Abstract
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.
Highlights
The follicular T helper (Tfh) cells are a CD4+T cell subpopulation essential in the regulation of humoral immunity, specialized in supporting B cell maturation and immunoglobulin production in secondary lymphoid organs
Percentages and absolute counts of CD4+ and CD8+ T cells, B, and NK cells in untreated RRMS patients were within reported ranges for Caucasians [21, 22] (Table 1)
Several immunological components have been implicated in the pathogenesis of multiple sclerosis (MS) with special relevance for CD4+ T cells [1], an important role for B lymphocytes has been demonstrated [6]
Summary
The follicular T helper (Tfh) cells are a CD4+T cell subpopulation essential in the regulation of humoral immunity, specialized in supporting B cell maturation and immunoglobulin production in secondary lymphoid organs. Tfh cells were first described as a CXCR5-expressing population localizing in “tonsillar” follicles [10, 11]. Morita et al originally demonstrated that analogous to non-follicular Th cells, circulating Tfh (cTfh) cells can be classified, according to the expression of CXCR3 and CCR6, into cTfh (CXCR3+CCR6−), cTfh (CXCR3−CCR6−), and cTfh (CXCR3−CCR6+) whose differentiation relies on distinct transcription factors [12]. These subpopulations produce a different set of cytokines and exert different B helper cell capabilities.
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