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

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is a rare and severe auto-immune disease of the central nervous system driven by pathogenic antibodies mainly directed against aquaporin-4 (AQP4-Ab). Treatment of NMOSD currently relies on immunosuppressants (mycophenolate mofetil, azathioprine) or B-cell-depleting therapy (rituximab). B-cell differentiation into antibody-producing cells requires T follicular helper cells (Tfh). There are several Tfh subsets that differentially affect B-cell differentiation; Tfh2 and Tfh17 subsets strongly support B-cell differentiation. By contrast, Tfh1 lack this capacity and T follicular regulatory cells (Tfr), inhibit B-cell differentiation into antibody-producing cells. We performed a broad characterization of circulating Tfh subsets in 25 NMOSD patients and analyzed the impact of different treatments on these subsets. Untreated NMOSD patients presented a Tfh polarization toward excessive B-helper Tfh subsets with an increase of Tfh17 and (Tfh2+Tfh17)/Tfh1 ratio and a decrease of Tfr and Tfh1. Rituximab restored the Tfh polarization to that of healthy controls. There was a trend toward a similar result for azathioprine and mycophenolate mofetil. Our results suggest that NMOSD patients present an impaired balance in Tfh subsets favoring B-cell differentiation which may explain the sustained antibody production. These findings provide new insights into the pathophysiology of NMOSD, and further suggest that Tfh and Tfr subsets could be considered as potential therapeutic target in NMOSD because of their upstream role in antibody production.

T follicular helper cell subsets: a potential key player in autoimmunity

“…Neuromyelitis optica spectrum disorders (NMOSD) are also inflammatory demyelinating diseases affecting CNS, characterized by presence of anti auqaporin-4 antibodies [85]. Multiple studies showed increased frequencies of cTfh cells in NMOSD patients [86][87][88]. They had correlation with disease activity and treatment with methylprednisolone led to a significant decrease of cTfh cells frequency [87].…”

“…They had correlation with disease activity and treatment with methylprednisolone led to a significant decrease of cTfh cells frequency [87]. Untreated NMOSD patients showed an imbalance of cTfh subsets: increase of cTfh17 and (cTfh2 þ cTfh17)/cTfh1 ratio [88]. Of interest, anti-CD20 antibody, rituximab, altered the Tfh polarization to that of healthy controls [88].…”

“…Untreated NMOSD patients showed an imbalance of cTfh subsets: increase of cTfh17 and (cTfh2 þ cTfh17)/cTfh1 ratio [88]. Of interest, anti-CD20 antibody, rituximab, altered the Tfh polarization to that of healthy controls [88].…”

Altered distributions in circulating follicular helper and follicular regulatory T cells accountable for imbalanced cytokine production in multiple sclerosis

“…Nicolas et al . reported that elevated cTfh cells can be reverted in patients with neuromyelitis optica after treatment with rituximab [43], suggesting exploring new therapeutic solutions for MS.…”

Pro‐inflammatory dopamine‐2 receptor‐specific T cells in paediatric movement and psychiatric disorders

“…In the case of a murine model of post-infection associated autoimmunity, reactive T cells migrate from the periphery into the CNS and contribute to neuroinflammation. [26][27][28] Indeed, a dysregulated T-cell compartment has been described in other neuroinflammatory disorders, most notably in multiple sclerosis (MS), [29][30][31] but also in neuromyelitis optica spectrum disorders (NMOSDs), [32][33][34] Rasmussen's encephalitis 35,36 and paraneoplastic syndromes. 37,38 In this study, we report on the presence of peripheral autoreactive T cells against D2R in paediatric patients with movement and psychiatric disorders.…”