Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients

Feger, Ute; Luther, Claudia; Poeschel, S.; Melms, Arthur; Tolosa, Eva; Wiendl, Heinz

doi:10.1111/j.1365-2249.2006.03271.x

Cited by 179 publications

(157 citation statements)

References 15 publications

(30 reference statements)

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“…Recent observations suggest that Treg should be equipped with a higher propensity to migrate [6] in order to efficiently suppress effector T cells at target sites of emerging inflammation, as they are hypoproliferative [8,9] and only form 6-10% of the whole CD4 1 T-cell subset. Reports on the accumulation of Treg within the murine CNS during EAE [3] and on containment of EAE relapses by CNS Treg [10,11] 15: p. 72) described the detection of low numbers of Treg in the CNS and in accordance with an earlier study elevated cell numbers in the cerebrospinal fluid of patients with MS [13]. Since increasing evidence supports an antiinflammatory role for Treg at parenchymal sites of inflammation [14], one could speculate that the repeatedly reported impairment in antiproliferative capacity of Treg found in patients with MS [15,16] is just one expression of a more thorough Treg dysfunction.…”

Section: Foxp3supporting

confidence: 62%

“…Under conditions of experimental autoimmune neuroinflammation as in EAE, Treg accumulate in the murine CNS [4,10], most notably in the remission phases [11], counterbalancing encephalitogenic CNS responses. As mentioned above, data on the presence and function of Treg in the human CNS are sparse [12][13][14]18]. To translate our findings into human pathophysiology, we used an in vitro model of the human BBB to mimic lymphocyte diapedesis in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned above, data on the presence and function of Treg in the human CNS are sparse [12][13][14]18]. To translate our findings into human pathophysiology, we used an in vitro model of the human BBB to mimic lymphocyte diapedesis in vivo.…”

mentioning

confidence: 99%

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Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

et al. 2010

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Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD41 Foxp31 regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.Key words: Blood-brain barrier . Brain microvascular endothelial cells . Migration . MS . Regulatory T cells Supporting Information available online IntroductionNaturally occurring CD4 1 Foxp3 1 regulatory T cells (Treg) are essential mediators of peripheral immune tolerance, regulating inflammation in the context of infection, autoimmunity, neoplasia and transplant rejection [1]. In addition to balancing immunity within lymphoid tissues, Treg enter non-lymphoid target sites of inflammation, exerting their anti-inflammatory function there [2][3][4][5]. First, regulatory as well as effector T-cell subsets have to undergo a non-lymphoid homing receptor switch after entering secondary lymphoid tissue [6]. Upon encountering specific antigens provided by dendritic cells in the T-cell area [7], the lymphocytes acquire an activated phenotype, expressing distinct surface markers of non-lymphoid homing Ã These authors contributed equally to this work. We here combined various murine and human models quantifying transmigratory capacity and locomotion to determine how constitutive, innate Treg motility translates into diapedesis across CNS endothelium. Results Murine Treg exhibit enhanced migratory capacity in vitro and in vivoWe first characterized lymph node-derived regulatory and nonregulatory T-cell subsets with regard to their expression of surface markers indicative for adhesion, migration and activation. In line with previous results for CCR6 [17], murine Treg consistently showed a significantly higher expression for all inspected markers apart from CCR7, where the higher expression was not significant (p 5 0.126), and a significantly lower e...

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Section: Foxp3supporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

et al. 2010

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“…Regulatory T cells actively suppress autoreactive T cells in the periphery, 28 and reduced regulatory T function has been detected in MS patients. 29,30 Our data replicate the reported independent effects of two polymorphisms in the IL2RA locus, but the studied IL2RB polymorphisms show no signs of an overall effect on MS risk. The association found in Graves' disease, 31 as well as the one previously reported with T1D 7,32 and MS, 9,16 suggests that the IL2RA/CD25 region acts as a general susceptibility locus for autoimmune diseases.…”

Section: Discussionsupporting

confidence: 86%

Polymorphisms in the IL2, IL2RA and IL2RB genes in multiple sclerosis risk

et al. 2010

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Interleukin (IL)-2/IL-2R signalling promotes proliferation and survival of activated T cells and has an essential non-redundant role in the production of regulatory T cells. Associations with different autoimmune diseases of polymorphisms in a linkage disequilibrium block in which the IL2/IL21 genes map (4q27), and also in genes encoding the IL2RA and IL2RB subunits (located in 10p15 and 22q13, respectively), were identified through genome-wide studies. Polymorphisms in these three genes were studied in 430 multiple sclerosis (MS) patients and in 550 ethnically matched controls from Madrid (Spain). Replication and meta-analysis with results from an independent cohort of 771 MS patients and 759 controls from Andalucía (Spain) confirmed the association of polymorphisms in the IL2RA gene (P Mantel-Haenszel, odds ratio (OR) M-H (95% confidence interval, CI) for rs2104286: 0.0001, 0.75 (0.65-0.87); for rs11594656/rs35285258: 0.004, 1.19 (1.06-1.34); for rs41295061: 0.03, 0.77 (0.60-0.98)); showed a trend for association of the IL2/IL21 rs6822844 (P M-H ¼0.07, OR M-H (95% CI)¼0.86 (0.73-1.01)), but did not corroborate the association for IL2RB. Regression analyses of the combined Spanish cohort revealed the independence of two IL2RA association signals: rs2104286 and rs11594656/rs35285258. The relevant role of the IL2RA gene on MS susceptibility adds support to its common effect on autoimmune risk and the suggestive association of IL2/IL21 warrants further investigation.

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“…Moreover, Th17Th1 cells, a subpopulation which secretes both IL-17 and IFN-γ, have also been related to MS pathogenesis (29). Regarding Treg subpopulations, most of the reports found a similar percentage of Tregs in MS patients compared with healthy donors, although a functional impairment has been found in in vitro assays (30)(31)(32). In this context, an increase of the Th17/Treg balance has been associated with higher disease activity and severity (20,33).…”

Section: Th17 and Treg Subpopulationsmentioning

confidence: 99%

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

Teniente‐Serra¹,

Ramo‐Tello

Martı́nez-Cáceres

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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Abstract:Advances in the understanding of pathogenic mechanisms of diseases have led to the defining of new biomarkers for diagnosis, prognosis, and therapy response. In this context, flow cytometry has been positioned as one of the most useful technologies for monitoring immune-mediated diseases, such as multiple sclerosis (MS), allowing a detailed analysis of lymphocyte subpopulations in peripheral blood. The autoimmune inflammatory response in MS results in changes in lymphocyte subpopulations that might be useful as surrogate markers for the evaluation of disease activity, progression, and monitoring of therapy response. This chapter discusses the role of T-lymphocyte and B-lymphocyte subpopulations in MS pathogenesis, the effect of MS treatments on these subsets, and their potential usefulness as biomarkers of treatment response.

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Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients

Cited by 179 publications

References 15 publications

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

Polymorphisms in the IL2, IL2RA and IL2RB genes in multiple sclerosis risk

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

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