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+CD25hiTreg. 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).
Conclusion: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.
McFarlandHFMartinR. Multiple sclerosis: a complicated picture of autoimmunity. Nature immunology2007; 8(9): 913–919.
2.
LublinFDReingoldSC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology1996; 46(4): 907–911.
3.
ThompsonAJMontalbanXBarkhofFBrochetBFilippiMMillerDH. Diagnostic criteria for primary progressive multiple sclerosis: a position paper. Annals of neurology2000; 47(6): 831–835.
4.
DymentDAHerreraBMCaderMZWillerCJLincolnMRSadovnickAD. Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. Human molecular genetics2005; 14(14): 2019–2026.
5.
LincolnMRMontpetitACaderMZSaarelaJDymentDATiislarM. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nature genetics2005; 37(10): 1108–1112.
6.
MatesanzFCaro-MaldonadoAFedetzMFernandezOMilneRLGuerreroM. IL2RA/CD25 polymorphisms contribute to multiple sclerosis susceptibility. Journal of neurology2007; 254(5): 682–684.
7.
TeutschSMBoothDRBennettsBHHeardRNStewartGJ. Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-alpha gene and their associations with multiple sclerosis. Eur J Hum Genet2003; 11(7): 509–515.
8.
TraugottUReinherzELRaineCS. Multiple sclerosis: distribution of T cell subsets within active chronic lesions. Science (New York, NY1983; 219(4582): 308–310.
9.
MosmannTRCherwinskiHBondMWGiedlinMACoffmanRL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol1986; 136(7): 2348–2357.
10.
de Waal MalefytRFigdorCGHuijbensRMohan-PetersonSBennettBCulpepperJ. Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10. J Immunol1993; 151(11): 6370–6381.
11.
WangZEReinerSLZhengSDaltonDKLocksleyRM. CD4+ effector cells default to the Th2 pathway in interferon gamma-deficient mice infected with Leishmania major. The Journal of experimental medicine1994; 179(4): 1367–1371.
12.
CurtisMMWaySS. Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology2009; 126(2): 177–185.
13.
KaoCYChenYThaiPWachiSHuangFKimC. IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-kappaB signaling pathways. J Immunol2004; 173(5): 3482–3491.
14.
ShierPHofstraCLMaXJWuYNgoKFung-LeungWP. Tbt-1, a new T-box transcription factor induced in activated Th1 and CD8+ T cells. Immunogenetics2000; 51(10): 771–778.
ZhengWFlavellRA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell1997; 89(4): 587–596.
17.
IvanovIIMcKenzieBSZhouLTadokoroCELepelleyALafailleJJ. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell2006; 126(6): 1121–1133.
18.
SakaguchiSSakaguchiNAsanoMItohMTodaM. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol1995; 155(3): 1151–1164.
19.
FontenotJDGavinMARudenskyAY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature immunology2003; 4(4): 330–336.
20.
CollisonLWWorkmanCJKuoTTBoydKWangYVignaliKM. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature2007; 450(7169): 566–569.
21.
NiedbalaWWeiXQCaiBHueberAJLeungBPMcInnesIB. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. European journal of immunology2007; 37(11): 3021–3029.
22.
WilliamsLMRudenskyAY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nature immunology2007; 8(3): 277–284.
23.
YangJYangMHtutTMOuyangXHaniduALiX. Epstein-Barr virus-induced gene 3 negatively regulates IL-17, IL-22 and RORgamma t. European journal of immunology2008; 38(5): 1204–1214.
24.
CuaDJSherlockJChenYMurphyCAJoyceBSeymourB. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature2003; 421(6924): 744–748.
25.
KomiyamaYNakaeSMatsukiTNambuAIshigameHKakutaS. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol2006; 177(1): 566–573.
26.
McDonaldWICompstonAEdanGGoodkinDHartungHPLublinFD. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals of neurology2001; 50(1): 121–127.
27.
RoxburghRHSeamanSRMastermanTHensiekAESawcerSJVukusicS. Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology2005; 64(7): 1144–1151.
28.
MjosbergJSvenssonJJohanssonEHellstromLCasasRJenmalmMC. Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17{beta}-estradiol. J Immunol2009; 183(1): 759–769.
29.
OuyangWRanganathSHWeindelKBhattacharyaDMurphyTLShaWC. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity1998; 9(5): 745–755.
30.
ZhangDHCohnLRayPBottomlyKRayA. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. The Journal of biological chemistry1997; 272(34): 21597–21603.
31.
IchiyamaKYoshidaHWakabayashiYChinenTSaekiKNakayaM. Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. The Journal of biological chemistry2008; 283(25): 17003–17008.
LassmannHRansohoffRM. The CD4-Th1 model for multiple sclerosis: a critical [correction of crucial] re-appraisal. Trends in immunology2004; 25(3): 132–137.
34.
PanitchHSHirschRLSchindlerJJohnsonKP. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology1987; 37(7): 1097–1102.
35.
HuanJCulbertsonNSpencerLBartholomewRBurrowsGGChouYK. Decreased FOXP3 levels in multiple sclerosis patients. Journal of neuroscience research2005; 81(1): 45–52.
36.
VenkenKHellingsNThewissenMSomersVHensenKRummensJL. Compromised CD4(+) CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology2007.
37.
VenkenKHellingsNHensenKRummensJLMedaerRD'HoogheMB. Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression. Journal of neuroscience research2006; 83(8): 1432–1446.
38.
FegerULutherCPoeschelSMelmsATolosaEWiendlH. Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clinical and experimental immunology2007; 147(3): 412–418.
39.
FrisulloGNocitiVIorioRPatanellaAKCaggiulaMMartiA. Regulatory T cells fail to suppress CD4(+)T-bet(+) T cells in relapsing multiple sclerosis patients. Immunology2008.
40.
HaasJHugAViehoverAFritzschingBFalkCSFilserA. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. European journal of immunology2005; 35(11): 3343–3352.
41.
VigliettaVBaecher-AllanCWeinerHLHaflerDA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. The Journal of experimental medicine2004; 199(7): 971–979.
42.
DevergneOCoulomb-L'HermineACapelFMoussaMCapronF. Expression of Epstein-Barr virus-induced gene 3, an interleukin-12 p40-related molecule, throughout human pregnancy: involvement of syncytiotrophoblasts and extravillous trophoblasts. The American journal of pathology2001; 159(5): 1763–1776.
43.
BardelELarousserieFCharlot-RabiegaPCoulomb-L'HermineADevergneO. Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL-35. J Immunol2008; 181(10): 6898–6905.
44.
CollisonLWPillaiMRChaturvediVVignaliDA. Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol2009; 182(10): 6121–6128.
45.
KornT. Pathophysiology of multiple sclerosis. Journal of neurology2008; 255(Suppl 6): 2–6.
46.
MatuseviciusDKivisakkPHeBKostulasNOzenciVFredriksonS. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler1999; 5(2): 101–104.
47.
TzartosJSFrieseMACranerMJPalaceJNewcombeJEsiriMM. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. The American journal of pathology2008; 172(1): 146–155.
48.
LockCHermansGPedottiRBrendolanASchadtEGarrenH. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature medicine2002; 8(5): 500–508.
49.
TubridyNBehanPOCapildeoRChaudhuriAForbesRHawkinsCP. The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group. Neurology1999; 53(3): 466–472.
50.
BrynedalBKhademiMWallstromEHillertJOlssonTDuvefeltK. Gene expression profiling in multiple sclerosis: A disease of the central nervous system, but with relapses triggered in the periphery?Neurobiol Dis2009.
51.
ReboldiACoisneCBaumjohannDBenvenutoFBottinelliDLiraS. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nature immunology2009; 10(5): 514–523.
