CD4+ T Cells of Myasthenia Gravis Patients Are Characterized by Increased IL-21, IL-4, and IL-17A Productions and Higher Presence of PD-1 and ICOS

Çebi, Merve; Durmuş, Hacer; Aysal, Fikret; Özkan, Berker; Gül, Gizem Engin; Çakar, Arman; Hocaoğlu, Mehmet; Mercan, Metin; Yentür, Sibel P.; Tütüncü, Melih; Yayla, Vildan; Akan, Onur; Dogan, Oner; Parman, Yeşim; Saruhan‐Direskeneli, Güher

doi:10.3389/fimmu.2020.00809

Cited by 35 publications

(21 citation statements)

References 49 publications

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“…supporting our results 26. These observations showed that cTfh, especially qualitative and quantitative changes of ICOS high cTfh, are essential for the pathogenic cytokine condition in MG.…”

supporting

confidence: 91%

“…25 In our analysis, cTfh exhibited significantly higher expression of ICOS in patients with MG compared with HS, a finding in agreement with a recent report. 26 IL-21 is a key cytokine of cTfh 17,18 and promotes B-cell differentiation and antibody production. [27][28][29] A study of ICOS-deficient mice reported that effector T cells showed an impaired ability to produce IL-21 and IL-4, and IgG production was also reduced.…”

Section: Discussionmentioning

confidence: 99%

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Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity

Ashida

Ochi

Hamatani

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo clarify functional alterations of follicular helper T cells (Tfh) in myasthenia gravis (MG) because Tfh play important roles in helping B cells generate antibody-producing cells.MethodsA total of 24 immunotherapy-naive patients with anti–acetylcholine receptor (AchR) antibody–positive MG and 18 age-matched healthy subjects (HS) were enrolled. Samples from 6 patients were available for posttreatment analysis. Subsets of circulating Tfh (cTfh) and B cells were identified by flow cytometry analysis of surface molecules. Cytokine production by isolated cTfh subsets from 5 patients with MG and 5 HS was measured in vitro. Analysis was performed to examine the correlation between the frequency of cTfh subsets and that of plasmablasts and between cTfh subsets and the quantitative MG score.ResultscTfh increased with elevated expression of inducible T-cell costimulator (ICOS) in patients with MG. cTfh shifted to Th2 and Th17 over Th1 in MG. ICOShighcTfh produced significantly higher levels of interleukin (IL)-21, IL-4, and IL-17A than ICOSlow cTfh only in patients with MG. The frequency of cTfh within CD4 T cells was more closely associated with disease severity than the serum anti-AchR antibody titer and frequency of plasmablasts within B cells. Abnormalities of cTfh were improved after immunotherapy in parallel with clinical improvement.ConclusionsAlternation of cTfh is a key feature in the development of MG and may become a biomarker for disease severity and therapeutic efficacy.Classification of EvidenceThis study provides Class II evidence that the level of cTfh is associated with disease severity in patients with MG.

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supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity

Ashida

Ochi

Hamatani

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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“…Tfr and Tfh cells primarily reside in GCs (98). However, some studies have identified counterpart CD4 + T cell subsets in peripheral blood, facilitating investigation of their pathogenic potential in the context of autoimmunity, including MG (107,108).…”

Section: Follicular Regulatory T Cellsmentioning

confidence: 99%

Immunoregulatory Cells in Myasthenia Gravis

Luo

Garden

2020

Front. Neurol.

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Myasthenia gravis (MG) is a T cell-dependent, B-cell mediated autoimmune disease caused by antibodies against the nicotinic acetylcholine receptor or other components of the post-synaptic muscle endplate at the neuromuscular junction. These specific antibodies serve as excellent biomarkers for diagnosis, but do not adequately substitute for clinical evaluations to predict disease severity or treatment response. Several immunoregulatory cell populations are implicated in the pathogenesis of MG. The immunophenotype of these populations has been well-characterized in human peripheral blood. CD4+FoxP3+ regulatory T cells (Tregs) are functionally defective in MG, but there is a lack of consensus on whether they show numerical perturbations. Myeloid-derived suppressor cells (MDSCs) have also been explored in the context of MG. Adoptive transfer of CD4+FoxP3+ Tregs or MDSCs suppresses ongoing experimental autoimmune MG (EAMG), a rodent model of MG, suggesting a protective role of both populations in this disease. An imbalance between follicular Tregs and follicular T helper cells is found in untreated MG patients, correlating with disease manifestations. There is an inverse correlation between the frequency of circulating IL-10–producing B cells and clinical status in MG patients. Taken together, both functional and numerical defects in various populations of immunoregulatory cells in EAMG and human MG have been demonstrated, but how they relate to pathogenesis and whether these cells can serve as biomarkers of disease activity in humans deserve further exploration.

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“…Plasma IL‐17A levels are increased and exhibit a correlation with the QMG score in anti‐AChR antibody‐positive MG, especially in patients with early‐onset, female, or non‐thymoma [7]. IL‐17A production from CD4 + T cells is increased in anti‐AChR antibody‐positive MG [17]. In addition, serum IL‐17 levels are increased in generalized anti‐AChR antibody‐positive MG and are correlated with anti‐AChR antibody titers [8], although a paper by Uzawa et al .…”

Section: Th17 Cells and Related Cytokines In Mgmentioning

confidence: 99%

“…In addition, it has been reported that serum IL-21, a Tfh cell-related cytokine, is elevated in MG. IL-21 levels are correlated with the QMG score in MG patients with hyperplasia [10] and anti-AChR immunoglobulin (Ig)G1 antibody titers [27], and decreases after steroid treatment in non-thymomatous anti-AChR antibody-positive MG [27]. IL-21 production from CD4 + T cells is increased in anti-AChR antibody-positive MG [17]. IL-21 is reportedly produced mainly from activated Tfh1 and Tfh17 cells [9].…”

Section: Tfh Cells and Related Cytokines In Mgmentioning

confidence: 99%

Roles of cytokines and T cells in the pathogenesis of myasthenia gravis

Uzawa

Kuwabara

Suzuki

et al. 2020

Clinical and Experimental Immunology

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Activated T cells, B cells, plasma cells, and related cytokines play central roles in the production of pathogenic autoantibodies in myasthenia gravis (MG). T helper 17 (Th17) cells, follicular Th (Tfh) cells, and related cytokines are upregulated, whereas regulatory T (Treg) cells and related cytokines are downregulated. Chronic inflammation by Th17 cells, the promotion of autoantibody production from B cells and plasma cells by Tfh cells or B‐cell‐related cytokines, and the activation of the immune response by dysfunction of Treg cells may be involved in the pathogenesis of MG.

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CD4+ T Cells of Myasthenia Gravis Patients Are Characterized by Increased IL-21, IL-4, and IL-17A Productions and Higher Presence of PD-1 and ICOS

Cited by 35 publications

References 49 publications

Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity

Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity

Immunoregulatory Cells in Myasthenia Gravis

Roles of cytokines and T cells in the pathogenesis of myasthenia gravis

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