple sclerosis (MS) is hypothetically caused by autoreactive Th1 and Th17 cells, whereas Th2 and regulatory T cells may confer protection. The development of Th subpopulations is dependant on the expression of lineage-specific transcription factors.


OBJECTIVE
The aim of this study was to assess the balance of CD4(+)T cell populations in relapsing-remitting MS.


METHODS
Blood mRNA expression of TBX21, GATA3, RORC, FOXP3 and EBI3 was assessed in 33 patients with relapsing-remitting MS and 20 healthy controls. In addition, flow cytometry was performed to assess T lymphocyte numbers.


RESULTS
In relapsing-remitting MS, diminished expression of FOXP3 (Treg) was found (p < 0.05), despite normal numbers of CD4(+)CD25(hi)Treg. Immunoregulatory EBI3 and Th2-associated GATA3 ([a-z]+) was also decreased in MS (p < 0.005 and p < 0.05, respectively). Expression of TBX21 (Th1) and RORC (Th17) did not differ between patients and controls. Similar changes were observed when analysing beta-interferon treated (n = 12) or untreated (n = 21) patients. Analysis of transcription factor ratios, comparing TBX21/GATA3 and RORC/FOXP3, revealed an increase in the RORC/FOXP3 ratio in patients with relapsing-remitting MS (p < 0.005).


CONCLUSIONS
Our findings indicate systemic defects at the mRNA level, involving downregulation of beneficial CD4(+)phenotypes. This might play a role in disease development by permitting activation of harmful T cell populations.
Edström
M
M
Clinical and Experimental Medicine, Faculty of Health Sciences, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, Sweden. mans.edstrom@liu.se
Mellergård
J
J
Mjösberg
J
J
Jenmalm
Mc
M
Vrethem
M
M
Press
R
R
Dahle
C
C
Ernerudh
J
J
D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007378:Interleukins / Q000235:genetics; D008297:Male; D015778:Minor Histocompatibility Antigens; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000235:genetics* / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics; D012333:RNA, Messenger / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
C097732:EBI3 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; C539900:RORC protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors