Home Interleukin-27 levels in patients with myasthenia gravis
Article Open Access

Interleukin-27 levels in patients with myasthenia gravis

  • Xiao-Jiao Liu , Lin-Jie Zhang , Ming Yi , Li-Min Li , Jing Wang , Yuan Qi , Peng Zhao , Da-Qi Zhang and Li Yang EMAIL logo
Published/Copyright: September 9, 2020
Download Article (PDF)
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Translational Neuroscience
From the journal Translational Neuroscience Volume 11 Issue 1

Abstract

Interleukin-27 (IL-27), which belongs to IL-12 family, influences the function of T cells (Tregs) through regulating the expression, and function of forkhead box P3 (FoxP3). In this study, we detected the IL-27 serum levels in 59 myasthenia gravis (MG) patients and 35 healthy controls (HCs). Among them, 32 MG patients received immunoglobulin intravenous (IVIG) injections (0.4 g/kg per day for 5 consecutive days). IL-27 levels were collected before and after the treatments and subjected to a comparative study. Finally, we assessed the correlations of IL-27 levels with the clinical characteristics of MG. As a result, serum IL-27 levels were significantly higher in MG patients than those in the HCs. Meanwhile, significant reduction was detected after the IVIG treatment. IL-27 levels positively correlated with both MG activities of daily living and quantitative MG score. IL-27 may participate in the pathogenesis of MG and can be used as an early marker for the diagnosis and prognosis of MG. In addition, IL-27 can be used as a target for MG treatment through the regulation of specific immune signaling and maintaining immune homeostasis.

Keywords: interleukin-27; myasthenia gravis; quantitative MG score; thymoma-associated myasthenia gravis; MG activities of daily living

1 Introduction

T-cell-mediated immune inflammation plays an important role in the pathogenesis of myasthenia gravis (MG). The differentiation imbalance in the cluster of four positive T-helper cells (T helper, Th) leads to an increase in Th1 and Th17 numbers and abnormal cytokine production, including interleukin-1 (IL-1), IL-6, IL-17, interferon-γ, and tumor growth factor α. This causes an imbalance in immune homeostasis and subsequently activates effector B cells that produce autoantibodies. Regulatory T cells (Tregs) play a key role in maintaining immune tolerance. Abnormal functions of Tregs have been reported in many autoimmune diseases including MG, multiple sclerosis (MS), and inflammatory bowel disease (IBD) [1,2]. Tregs are mainly divided into natural Tregs which are produced by thymus and express the transcription factor forkhead box P3 (FoxP3), induced Tregs, which are generated in vitro, and IL-10-secreting type 1 regulatory T cells (Tr1) according to the differences in cell surface antigens, cytokine produced, and mechanism of actions [3,4]. FoxP3 is a key transcription factor that determines the development of Tregs and its expression of immunosuppressive molecules, which is an essential element for Tregs to exert their regulatory functions [4]. Tregs maintain immune homeostasis through various ways including secretion of anti-inflammatory factors including IL-10, IL-35, and transforming growth factor-β; adhesion with cell surface molecules such as CD25 and cytotoxic T-lymphocyte antigen 4; and secretion of perforin or granzyme, which directly inhibits or kills effector cells such as antigen presenting cells (APCs) and B cells that produce autoantibodies [5,6].

IL-27 is a cytokine that belongs to the IL-12 family, which is mainly secreted by activated APCs, and is composed of a heterodimeric structure containing Epstein–Barr virus-induced gene protein 3 and p28 subunits. IL-27 plays an immunosuppressive role by inducing the expression of transcription factors c-Maf, AhR, Egr-2, and Blimp-1 through STAT1 and STAT3 signaling pathways, promoting the differentiation of Tr1 and the production of IL-10, which subsequently promotes the further production of IL-10 by Tr1, and eliminating the self-reactive B cells [7,8]. Cox et al. found that IL-27 restricts their conversion by limiting the model of colitis T-cell transfer and ovalbumin-dependent tolerance [9], resulting in a decreased number of Tregs. IL-27 neutralization (by p28-specific antibody) reduced the severity of graft-versus-host disease [10]. Belle et al. found reconstitution of Treg, increased FoxP3 expression, and promoted expression of IL-10 by Tregs in the IL-27 receptor defect mice [10]. However, Kim et al. demonstrated that while CD4+CD25+ T-cell transplantation was able to induce colitis in the recipient mice, CD4+CD25+ T cells from IL-27 receptor defect donor mice failed to do so due to a defect in T-cell survival [11]. The regulatory effect of IL-27 on Treg has been widely accepted with the changes in different diseases and animal models. However, only few studies have investigated the functions of IL-27, IL-27 receptor subunit alpha, and FoxP3 in MG. In this study, we detected the serum IL-27 levels of patients with MG and discussed its association with the severity and prognosis of the disease.

2 Materials and methods

2.1 Subjects

The study was a prospective study and mainly described 59 patients with MG and 35 healthy controls (HCs) who were all enrolled in Tianjin Medical University General Hospital from January 2015 to January 2018. Patients with MG were subcategorized according to their disease subtypes, which included 20 cases of ocular MG (OMG), 39 cases of generalized myasthenia gravis (GMG), 15 cases of thymoma-associated MG (TAMG), and 49 cases of anti-acetylcholine receptor (AChR)-positive MG. All patients did not receive any cholinesterase inhibitor or immunosuppressive agent treatment 6 months prior to this study. The diagnostic criteria of MG were based on an experienced neurologist. The clinical diagnosis of MG was mainly based on medical histories and clinical manifestations (fluctuating skeletal muscle weakness and fatigue) of the patients, and at least one positive result from the following indicators: antibody levels (AChR and muscle-specific tyrosine kinase [MuSK] antibody), electrophysiological results (repeated nerve stimulation or single-fiber electromyography), and response to the therapeutic effects of acetylcholinesterase inhibitor. Patients in this study did not suffer from any migraine, muscular dystrophy, paraneoplastic neurological syndromes, hyperthyroidism, or any other systemic diseases which can also cause muscle weakness. The exclusion criteria included infection, autoimmune diseases, and cancers. Patients with one of the following conditions were also excluded: allergic to immunoglobulin, serum IgA levels are lower than 5% of the normal minimum limit, severe heart disease, renal insufficiency, and thrombotic events.

  1. Informed consent: All patients have signed informed consent forms.

  2. Ethical approval: The research is in compliance with all the relevant national regulations, institutional policies, and in accordance with the tenets of the Helsinki Declaration. This study was approved by the ethics committee of Tianjin Medical University General Hospital (Ethical No. IRB2019-WZ-131).

2.2 Clinical evaluation and sample collection

Demographic features, MG Foundation of America (MGFA) classification, quantitative MG (QMG), MG-activities of daily living (MG-ADLs) score, thymus CT, electrophysiology test, and therapy data were obtained from the MG database. Anti-AChR antibody and anti-MuSK antibody were detected by cell-based immunofluorescence assay. Plasmids of AChR and MuSK were donated by Professor Angela Vincent and Professor David Beeson (University of Oxford). Patients were clinically assessed according to their scores in MG-ADLs and QMG and postintervention status of MG defined in accordance with MGFA. Serum samples of 59 patients were collected before immunoglobulin intravenous injection (IVIG) treatment, followed by 32 matched samples collected again at minimal manifestation-3 status after IVIG treatment.

2.3 ELISA-based measurement of serum IL-27 levels

Serum IL-27 levels were detected using a human IL-27 enzyme-linked immunosorbent assay (ELISA) kit (e-Bioscience, San Diego, CA, USA), according to the manufacturer’s protocol. Generally, serum samples and standard solutions were incubated with antibody-coated plates according to the manufacturer’s protocol. Subsequently, 50 µL of diluted biotin-conjugate, 100 µL of diluted streptavidin–HRP, and 100 µL of TMB substrate solution were subsequently incubated at room temperature for 2 h, 1 h, and 30 min, respectively. Stop solution of 100 µL was used to stop the reaction. The sample was directly used for detection without dilution and was repeated three times to obtain the average value. The optical density was read at 450 nm using a microplate reader (SYNERGY 2; BioTek, USA). Serum IL-27 levels were determined according to the standard curves. The minimum threshold concentration of IL-27 was 9.5 pg/mL.

2.4 Statistical analysis

Statistical analysis was carried our employing Statistical Package for the Social Sciences 22.0 (SPSS Inc., Chicago, IL, USA). GraphPad PRISM Version5 (Graph Pad Software Inc., San Diego, CA, USA) was used to generate graphs. The serum IL-27 levels between different MG subgroups and HCs were compared by analysis of variance. A paired t test was used to compare serum IL-27 levels before and after treatment. Spearman or Pearson was used for correlation analysis between IL-27 and scores of QMG or MG-ADLs. Differences or correlations with P values of <0.05 were considered as statistically significant.

3 Results

3.1 Demographic and clinical features of subjects

Demographic and clinical features of the subjects are displayed in Table 1. A total of 35 HCs (17 females and 18 males) without any acute or chronic inflammatory diseases were recruited at the Medical Examination Center of Tianjin Medical University General Hospital. All MG patients included in this study were diagnosed and hospitalized for the first time with exceptions for OMG patients, which did not progress to GMG during the first 2 years of follow-up. The OMG patients were recruited at the outpatient clinic. They have not received any treatment (poor acetylcholinesterase inhibitor effects or side effects of immunosuppressive agents) within the past 6 months and have been followed up. All enrolled patients underwent MGFA clinical classification to assess their severity of the disease. Most of them were classified as MGFA Classes I–III, except for nine patients who were classified as MGFA V. During second month of follow-up, two patients died from respiratory failure. From a total of 59 patients, 32 patients completed enrollment before and after IVIG treatment (20 OMG, 2 deaths, and 5 transferred patients). Most patients were positive for anti-AChR antibody and 10 patients were seronegative, while all patients were negative for anti-MuSK antibody. This study did not detect LRP4 antibody.

Table 1

Demographic and clinical features of MG and HCs

Characteristics Patients with MG (n = 59) Controls (n = 35) P value
Age at disease onset (years) 54.97 ± 14.54 55.31 ± 11.02 0.81
Female:male 20:39 17:18 0.64
MG-ADLs 5.90 ± 4.12 — —
MG-QMG 10.25 ± 6.06 — —
MGFA I–V — —
GMG:OMG 21:10 — —
Thymoma 15/59(25.42%) — —
AChR-Ab (+) 49/59(83.05%) — —

GMG, generalized myasthenia gravis; OMG, ocular myasthenia gravis; MG-ADLs, MG activities of daily living; MGFA, MG Foundation of America classification; QMG, quantitative MG score; AChR-Ab (+), anti-AChR antibody positive.

3.2 Serum IL-27 levels increased before treatment and decreased after treatment and positively correlated with QMG and MG-ADLs

Serum IL-27 levels in patients with MG (168.44 ± 97.98) are higher than those in HCs (116.60 ± 53.13). Serum IL-27 levels varied in different MG subtypes. The IL-27 levels in MG patients in GMG subtype (190.93 ± 101.07) were significantly higher than those in OMG (117.69 ± 63.82, p < 0.01) and HCs (116.60 ± 53.13, p < 0.01; Figure 1a). Patients with TAMG (216.75 ± 91.31) had significantly higher IL-27 levels than both no-TAMG (NTAMG, 156.51 ± 94.92, p = 0.01; Figure 1b) and HCs (116.60 ± 53.13, p < 0.01; Figure 1b). The serum IL-27 levels of AChR-MG patients (182.13 ± 100.43) were significantly higher compared with AChR(−)-MG patients (121.36 ± 57.67, p < 0.01) and HCs (116.60 ± 53.13, p < 0.01; Figure 1c). Again, serum IL-27 levels in patients with OMG (117.69 ± 63.82) and AChR(−)-MG (121.36 ± 57.67) were not statistically significant than HCs (116.60 ± 53.13) but directionally consistent (p = 0.96, Figure 1a; p = 0.87, Figure 1c). Meanwhile, NTAMG patients had significantly higher serum IL-27 levels than HCs (116.60 ± 53.13, p = 0.03; Figure 1b). The serum IL-27 levels significantly decreased after IVIG treatments, as evidenced by the comparative study conducted in the 32 patients (before the treatment: 198.34 ± 104.28 and after the treatment: 144.14 ± 100.35, p = 0.02; Figure 1d).

Figure 1 Serum levels of IL-27 in different subtypes of MG and HC and correlated with QMG and ADL in patients with MG. (a) Serum IL-27 titers in 59 patients with MG, including 39 GMG, 20 OMG, and 35 HCs. (b) Serum IL-27 titers in MG patients with or without thymoma. (c) Serum IL-27 titers in MG patients with or without AChR antibody. (d) Serum IL-27 titers in MG patients before and after treatments. The relationship between the serum IL-27 titers with MG-ADLs (e) and QMG score (f) in MG patients with thymoma. The relationship between the serum IL-27 titers with MG-ADLs (g) and QMG scores (h) in GMG.
Figure 1

Serum levels of IL-27 in different subtypes of MG and HC and correlated with QMG and ADL in patients with MG. (a) Serum IL-27 titers in 59 patients with MG, including 39 GMG, 20 OMG, and 35 HCs. (b) Serum IL-27 titers in MG patients with or without thymoma. (c) Serum IL-27 titers in MG patients with or without AChR antibody. (d) Serum IL-27 titers in MG patients before and after treatments. The relationship between the serum IL-27 titers with MG-ADLs (e) and QMG score (f) in MG patients with thymoma. The relationship between the serum IL-27 titers with MG-ADLs (g) and QMG scores (h) in GMG.

Positive correlations between serum IL-27 levels and scores of MG-ADLs or QMG were identified in TAMG and GMG groups, respectively (r = 0.85, p < 0.01; r = 0.65, p = 0.01, Figure 1e and f; r = 0.39, p = 0.02; r = 0.44, p < 0.01; Figure 1g and h). Meanwhile, no statistically significant correlations were observed between the serum IL-27 levels and scores of MG-ADLs or QMG in either of the subgroups of anti-AChR antibody-positive or -negative MG (r = 0.24, p = 0.09; r = 0.23, p = 0.11; r = 0.31, p = 0.39; r = 0.35, p = 0.33); in addition, no significant correlation was found between serum IL-27 levels and OMG (r = 0.59, p = 0.11; r = 0.43, p = 0.06).

4 Discussion

Previous studies have demonstrated the association of rheumatoid arthritis with the increase in IL-27 levels in serum, synovial membranes, and synovial fluid. The serum IL-27 levels were correlated with disease activity [12,13]. Similar results were observed in patients with psoriasis [14]. Serum IL-27 decreased during the acute phase of the disease and increased after immunomodulatory therapy in MS [15]. Another study found that IL-27 levels were increased in cerebrospinal fluid and active plaque in MS [16]. IL-27 administration in experimental autoimmune meningococcal meningitis mice attenuated the degree of disease and disability [17]. Meanwhile, the same intervention constructs in Tregs IL27Ra knockout mice cannot effectively relieve the clinical symptoms [17]. Besides, serum IL-27 levels were elevated in patients with IBD during the acute phase of the disease [18]. IL-27 stimulation enhanced Tregs functions and FoxP3 expression in vivo [18]. While the IL27Ra-defected Tregs cannot exert inhibitory functions in vitro [18]. IL-27 levels can be either increased or decreased in MG patients, based on their disease stages and treatment status. Previous study found that the serum IL-27 levels were higher in MG patients than those in HCs [19], which was consistent with our results.

Previous studies demonstrated the functions and number of Tregs and the expression of FoxP3 reduced in TAMG [20,21]. Meanwhile, other studies observed that the reduction in Tregs inhibitory function leads to increased production of autoantibody, which intensified the severity and contributed to the progression of AChR-MG [22,23,24]. Jeong and his colleagues demonstrated that higher IL-27 levels were observed in early-onset myasthenia gravis (EOMG) and the TAMG subpopulation contains lower IL-27 levels [19]. In our study, IL-27 levels in TAMG and AChR-MG were higher than those in NTAMG and AChR(−)-MG, respectively. Most importantly, IL-27 levels were positively correlated with both QMG and MG-ADLs. We speculated that the IL-27 may affect the function or quantity of Tregs. However, the exact relationship between IL-27 levels, Treg function, and FoxP3 expression in MG was not clear; therefore, further studies were needed. IL-27 promoted the production of IL-21, which promoted the transformation of anti-AchR antibody and in worse case the pathological process of MG [25]. Besides, their subsequent research showed that the serum IL-27 levels in the anti-AchR antibody-positive group were positively correlated with the antibody concentrations [26]. About 80–85% of patients in GMG were positive for anti-AChR antibodies, which was higher than that in OMG [27]. These findings combined with Jeong et al. study explain why patients with GMG have higher levels of IL-27 than those with OMG. In recent years, the effects of IVIG treatments on Tregs functions have been studied in different autoimmune diseases [28,29,30,31]. IVIG treatments affected the Treg functions and the regulation of inflammatory factors through altered APC functions [32,33], while IL-27 was mainly secreted by activated APCs [34]. Our study found that the serum IL-27 levels in patients with MG significantly decreased after the IVIG treatments. However, the underlying mechanisms and signaling pathways involved in this process were still not clear.

IL-27 exerts different immunomodulatory effects in different diseases, even in different periods of the same disease. The main factors are related to its potential effector pathway, disease period, and the presence or absence of interacting regulatory cytokines or T-cell subsets [35]. Both increase and decrease in IL-27 levels may only be a manifestation. Further studies of the underlying mechanisms are needed for the clinical transformation and application of targeting IL-27 in the treatments of MG. Here, we proposed a scientific hypothesis that IL-27 may participate in the pathogenesis of MG by acting on Tregs and may serve as an early marker for the diagnosis and prognosis of MG. Most importantly, IL-27 can be used as a new target for the clinical treatments of MG through regulating specific immune signaling and maintaining immune homeostasis. Therefore, further study is worth in order to clarify the role of IL-27, IL-27Rα, and FoxP3 in the progression of MG, and to study the association between IL-27 levels and the clinical characteristics of MG.

5 Conclusions

Taken together, our study demonstrated that serum IL-27 levels were significantly increased in patients with MG and decreased after IVIG treatments. Positive correlations were identified between serum IL-27 levels and scores of MG-ADLs and QMG, although the increase or decrease in IL-27 levels may only be a manifestation. Further studies of the underlying mechanisms are needed for the clinical transformation and application of targeting IL-27 in the treatment of MG.

These authors have contributed equally to this work.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant number 81771363), the National Natural Science Foundation of China (grant number 81701239), the Natural Science Foundation of Tianjin (grant numbers 18JCQNJC81700), and the Natural Science Foundation of Tianjin (grant number 18JCYBJC25900). XL and LZ organized the whole experiment and wrote the manuscript; MY and LL participated in the experimental design; JW and YQ collected and organized the experimental data; PZ and DZ participated in manuscript modification; LY designed the research program and corrected the manuscript.

  1. Conflict of interest: The authors stated no conflicts of interest.

References

[1] Andrews C, McLean MH, Durum SK. Interleukin-27 as a novel therapy for inflammatory bowel disease: a critical review of the literature. Inflamm Bowel Dis. 2016;22:2255–64.10.1097/MIB.0000000000000818Search in Google Scholar PubMed PubMed Central

[2] Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflamm. 2017;14:117.10.1186/s12974-017-0892-8Search in Google Scholar PubMed PubMed Central

[3] Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006;212:28–50.10.1111/j.0105-2896.2006.00420.xSearch in Google Scholar PubMed

[4] Yang G, Yang X, Zhang J, Li G, Zheng D, Peng A, et al. Transcriptional repressor Blimp1 regulates follicular regulatory T-cell homeostasis and function. Immunology. 2018;153:105–17.10.1111/imm.12815Search in Google Scholar PubMed PubMed Central

[5] Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood. 2006;107:3925–32.10.1182/blood-2005-11-4502Search in Google Scholar PubMed PubMed Central

[6] Wen Y, Yang B, Lu J, Zhang J, Yang H, Li J. Imbalance of circulating CD4(+) CXCR5(+) FOXP3(+) Tfr-like cells and CD4(+) CXCR5(+) FOXP3(−) Tfh-like cells in myasthenia gravis. Neurosci Lett. 2016;630:176–82.10.1016/j.neulet.2016.07.049Search in Google Scholar PubMed

[7] Zhang LJ, Guo HY, Zhang DQ, Wang R, Li T, Li L-M, et al. Analysis of serum interleukin-27 and interleukin-35 concentrations in patients with Guillain-Barre syndrome. Clin Chim Acta. 2017;468:5–9.10.1016/j.cca.2017.02.003Search in Google Scholar PubMed

[8] Meka RR, Venkatesha SH, Dudics S, Acharya B, Moudgil KD. IL-27-induced modulation of autoimmunity and its therapeutic potential. Autoimmun Rev. 2015;14:1131–41.10.1016/j.autrev.2015.08.001Search in Google Scholar PubMed PubMed Central

[9] Cox JH, Kljavin NM, Ramamoorthi N, Diehl L, Batten M, Ghilardi N. IL-27 promotes T cell-dependent colitis through multiple mechanisms. J Exp Med. 2011;208:115–23.10.1084/jem.20100410Search in Google Scholar PubMed PubMed Central

[10] Belle L, Agle K, Zhou V, Yin-Yuan C, Komorowski R, Eastwood D, et al. Blockade of interleukin-27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression. Blood. 2016;128:2068–82.10.1182/blood-2016-02-698241Search in Google Scholar PubMed PubMed Central

[11] Kim G, Shinnakasu R, Saris CJ, Cheroutre H, Kronenberg M. A novel role for IL-27 in mediating the survival of activated mouse CD4 T lymphocytes. J Immunol. 2013;190:1510–8.10.4049/jimmunol.1201017Search in Google Scholar PubMed PubMed Central

[12] Shen H, Xia L, Xiao W, Lu J. Increased levels of interleukin-27 in patients with rheumatoid arthritis. Arthritis Rheum. 2011;63:860–1.10.1002/art.30180Search in Google Scholar PubMed

[13] Wong CK, Chen DP, Tam LS, Li EK, Yin YB, Lam CW. Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther. 2010;12:R129.10.1186/ar3067Search in Google Scholar PubMed PubMed Central

[14] Shibata S, Tada Y, Kanda N, Nashiro K, Kamata M, Karakawa M, et al. Possible roles of IL-27 in the pathogenesis of psoriasis. J Invest Dermatol. 2010;130:1034–9.10.1038/jid.2009.349Search in Google Scholar PubMed

[15] Mindur JE, Valenzuela RM, Yadav SK, Boppana S, Dhib-Jalbut S, Ito K. IL-27: a potential biomarker for responders to glatiramer acetate therapy. J Neuroimmunol. 2017;304:21–8.10.1016/j.jneuroim.2016.07.004Search in Google Scholar PubMed

[16] Lalive PH, Kreutzfeldt M, Devergne O, Metz I, Bruck W, Merkler D, et al. Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients. J Neuroinflamm. 2017;14:144.10.1186/s12974-017-0919-1Search in Google Scholar PubMed PubMed Central

[17] Do J, Kim D, Kim S, Valentin-Torres A, Dvorina N, Jang E, et al. Treg-specific IL-27Ralpha deletion uncovers a key role for IL-27 in Treg function to control autoimmunity. Proc Natl Acad Sci U S A. 2017;114:10190–5.10.1073/pnas.1703100114Search in Google Scholar PubMed PubMed Central

[18] Do JS, Visperas A, Sanogo YO, Bechtel JJ, Dvorina N, Kim S, et al. An IL-27/Lag3 axis enhances Foxp3+ regulatory T cell-suppressive function and therapeutic efficacy. Mucosal Immunol. 2016;9:137–45.10.1038/mi.2015.45Search in Google Scholar PubMed PubMed Central

[19] Jeong HN, Lee JH, Suh BC, Choi YC. Serum interleukin-27 expression in patients with myasthenia gravis. J Neuroimmunol. 2015;288:120–2.10.1016/j.jneuroim.2015.09.010Search in Google Scholar PubMed

[20] Marx A, Hohenberger P, Hoffmann H, Pfannschmidt J, Schnabel P, Hofmann H-S, et al. The autoimmune regulator AIRE in thymoma biology: autoimmunity and beyond. J Thorac Oncol. 2010;5:S266–72.10.1097/JTO.0b013e3181f1f63fSearch in Google Scholar PubMed

[21] Scarpino S, Di Napoli A, Stoppacciaro A, et al. Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas. Clin Exp Immunol. 2007;149:504–12.10.1111/j.1365-2249.2007.03442.xSearch in Google Scholar PubMed PubMed Central

[22] Thiruppathi M, Rowin J, Ganesh B, Sheng JR, Prabhakar BS, Meriggioli MN. Impaired regulatory function in circulating CD4(+) CD25(high)CD127(low/−) T cells in patients with myasthenia gravis. Clin Immunol. 2012;145:209–23.10.1016/j.clim.2012.09.012Search in Google Scholar PubMed PubMed Central

[23] Luther C, Adamopoulou E, Stoeckle C, Brucklacher-Waldert V, Rosenkranz D, Stoltze L, et al. Prednisolone treatment induces tolerogenic dendritic cells and a regulatory milieu in myasthenia gravis patients. J Immunol. 2009;183:841–8.10.4049/jimmunol.0802046Search in Google Scholar PubMed

[24] Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4(+) CD25+T cells in the thymus of patients with autoimmune myasthenia gravis. Blood. 2005;105:735–41.10.1182/blood-2003-11-3900Search in Google Scholar PubMed PubMed Central

[25] Li Y, Rauniyar VK, Yin WF, Hu B, Ouyang S, Xiao B, et al. Serum IL-21 levels decrease with glucocorticoid treatment in myasthenia gravis. Neurol Sci. 2014;35:29–34.10.1007/s10072-013-1460-3Search in Google Scholar PubMed

[26] Hu B, Tian X, Huang H, Jian A, Ouyang S, Yin W, et al. Expression of IL-21 in the peripheral blood of myasthenia gravis patients and its correlation with anti-AChR-Ab class switch. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010;35:958–63.Search in Google Scholar

[27] Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375:2570–81.10.1016/B978-0-12-820472-6.00046-3Search in Google Scholar

[28] Tseng WN, Lo MH, Guo MM, Hsieh KS, Chang WC, Kuo HC. IL-31 associated with coronary artery lesion formation in Kawasaki disease. PLoS One. 2014;9:e105195.10.1371/journal.pone.0105195Search in Google Scholar PubMed PubMed Central

[29] Maddur MS, Rabin M, Hegde P, Bolgert F, Guy M, Vallat J-M, et al. Intravenous immunoglobulin exerts reciprocal regulation of Th1/Th17 cells and regulatory T cells in Guillain-Barre syndrome patients. Immunol Res. 2014;60:320–9.10.1007/s12026-014-8580-6Search in Google Scholar PubMed

[30] Kozicky LK, Menzies SC, Hotte N, Madsen KL, Sly LM. Intravenous immunoglobulin (IVIg) or IVIg-treated macrophages reduce DSS-induced colitis by inducing macrophage IL-10 production. Eur J Immunol. 2019;49:1251–68.10.1002/eji.201848014Search in Google Scholar PubMed

[31] Ahmadi M, Aghdam SA, Nouri M, Babaloo Z, Farzadi L, Ghasemzadeh A, et al. Intravenous immunoglobulin (IVIG) treatment modulates peripheral blood Th17 and regulatory T cells in recurrent miscarriage patients: nonrandomized open-label clinical trial. Immunol Lett. 2017;192:12–9.10.1016/j.imlet.2017.10.003Search in Google Scholar PubMed

[32] Galeotti C, Kaveri SV, Bayry J. IVIG-mediated effector functions in autoimmune and inflammatory diseases. Int Immunol. 2017;29:491–8.10.1093/intimm/dxx039Search in Google Scholar PubMed

[33] Das M, Karnam A, Stephen-Victor E, Gilardin L, Bhatt B, Sharma VK, et al. Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy. Cell Death Dis. 2020;11:50.10.1038/s41419-020-2249-ySearch in Google Scholar PubMed PubMed Central

[34] Meka RR, Venkatesha SH, Dudics S, Acharya B, Moudgil KD. IL-27-induced modulation of autoimmunity and its therapeutic potential. Autoimmun Rev. 2015;14:1131–41.10.1016/j.autrev.2015.08.001Search in Google Scholar PubMed PubMed Central

[35] Meka RR, Venkatesha SH, Dudics S, Acharya B, Moudgil KD. IL-27-induced modulation of autoimmunity and its therapeutic potential. Autoimmun Rev. 2015;14:1131–41.10.1016/j.autrev.2015.08.001Search in Google Scholar
Received: 2020-03-19
Revised: 2020-06-16
Accepted: 2020-06-29
Published Online: 2020-09-09

© 2020 Xiao-Jiao Liu et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Research Articles
  2. Changing the tone of clinical study design in the cannabis industry
  3. Integrated Chinese and western medicine for acute guillain-barré syndrome treatment
  4. Hydrochloride fasudil attenuates brain injury in ICH rats
  5. Protective role of maize purple plant pigment against oxidativestress in fluorosis rat brain
  6. A novel low-cost electrode for recording the local field potential of freely moving rat’s brain
  7. Neuroprotective mechanisms of erythropoietin in a rat stroke model
  8. Plasma cholesterol in Alzheimer’s disease and frontotemporal dementia
  9. Dysbiosis characteristics of gut microbiota in cerebral infarction patients
  10. miR-142-3p suppresses apoptosis in spinal cord-injured rats
  11. Decreased MiR-30a promotes TGF-β1-mediated arachnoid fibrosis in post-hemorrhagic hydrocephalus
  12. Effect of C-phycocyanin on HDAC3 and miRNA-335 in Alzheimer’s disease
  13. EGCG modulates PKD1 and ferroptosis to promote recovery in ST rats
  14. Efficacy of Novavit in ameliorating the neurotoxicity of propionic acid
  15. High-fat diet-induced obesity and impairment of brain neurotransmitter pool
  16. Erratum to “Changing the tone of clinical study design in the cannabis industry”
  17. Development of a trunk motor paradigm for use in neuroimaging
  18. Notoginsenoside R1 attenuates sevoflurane-induced neurotoxicity
  19. Saikosaponin A attenuates neural injury caused by ischemia/reperfusion
  20. Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice
  21. Partial enzyme digestion facilitates regeneration of crushed nerve in rat
  22. Correlation between calcium, water contents and ultrasonographic appearance of atherosclerotic lesions of carotid artery lesions
  23. Diabetes does not affect motor recovery after intracerebral hemorrhage
  24. IRF8 is crucial for the nicotine withdrawal-induced hyperalgesia in mice
  25. Prediction of muscle loss after stroke by analysis of corticospinal tract
  26. Interleukin-27 levels in patients with myasthenia gravis
  27. Artesunate attenuates traumatic brain injury-induced impairments in rats
  28. BDMC protects AD in vitro via AMPK and SIRT1
  29. Injury of the optic radiation in patients with mild TBI: A DTT study
  30. Time-restricted feeding alters isoflurane-induced memory deficits
  31. Video-based education improves the image quality of diagnostic percutaneous cerebral angiography among elderly patients
  32. The effect of rTMS in the management of pain associated with CRPS
  33. EGCG treats ICH via up-regulating miR-137-3p and inhibiting Parthanatos
  34. Modified hemispherectomy for infantile hemiparesis and epilepsy
  35. Isovitexin modulates autophagy in Alzheimer’s disease via miR-107 signalling
  36. Epitranscriptome of the ventral tegmental area in a deep brain-stimulated chronic unpredictable mild stress mouse model
  37. Role of prefrontal cortex during Sudoku task: fNIRS study
  38. Tongxinluo promotes axonal plasticity and functional recovery after stroke
  39. Eriodictyol corrects functional recovery and myelin loss in SCI rats
  40. Letter to the Editor
  41. Ataxic hemiparesis after corona radiata infarct: Diffusion tensor imaging correlation of corticoponto-cerebellar tract injury
  42. Compression of the lateral antebrachial cutaneous nerve by a traumatic arteriovenous fistula
  43. Rapid Communication
  44. Anticholinergic drugs and oral health-related quality of life in patients with schizophrenia: a pilot study
  45. Deviant cortical sulcation related to schizophrenia and cognitive deficits in the second trimester
  46. Case Report
  47. A case of primary central nervous system lymphoma mimic neuromyelitis optica
  48. A Moving Residual Limb: Botulinum Toxin to the Rescue
  49. Clinical and imaging features of reversible splenial lesion syndrome with language disorder
  50. Impaired consciousness due to injury of the ascending reticular activating system in a patient with bilateral pontine infarction: A case report
  51. Commentary
  52. A comment on Morey et al. (2020)
  53. Review Articles
  54. Advances in transcription factors related to neuroglial cell reprogramming
  55. The “authentic subjective experience” of memory in Alzheimer’s disease
  56. Chronic neurological diseases and COVID-19: Associations and considerations
  57. Special Issue "Neuroinflammation: from basic to clinical perspectives"
  58. Ormosanine improves neuronal functions in spinal cord-injured rats by blocking peroxynitrite/calpain activity
  59. Retraction
  60. Retraction of: Identification of biological markers for better characterization of older subjects with physical frailty and sarcopenia
https://doi.org/10.1515/tnsci-2020-0134
Keywords for this article
interleukin-27; myasthenia gravis; quantitative MG score; thymoma-associated myasthenia gravis; MG activities of daily living
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Changing the tone of clinical study design in the cannabis industry
  3. Integrated Chinese and western medicine for acute guillain-barré syndrome treatment
  4. Hydrochloride fasudil attenuates brain injury in ICH rats
  5. Protective role of maize purple plant pigment against oxidativestress in fluorosis rat brain
  6. A novel low-cost electrode for recording the local field potential of freely moving rat’s brain
  7. Neuroprotective mechanisms of erythropoietin in a rat stroke model
  8. Plasma cholesterol in Alzheimer’s disease and frontotemporal dementia
  9. Dysbiosis characteristics of gut microbiota in cerebral infarction patients
  10. miR-142-3p suppresses apoptosis in spinal cord-injured rats
  11. Decreased MiR-30a promotes TGF-β1-mediated arachnoid fibrosis in post-hemorrhagic hydrocephalus
  12. Effect of C-phycocyanin on HDAC3 and miRNA-335 in Alzheimer’s disease
  13. EGCG modulates PKD1 and ferroptosis to promote recovery in ST rats
  14. Efficacy of Novavit in ameliorating the neurotoxicity of propionic acid
  15. High-fat diet-induced obesity and impairment of brain neurotransmitter pool
  16. Erratum to “Changing the tone of clinical study design in the cannabis industry”
  17. Development of a trunk motor paradigm for use in neuroimaging
  18. Notoginsenoside R1 attenuates sevoflurane-induced neurotoxicity
  19. Saikosaponin A attenuates neural injury caused by ischemia/reperfusion
  20. Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice
  21. Partial enzyme digestion facilitates regeneration of crushed nerve in rat
  22. Correlation between calcium, water contents and ultrasonographic appearance of atherosclerotic lesions of carotid artery lesions
  23. Diabetes does not affect motor recovery after intracerebral hemorrhage
  24. IRF8 is crucial for the nicotine withdrawal-induced hyperalgesia in mice
  25. Prediction of muscle loss after stroke by analysis of corticospinal tract
  26. Interleukin-27 levels in patients with myasthenia gravis
  27. Artesunate attenuates traumatic brain injury-induced impairments in rats
  28. BDMC protects AD in vitro via AMPK and SIRT1
  29. Injury of the optic radiation in patients with mild TBI: A DTT study
  30. Time-restricted feeding alters isoflurane-induced memory deficits
  31. Video-based education improves the image quality of diagnostic percutaneous cerebral angiography among elderly patients
  32. The effect of rTMS in the management of pain associated with CRPS
  33. EGCG treats ICH via up-regulating miR-137-3p and inhibiting Parthanatos
  34. Modified hemispherectomy for infantile hemiparesis and epilepsy
  35. Isovitexin modulates autophagy in Alzheimer’s disease via miR-107 signalling
  36. Epitranscriptome of the ventral tegmental area in a deep brain-stimulated chronic unpredictable mild stress mouse model
  37. Role of prefrontal cortex during Sudoku task: fNIRS study
  38. Tongxinluo promotes axonal plasticity and functional recovery after stroke
  39. Eriodictyol corrects functional recovery and myelin loss in SCI rats
  40. Letter to the Editor
  41. Ataxic hemiparesis after corona radiata infarct: Diffusion tensor imaging correlation of corticoponto-cerebellar tract injury
  42. Compression of the lateral antebrachial cutaneous nerve by a traumatic arteriovenous fistula
  43. Rapid Communication
  44. Anticholinergic drugs and oral health-related quality of life in patients with schizophrenia: a pilot study
  45. Deviant cortical sulcation related to schizophrenia and cognitive deficits in the second trimester
  46. Case Report
  47. A case of primary central nervous system lymphoma mimic neuromyelitis optica
  48. A Moving Residual Limb: Botulinum Toxin to the Rescue
  49. Clinical and imaging features of reversible splenial lesion syndrome with language disorder
  50. Impaired consciousness due to injury of the ascending reticular activating system in a patient with bilateral pontine infarction: A case report
  51. Commentary
  52. A comment on Morey et al. (2020)
  53. Review Articles
  54. Advances in transcription factors related to neuroglial cell reprogramming
  55. The “authentic subjective experience” of memory in Alzheimer’s disease
  56. Chronic neurological diseases and COVID-19: Associations and considerations
  57. Special Issue "Neuroinflammation: from basic to clinical perspectives"
  58. Ormosanine improves neuronal functions in spinal cord-injured rats by blocking peroxynitrite/calpain activity
  59. Retraction
  60. Retraction of: Identification of biological markers for better characterization of older subjects with physical frailty and sarcopenia
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 10.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/tnsci-2020-0134/html
Scroll to top button