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oai:repisalud.isciii.es:20.500.12105/225612024-11-28T20:55:57Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Cunill, Vanesa author Massot, Margarita author Clemente, Antonio author Calles-Hernandez, M. Carmen author Andreu, Valero author Nunez, Vanessa author Lopez-Gomez, Antonio author Maria Diaz, Rosa author de los Reyes Jimenez, Maria author Pons De Ves, Jaime author Vives-Bauza, Cristofol author Maria Ferrer, Joana author 2018-05-29 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 naive 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 sub-populations that is reverted by DMF treatment. Monitoring cTfh subsets during treatment may become a biological marker of DMF effectiveness. Cunill Monjo V, Massot M, Clemente A, Calles C, A Matillas Valero, Nunez V, et al. Relapsing-Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment. Front Immunol. 2018 May 29;9:1097. 10.3389/fimmu.2018.01097 1664-3224 Frontiers in Immunology http://hdl.handle.net/20.500.13003/9296 29896193 L622332821 2-s2.0-85047668198 https://hdl.handle.net/20.500.12105/22561 433352700001 Multiple sclerosis Dimethyl fumarate Follicular T cells cTfh17.1 B cells Relapsing-Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment