The expansion of circulating IL-6 and IL-17-secreting follicular helper T cells is associated with neurological disabilities in neuromyelitis optica spectrum disorders

Monteiro, Clarice; Fernandes, Gabriel; Kasahara, Taissa M.; Barros, Priscila O.; Dias, Aleida S.O.; Araújo, Ana Carolina R.A.; Ornelas, Alice M.M.; Aguiar, Renato Santana; Alvarenga, Regina; Bento, Cleonice A.M.

doi:10.1016/j.jneuroim.2019.01.015

Cited by 18 publications

(14 citation statements)

References 23 publications

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“…Several autoimmune diseases are associated with either an increase in strong B-helper Tfh subsets (Tfh2 and Tfh17) and/or a decrease in non B-helper Tfh subsets (Tfh1) or regulatory subset (Tfr) (15, 17–19). 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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Up to now, a few studies have indicated that peripheral blood Tfh cells were increased in patients with NMOSD (8)(9)(10)(11)(12). Studies have shown that the percentages of peripheral blood CD4 + CXCR5 + PD-1 + Tfh cells in NMOSD patients were increased compared with those in MS and healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Association of Circulating T Follicular Helper Cells With Idiopathic Optic Neuritis and Neuromyelitis Optica Spectrum Disorders

Yang

Wang

2021

Front. Neurol.

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Background: T follicular helper cells (Tfh cells) play an important role in activating B lymphocytes and may associate with idiopathic Optic Neuritis (ON) and Neuromyelitis Optica Spectrum Disorders (NMOSD).Objective: This study aimed to examine the potential role of Tfh cells in pathogenesis of idiopathic ON and NMOSD.Methods: Circulating CD4+CXCR5+ and CD4+CXCR5+PD-1+ cells in 46 idiopathic ON and 68 NMOSD patients as well as 28 healthy controls were examined by flow cytometry before treatment. Serum AQP4 antibody, Expended Disability Status Scale (EDSS) and Visual Outcome Scale (VOS) were detected before and after treatment.Results: The percentages of circulating CD4+CXCR5+ and CD4+CXCR5+PD-1+Tfh cells in CD4+ cells (%) were significantly increased in idiopathic ON and NMOSD compared with those of healthy controls (p < 0.01). No significant difference of Tfh cells in blood and cerebral spinal fluid (CSF) was found between ON and NMOSD patients. The percentages of CSF, CD4+, CXCR5+, and CD4+CXCR5+PD-1+ cells in CD4+ cells (%) were positively correlated with those of the blood (r = 0.5781, r = 0.6079, p = 0.0076, and p = 0.0045, respectively). EDSS scores of NMOSD group were higher than those of ON group and the time course of NMOSD patients was longer than that of ON patients (p < 0.01). After methylprednisolone treatment, both EDSS and VOS scores were significantly decreased at discharge compared with before treatment (p < 0.01). There was no significant correlation among Tfh cell percentages in CD4+ cells, CSF leukocytes, CSF protein, annual recurrence rate, EDSS and VOS scores between two groups (p > 0.05).Conclusion: The Circulating T follicular helper cells were increased in both idiopathic ON and NMOSD.

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“…In the course of NMOSD, IL-6 as a humoral immune system factor plays an essential role in NMOSD pathogenesis [29][30][31]. Interleukin-6 supports plasma cell differentiation and survival and has a potential role in the induction of plasmablasts and/or plasma cells that produce autoantibodies against AQP4 and other relevant antigens [32,33].…”

Section: Discussionmentioning

confidence: 99%

The Possible Role of Interleukin-6 as a Regulator of Insulin Sensitivity in Patients With Neuromyelitis Optica Spectrum Disorder

Maghbooli

Moghadasi

Rezaeimanesh

et al. 2020

Preprint

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Background: The aquaporin 4- Immunoglobulin G (AQP4-IgG) is the disease-specific autoantibody that has a significant role in the pathogenesis of Neuromyelitis optica spectrum disorder (NMOSD). Circulating AQP4-IgG induces pro-inflammatory cytokines and may also trigger downstream signaling pathways leading to metabolic dysregulation.Methods: We aimed to determine the risk association of hyperinsulinemia in NMOSD patients with seropositive AQP4-IgG and the serum levels of interleukin (IL)-6 and IL-17 compared with the control group.Serum levels of metabolic (Insulin, Fasting Blood Sugar (FBS), lipid profile) and inflammatory (IL-6 and IL-17) markers were assessed in 56 NMOSD patients and 100 controls.Results: Hyperinsulinemia was more prevalent in NMOSD patients independent of age, gender and body mass index (BMI) (48.2% vs. 26%, p=0.005). After adjusting age, sex and BMI, there was significant association between lower insulin sensitivity (IS) and NMOSD risk (95% CI: Beta=0.73, 0.62 to 0.86, p=0.0001).The correlation between the duration of disease and circulating levels of insulin and FBS in NMOSD patients was not significant (P>0.05). Circulating levels of IL-6 and IL-17 were higher in NMOSD patients, and only IL-6 had an effect modifier for the association between lower insulin sensitivity and NMOSD risk. Conclusions: Our data suggests that inflammatory pathogenesis of NMOSD leads to hyperinsulinemia and increases the risk of insulin resistance.

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The expansion of circulating IL-6 and IL-17-secreting follicular helper T cells is associated with neurological disabilities in neuromyelitis optica spectrum disorders

Cited by 18 publications

References 23 publications

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

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

Association of Circulating T Follicular Helper Cells With Idiopathic Optic Neuritis and Neuromyelitis Optica Spectrum Disorders

The Possible Role of Interleukin-6 as a Regulator of Insulin Sensitivity in Patients With Neuromyelitis Optica Spectrum Disorder

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