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Front. Immunol. | doi: 10.3389/fimmu.2018.01097

Relapsing Remitting Multiple Sclerosis is characterized by a T follicular cell pro-inflammatory shift, reverted by Dimethyl fumarate treatment

 Vanesa Cunill1, 2, Margarita Massot3,  Antonio Clemente2, 4,  Carmen Calles3,  Valero Andreu2, Vanessa Núñez3, Antonio López-Gómez1, 2,  Rosa María Díaz3, María de los Reyes Jiménez1, 2,  Jaime Pons1, 2, Cristòfol Vives-Bauzá2 and  Joana M. Ferrer1, 2*
  • 1Immunology, Hospital Universitario Son Espases, Spain
  • 2Institut d'Investigació Sanitària de les Illes Balears (IdISBa), Spain
  • 3Neurology, Hospital Universitario Son Espases, Spain
  • 4Clinical Trials and Methodology Support Platform, Institut d'Investigació Sanitaria Illes Balears (IdISBa), Spain

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.

Keywords: Multiple Sclerosis, Dimethyl fumarate, Follicular T cells, cTfh17.1, B cells

Received: 08 Feb 2018; Accepted: 02 May 2018.

Edited by:

Georgia Fousteri, San Raffaele Hospital (IRCCS), Italy

Reviewed by:

Xing Chang, Shanghai Institutes for Biological Sciences (CAS), China
Hu Zeng, Mayo Clinic, United States  

Copyright: © 2018 Cunill, Massot, Clemente, Calles, Andreu, Núñez, López-Gómez, Díaz, Jiménez, Pons, Vives-Bauzá and Ferrer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Joana M. Ferrer, Hospital Universitario Son Espases, Immunology, Palma de Mallorca, Spain, juanam.ferrer@ssib.es