Relapsing-Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment.
Relapsing-Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment.
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DOI：
10.3389/fimmu.2018.01097
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发表时间：
2018
影响因子：
7.3
通讯作者：
Ferrer JM
中科院分区：
文献类型：
--
作者：
Cunill V;Massot M;Clemente A;Calles C;Andreu V;Núñez V;López-Gómez A;Díaz RM;Jiménez MLR;Pons J;Vives-Bauzà C;Ferrer JM
多发性硬化（MS）被认为是T细胞介导的自身免疫性疾病，尽管一些证据也证明B细胞参与其病因。滤泡性T辅助细胞（Tfh）是一种表达CXCR 5的CD 4 + T细胞亚群，在调节B细胞分化和维持体液免疫中起重要作用。循环（c）Tfh分布和/或功能的改变与自身免疫性疾病（包括MS）相关。富马酸二甲酯（DMF）是最近批准的复发缓解型MS（RRMS）患者的一线治疗药物，其作用机制尚未完全了解。我们研究的目的是比较RRMS患者和健康受试者之间的cTfh亚群，并评价DMF治疗对这些亚群的影响，将其与B细胞和体液应答的变化联系起来。我们通过流式细胞术分析了29名未经治疗的RRMS受试者与健康受试者中cTfh 1（CXCR 3 + CCR 6 −）、cTfh 2（CXCR 3 − CCR 6 −）、cTfh 17（CXCR 3 − CCR 6+）和最近描述的CD 4 + Tfh（CD 45 RA − CXCR 5+）细胞的cTfh17.1（CXCR 3 + CCR 6+）亚群的分布。还研究了CD 4+非滤泡性T辅助（Th）细胞（CD 45 RA − CXCR 5 −）。我们还评价了DMF治疗6个月和12个月后对这些亚群的影响。与健康受试者相比，未经治疗的RRMS患者呈现出较高的cTfh17.1细胞百分比和较低的cTfh 2细胞百分比，这与促炎偏倚一致。DMF处理诱导cTfh 2细胞进行性增加，同时伴有cTfh 1和致病性cTfh17.1细胞减少。DMF给药后，除抗炎性Th 2亚群增加外，还检测到非滤泡性Th 1和Th17.1细胞出现类似减少，伴随幼稚B细胞增加和转换记忆B细胞以及伊加、IgG 2和IgG 3血清水平降低。有趣的是，在因无临床应答而不得不停用DMF的3例患者中未观察到该效应。我们的研究结果表明，RRMS患者中可能存在致病性cTfh促炎特征，定义为DMF治疗可逆转的高cTfh 17.1和低cTfh 2亚群。治疗期间监测cTfh亚群可能成为DMF有效性的生物学标志物。
Multiple sclerosis (MS) is considered a T cell-mediated autoimmune disease, although several evidences also demonstrate a B cell involvement in its etiology. Follicular T helper (Tfh) cells, a CXCR5-expressing CD4+ T cell subpopulation, are essential in the regulation of B cell differentiation and maintenance of humoral immunity. Alterations in circulating (c)Tfh distribution and/or function have been associated with autoimmune diseases including MS. Dimethyl fumarate (DMF) is a recently approved first-line treatment for relapsing–remitting MS (RRMS) patients whose mechanism of action is not completely understood. The aim of our study was to compare cTfh subpopulations between RRMS patients and healthy subjects and evaluate the impact of DMF treatment on these subpopulations, relating them to changes in B cells and humoral response. We analyzed, by flow cytometry, the distribution of cTfh1 (CXCR3+CCR6−), cTfh2 (CXCR3−CCR6−), cTfh17 (CXCR3−CCR6+), and the recently described cTfh17.1 (CXCR3+CCR6+) subpopulations of CD4+ Tfh (CD45RA−CXCR5+) cells in a cohort of 29 untreated RRMS compared to healthy subjects. CD4+ non-follicular T helper (Th) cells (CD45RA−CXCR5−) were also studied. We also evaluated the effect of DMF treatment on these subpopulations after 6 and 12 months treatment. Untreated RRMS patients presented higher percentages of cTfh17.1 cells and lower percentages of cTfh2 cells consistent with a pro-inflammatory bias compared to healthy subjects. DMF treatment induced a progressive increase in cTfh2 cells, accompanied by a decrease in cTfh1 and the pathogenic cTfh17.1 cells. A similar decrease of non-follicular Th1 and Th17.1 cells in addition to an increase in the anti-inflammatory Th2 subpopulation were also detected upon DMF treatment, accompanied by an increase in naïve B cells and a decrease in switched memory B cells and serum levels of IgA, IgG2, and IgG3. Interestingly, this effect was not observed in three patients in whom DMF had to be discontinued due to an absence of clinical response. Our results demonstrate a possibly pathogenic cTfh pro-inflammatory profile in RRMS patients, defined by high cTfh17.1 and low cTfh2 subpopulations that is reverted by DMF treatment. Monitoring cTfh subsets during treatment may become a biological marker of DMF effectiveness.
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影响因子：
3.4
作者：
Boldt, Andreas;Borte, Stephan;Sack, Ulrich
通讯作者：
Sack, Ulrich
DOI：
10.1084/jem.192.11.1553
发表时间：
2000-12-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Schaerli P;Willimann K;Lang AB;Lipp M;Loetscher P;Moser B
通讯作者：
Moser B
DOI：
10.1016/j.jaci.2015.05.036
发表时间：
2015-10
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Ma CS;Wong N;Rao G;Avery DT;Torpy J;Hambridge T;Bustamante J;Okada S;Stoddard JL;Deenick EK;Pelham SJ;Payne K;Boisson-Dupuis S;Puel A;Kobayashi M;Arkwright PD;Kilic SS;El Baghdadi J;Nonoyama S;Minegishi Y;Mahdaviani SA;Mansouri D;Bousfiha A;Blincoe AK;French MA;Hsu P;Campbell DE;Stormon MO;Wong M;Adelstein S;Smart JM;Fulcher DA;Cook MC;Phan TG;Stepensky P;Boztug K;Kansu A;İkincioğullari A;Baumann U;Beier R;Roscioli T;Ziegler JB;Gray P;Picard C;Grimbacher B;Warnatz K;Holland SM;Casanova JL;Uzel G;Tangye SG
通讯作者：
Tangye SG
DOI：
10.5493/wjem.v4.i3.27
发表时间：
2014-08-20
期刊：
World journal of experimental medicine
影响因子：
--
作者：
Hoglund, Rune A;Maghazachi, Azzam A
通讯作者：
Maghazachi, Azzam A
影响因子：
5.8
作者：
Kroth, Julia;Ciolac, Dumitru;Groppa, Sergiu
通讯作者：
Groppa, Sergiu