Relapsing–Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment

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.

Imbalance in B cell and T Follicular Helper Cell Subsets in Pulmonary Sarcoidosis

“…High level of Th2-like and Th17-like CXCR5 + CD4+ T cells was shown in patients with juvenile dermatomyositis 30 , in SS 39 . Moreover, the imbalance in circulating Tfh cell subsets was founded in multiple sclerosis patient's peripheral blood and it was closely related to the increase of "pro-inflammatory" Tfh17.1 cells and decrease of Th1-like Tfh cells 41,42 . Thus, the frequency of Th2 was significantly higher, while Tfh1 cells were lower in blood samples from patients with active SLE (SLEDAI score > 8) if compared with HC 43 .…”

Follicular helper T cells in type 1 diabetes

“…[98][99][100][101][102][103][104] A very interesting question is why Tfh cells are specifically involved in the destruction of islet β cells but not other organs in T1D patients. [98][99][100][101][102][103][104] A very interesting question is why Tfh cells are specifically involved in the destruction of islet β cells but not other organs in T1D patients.…”

“…The increase of Tfh cells has been well documented in several autoimmune diseases, including SLE, RA, myasthenia gravis (MG), multiple sclerosis (MS), juvenile dermatomyositis, and Sjögren's syndrome. [98][99][100][101][102][103][104] A very interesting question is why Tfh cells are specifically involved in the destruction of islet β cells but not other organs in T1D patients. One of the reasons could be the genetic susceptibility.…”

Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

“…The Th17-like TFH cells are considered the most pathogenic and are the most effective cell type in supporting B-cell activity, particularly antibody production [ 39 ]. Importantly, another study has demonstrated that effective treatment with dimethyl fumarate results in a rebalancing of these ratios by decreasing the pathogenic Th17-like TFH cells and increasing the Th2-like TFH cells [ 63 ]. It is currently unclear how changes in these occur.…”