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Study of CD4+CD25+FOXP3+ regulatory T cells in patients with multiple sclerosis
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Study of CD4+CD25+FOXP3+ regulatory T cells in patients with multiple sclerosis
No full textnot availabl
Natural naive CD4(+)CD25(+)CD127(low) regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: Recovery of memory treg homeostasis during disease progression
No full textPatients with relapsing-remitting multiple sclerosis (RR-MS) show a suboptimal CD4(+)CD25(+) regulatory T cell (Treg) function, whereas no Treg alterations are observed in secondary progressive MS (SP-MS) patients. To clarify the difference in Treg activity between early and chronic disease stages in MS, we analyzed the functional capacity and homeostatic parameters of naive CD4(+)CD25(+)CD127(low)CD45RA(+) Tregs (nTregs) and their memory counterparts CD4(+)CD25(+)CD127(low) CD45RO(+) Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg function. Consistent with this observation, chronic MS patients had increased numbers of mTregs as compared with age-matched early MS patients, whereas nTreg frequencies did not differ significantly. TCR excision circle numbers were reduced in nTregs of early MS patients, suggestive of a diminished nTreg thymic output. Moreover, a decreased number of CD31(+) mTregs were observed in early vs chronic MS patients, indicating that inflammatory processes drive the homeostatic turnover of mTregs during the early disease stage. Additionally, early MS patients showed a more restricted nTreg and mTreg TCR BV gene profile as compared with healthy controls and chronic MS patients. Finally, analysis of IFN-beta and glatiramer acetate-treated MS patients showed that these immunomodulatory drugs modify nTreg homeostasis. Taken together, this study provides strong evidence for a disturbed thymic nTreg development and function in MS patients. Moreover, memory Treg but not naive Treg homeostasis recovers during disease progression
Natural naive CD4(+)CD25(+)CD127(low) regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: Recovery of memory treg homeostasis during disease progression
No full textPatients with relapsing-remitting multiple sclerosis (RR-MS) show a suboptimal CD4(+)CD25(+) regulatory T cell (Treg) function, whereas no Treg alterations are observed in secondary progressive MS (SP-MS) patients. To clarify the difference in Treg activity between early and chronic disease stages in MS, we analyzed the functional capacity and homeostatic parameters of naive CD4(+)CD25(+)CD127(low)CD45RA(+) Tregs (nTregs) and their memory counterparts CD4(+)CD25(+)CD127(low) CD45RO(+) Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg function. Consistent with this observation, chronic MS patients had increased numbers of mTregs as compared with age-matched early MS patients, whereas nTreg frequencies did not differ significantly. TCR excision circle numbers were reduced in nTregs of early MS patients, suggestive of a diminished nTreg thymic output. Moreover, a decreased number of CD31(+) mTregs were observed in early vs chronic MS patients, indicating that inflammatory processes drive the homeostatic turnover of mTregs during the early disease stage. Additionally, early MS patients showed a more restricted nTreg and mTreg TCR BV gene profile as compared with healthy controls and chronic MS patients. Finally, analysis of IFN-beta and glatiramer acetate-treated MS patients showed that these immunomodulatory drugs modify nTreg homeostasis. Taken together, this study provides strong evidence for a disturbed thymic nTreg development and function in MS patients. Moreover, memory Treg but not naive Treg homeostasis recovers during disease progression
Natural naive regulatory T cell development and function are disturbed in multiple sclerosis patients
No full textBackground: Myelin-reactive T cells may play a pathogenic role in
multiple sclerosis (MS). We and others have shown that regulatory
CD4+CD25+FOXP3+CD127low T cells (Tregs) are functionally disturbed
in relapsing-remitting (RR) MS patients but not in secondary
progressive (SP) MS patients. Objective: To clarify this difference in
Treg activity between early and chronic disease stages in MS.
Methods: We analyzed the functional capacity and homeostatic
parameters of (precursor) naive Tregs (nTregs) and memory Tregs
(mTregs). We also measured myelin basic protein (MBP) and myelin
oligodendrocyte glycoprotein (MOG) proliferative responses of
CD4total T cells (including Tregs), naive (CD45RAhigh) and memory
(CD45RA-) CD4+CD25-CD127high T cells (no Tregs included) of
RRMS and SPMS patients and healthy controls (HC) by means of a
CFSE dilution assay and measured cytokine production of the myelinreactive
T cells. Results: The suppressive capacity of FACS-sorted
nTregs was impaired in both early and chronic MS patients, whereas
only the latter group showed a restored mTreg function. Chronic MS
patients had increased numbers of mTregs as compared with agematched
early MS patients, whereas nTreg frequencies did not differ
A CFSE based assay for measuring CD4+CD25+ regulatory T cell mediated suppression of auto-antigen specific and polyclonal T cell responses
No full textCD4(+)CD25(+) regulatory T cells (Tregs) are considered to play a key role as suppressors of immune inediated reactions. The analysis of Treg function in patients with autoimmune, allergic or oncogenic diseases has emerged over the past years. In the present study we describe a CFSE based protocol to measure Treg mediated suppression of CD4(+) T cells. Measuring Treg suppressive capacity towards proliferation of anti-CD3 Ab stimulated CD4(+)CD25(-) T cells in coculture experiments by means of a CFSE based and a classical [H-3]thymidine incorporation assay gave similar results, provided that CD4(+)CD25(+) T cells were anergic. However, when CD4(+)CD25(+) T cells proliferated upon mitogenic stimulation, data obtained by the CFSE assay allowed the detection of a significant Treg suppression whereas this was clearly underestimated using the [H-3]thymidine assay. In addition, an indirect CFSE based method was developed to analyze antigen specific responses of total CD4(+) T cells and Treg depleted CD4(+) T cells (i.e. CD4(+)CD25(-) T cells). Our results indicate that, in healthy individuals, CD4(+) T cell responses against the multiple sclerosis (MS) auto-antigens, myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG), were increased in Treg depleted CD4(+) T cells as compared to total CD4(+) T cells. Our initial data suggest that Tregs in MS patients show an impaired suppression of myelin reactive T cells when compared to healthy controls. Moreover, this experimental setup permits the measurement of cytokine production of the antigen proliferated CFSElow T cells by additional flow cytometric analyses. In conclusion, the described CFSE based Treg suppression assay is a valuable tool to study suppressor T cells in (auto)immune disorders. (C) 2007 Elsevier B.V. All rights reserved
Caspr1/Paranodin/Neurexin IV is most likely not a common disease-causing gene for inherited peripheral neuropathies
No full textContactin associated protein 1 (Caspr1/Paranodin/Neurexin IV) is an axonal transmembrane molecule mainly localised at the paranodal junction. Since molecular alterations in septate-like junctions at the paranodes might have important consequences for the function of the nerve fiber, we considered that Caspr1 could be involved in the pathogenesis of inherited peripheral neuropathies. In this study, we physically mapped the Caspr1 gene on chromosome 17q21.1 and determined its genomic structure. We performed a mutation analysis of the Caspr1 gene in a cohort of 64 unrelated patients afflicted with distinct inherited peripheral neuropathies. Since no disease causing mutations were found, we suggest that Caspr1 is probably not a common cause of inherited peripheral neuropathies
Natural naive regulatory T cell development and function are disturbed in multiple sclerosis patients
No full textCaspr1/Paranodin/Neurexin IV is most likely not a common disease-causing gene for inherited peripheral neuropathies
No full textContactin associated protein 1 (Caspr1/Paranodin/Neurexin IV) is an axonal transmembrane molecule mainly localised at the paranodal junction. Since molecular alterations in septate-like junctions at the paranodes might have important consequences for the function of the nerve fiber, we considered that Caspr1 could be involved in the pathogenesis of inherited peripheral neuropathies. In this study, we physically mapped the Caspr1 gene on chromosome 17q21.1 and determined its genomic structure. We performed a mutation analysis of the Caspr1 gene in a cohort of 64 unrelated patients afflicted with distinct inherited peripheral neuropathies. Since no disease causing mutations were found, we suggest that Caspr1 is probably not a common cause of inherited peripheral neuropathies
Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants
No full textThe receptor for the homeostatic T cell cytokine interleukin-7 (IL-7R alpha) has recently shown genetic association to multiple sclerosis (MS). To investigate the functional contribution of IL-7R alpha polymorphisms to the pathogenesis of MS, we correlated the IL-7R alpha haplotypes with different T cell parameters in a group of MS patients and healthy controls. We show that carriers of one of the four IL-7R alpha haplotypes (Hap4) show a higher expression of IL-7R alpha (CD127) on their CD4(+) T cells, compared with noncarriers (P = 0.04). Moreover, Hap4 carriers possess higher frequencies of recent thymic emigrants (RTEs, CD31(+)) in both the regulatory T cell (Treg; P = 0.007) and conventional T cell (Tconv) population (P = 0.0001). This effect is most pronounced within the MS population (Treg, P = 0.0077; Tconv, P = 0.0007), whereas in healthy controls significance was only reached for Tconv (P = 0.043; Treg, P = 0.11). Because previous studies showed a decreased RTE-Treg frequency in MS patients compared to healthy subjects, we here conclude that this decrease is localized within the MS population of non-Hap4 carriers. In conclusion, our findings suggest that IL-7Ra polymorphisms can influence T cell development and homeostasis, and thereby contribute to the altered immune regulation associated with disease development in patients with MS
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