Increased Circulating T Follicular Helper Cells Are Inhibited by Rituximab in Neuromyelitis Optica Spectrum Disorder

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease of the central nervous system. The existence of autoantibody targeting aquaporin-4 (AQP4-Ab) indicates the involvement of humoral immunity in the pathogenesis of this disease. Rituximab (RTX), a monoclonal antibody against CD20, has been used to treat NMOSD by depleting circulating B cells and overall satisfactory outcome has been achieved. Although T follicular helper cells have been proved to regulate B cell activation and antibody production, the role of these cells in NMOSD and the impact of RTX treatment on these cells remain less understood. In this study, we found that frequencies of circulating T follicular helper (cTfh) cells and B cells together with the related cytokines, IL-21 and IL-6, were closely correlated with disease activity of NMOSD. Furthermore, B cell depletion with RTX treatment inhibited the expansion of cTfh cells, and these effects were achieved through eliminating IL-6-producing B cells and blocking the direct contact between cTfh cells and B cells. These findings imply the complicated cross talk between cTfh cells and B cells and may provide a novel therapeutic target for NMOSD.

The Balance in T Follicular Helper Cell Subsets Is Altered in Neuromyelitis Optica Spectrum Disorder Patients and Restored by Rituximab

“…In the present study, we reproduced previous results suggesting that RTX inhibits Tfh increase in NMOSD as well as the impact of RTX on Tfh frequency (22) by a confirmatory analysis. We further performed an exploratory analysis after considering consistent and coherent hypothesis pre-tests based on the similarly altered distribution of Tfh subsets in other antibody-mediated autoimmune disorders such as myastenia gravis, guillain-barré syndrome or lupus (15, 17–19).…”

“…We confirm herein that Tfh population is altered in non-treated NMOSD patients (20–22) but only at the subset level with a higher proportion of Tfh17, a lower proportion of the Tfh1, a higher (Tfh2+Tfh17)/Tfh1 ratio, and a lower proportion of Tfr, compared with HC. These findings suggest that the altered balance in Tfh subsets may facilitate B cell differentiation into antibody producing cells in NMOSD patients.…”

“…The present study suggests an alternative mechanism of action; RTX could restore the altered balance in Tfh subsets in NMOSD patients. Zhao et al have already shown that the frequency of circulating Tfh cells (CD3+CD4+CXCR5+PD-1+) was significantly decreased under RTX in NMOSD (22). They also showed ex vivo , that Tfh maintenance was dependent on B cell, throw IL6 signaling and direct contact (22) and suggested a positive feedback loop between B cells and Tfh cells, that could be disrupted by RTX.…”

“…Only a few studies have focused on circulating Tfh in NMOSD (20–23). Circulating Tfh were found to be increased in NMOSD patients, and even more during relapses (20–22). Tfh cell frequency decreased under methylprednisolone (20) and rituximab treatments (22).…”

“…Circulating Tfh were found to be increased in NMOSD patients, and even more during relapses (20–22). Tfh cell frequency decreased under methylprednisolone (20) and rituximab treatments (22). However, a large and prospective analysis of Tfh subsets (Tfh1, Tfh2, Tfh17, Tfr) in NMOSD is lacking.…”