Effects of Tocilizumab Therapy on Circulating B Cells and T Helper Cells in Patients With Neuromyelitis Optica Spectrum Disorder.

Ye Liu,Fu-Dong Shi,Zhenning Huang,Tian-Xiang Zhang,Chao Zhang,Huiming Zhang,Chen Du,Pei Zeng,Dongmei Jia,Guili Yang,Meng Yuan

doi:10.3389/fimmu.2021.703931

Abstract

Tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, showed its therapeutic efficacy on neuromyelitis optica spectrum disorder (NMOSD). To assess the immunological effects of this drug on B cells, follicular T helper (Tfh) cells, and peripheral T helper (Tph) cells in patients with NMOSD, peripheral B cell and Tfh cell phenotypes were evaluated in 26 patients with NMOSD before and after tocilizumab treatment by nine-color flow cytometry, as well as the expression of costimulatory and co-inhibitory molecules on B cells. Results showed that the frequency of CD27+IgD− switched memory B cells, CD27-IgD- double-negative B cells, and CD27highCD38high antibody-secreting cells was increased in patients with NMOSD. Tocilizumab treatment led to a significant shift of B cells to naïve B cells from memory B cells after 3 months. Three markers on B cells associated with T-cell activation (i.e., CD86 CD69, and HLA-DR) were downregulated after tocilizumab treatment. The frequencies of total Tfh and Tph cells were decreased, whereas that of follicular regulatory T cells tended to increase. Intrinsic increased PD-L1 and PD-L2 expression was characteristic of B cells in patients with NMOSD. Tocilizumab selectively restored PD-L1 on B-cell subsets. These results provided evidence that tocilizumab enhanced B- and T-cell homoeostasis by regulating B-cell differentiation and inhibiting lymphocyte activation in patients with NMOSD.

Highlights

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system involving pathogenic autoantibodies against aquaporin-4 (AQP4IgG) [1, 2]
The frequency of naïve B cells was normalized in response to tocilizumab, and the changes in naïve B cells were attributed to the recovery of the reduced number of memory B cells, antibody-secreting cells (ASCs), and double negative (DN) B cells and, to a lesser degree, to a decline in the number of USW B cells
Consistent with previous studies, we found an upregulation of Tfh cells, Tfh1 cells, in NMOSD patients compared with healthy controls (HCs) [6, 28, 29], while 3 months of treatment with tocilizumab reduced the frequency of Tfh cells, and we found that Tfh cell differentiation was associated with IL-6 and plasmablast formation

Summary

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system involving pathogenic autoantibodies against aquaporin-4 (AQP4IgG) [1, 2]. Follicular T helper (Tfh) cells are critical in promoting B-cell autoimmunity and autoantibody production [6]. Peripheral helper T (Tph) cells was first defined with the markers of CD4+PD1highCXCR5-. These cells expressed indispensable cytokines that enable B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like Tfh cells, Tph cells can induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction. Different from Tfh cells, Tph cells have unique expression of chemokine receptors (such as CCR2, CX3CR1, and CCR5) that direct migration to inflamed sites [7]. AQP4-specific T cells are expanded in patients with NMOSD and exhibit proinflammatory Th17 polarization [8, 9]

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Results

Conclusion