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

Cong Zhao,Ya-Nan Bai,Chao Ma,Hong-Zeng Li,Fang Wu,Jun Guo,Min Zhang,Zhu-Yi Li,Dai-Di Zhao

doi:10.3389/fneur.2017.00104

Cong Zhao, Ya-Nan Bai + Show 7 more

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https://doi.org/10.3389/fneur.2017.00104

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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.

Highlights

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory demyelinating disease of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis and transverse myelitis [1]
There was a significant increase of plasma IL-21 and IL-6 levels in the relapsing patients with NMOSD compared with the remitting patients and HCs (Figures 2A,B), which was consistent with the changes of circulating T follicular helper (cTfh) cells and B cells
Morita and colleagues have demonstrated that circulating CD4+CXCR5+ T cells appeared to be the memory subset of germinal center (GC) T follicular helper (Tfh) pool and had the same capacity to regulate B cells [13], which facilitated researchers to explore the role of these cells in human diseases

Summary

INTRODUCTION

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory demyelinating disease of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis and transverse myelitis [1]. In patients with MS, RTX treatment resulted in a significant decline of CNS-infiltrated T cells, which suggested this agent may modulate T cell immune response besides depleting B cells [19]. We found that frequencies of cTfh cells and circulating B cells together with the related molecules were closely associated with the disease activity of NMOSD. The results strongly suggest the existence of B–cTfh cell interaction in NMOSD, which might provide a possible therapeutic target for this disease. Blood samples were drawn from all the patients and HCs to collect peripheral blood mononuclear cells (PBMCs) and plasma for detecting cell frequencies and cytokine concentrations, respectively. Rituximab (RTX) treatment was carried out in the patients based on clinical status and patient’s preference. Plasma AQP4-Ab levels were measured, respectively, before and 1 month after RTX treatment in seropositive patients. A P value of less than 0.05 was considered as statistically significant

RESULTS

DISCUSSION

ETHICS STATEMENT