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Sun S, Wen Y, Li S, Huang Z, Zhu J, Li Y. Neutrophil-to-lymphocyte ratio is a risk indicator of Guillain-Barré syndrome and is associated with severity and short-term prognosis. Heliyon 2023; 9:e14321. [PMID: 36967912 PMCID: PMC10036506 DOI: 10.1016/j.heliyon.2023.e14321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 01/27/2023] [Accepted: 02/28/2023] [Indexed: 03/12/2023] Open
Abstract
Introduction Guillain-Barré syndrome (GBS) is an autoimmune disorder targeting the peripheral nervous system. The neutrophil-to-lymphocyte ratio (NLR), a simple indicator of immune function, is potentially related to its incidence and severity; however, this should be confirmed. We aimed to evaluate the role of NLR in the diagnosis, severity, and prognosis of GBS. Methods Data of GBS patients and controls visiting our hospital from January 2010 to December 2020 were retrospectively analyzed (Clinical trial registration: ChiCTR2100053540). Risk factors were determined through logistic regression. Smoothing curves, receiver-operating characteristic curves, and forest plots were drawn. Results We included 136 GBS patients and 211 controls. NLR, as a continuous variable, was associated with GBS risk (OR, 2.32; 95% CI, 1.68-3.21; p < 0.001), severe functional disability (OR, 1.23; 95% CI, 1.06-1.43; p = 0.006), severe weakness (OR, 1.19; 95% CI, 1.06-1.35, p = 0.004), and short-term prognosis (OR, 1.21; 95% CI, 1.08-1.36; p = 0.001). NLR was more strongly associated with GBS risk in older (≥60 years) (OR, 7.17; 95% CI, 2.38-21.61) or male (OR, 2.88; 95% CI, 1.78-4.64) patients than in younger (<60 years) (OR, 1.88; 95% CI, 1.37-2.57) or female (OR, 1.85; 95% CI, 1.24-2.77) patients. NLR was significantly associated with severe functional disability in faster disease progression (OR, 1.53; 95% CI, 1.03-12.29) and male patients (OR, 1.41; 95% CI, 1.03-1.92) versus in slower disease progression (OR, 1.12; 95% CI, 0.77-1.64) and female patients (OR, 1.12; 95% CI, 0.77-1.64). Conclusions NLR may be an independent GBS risk factor and predictor of severe functional disability, severe weakness, and short-term prognosis.
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Arias C, Sepúlveda P, Castillo RL, Salazar LA. Relationship between Hypoxic and Immune Pathways Activation in the Progression of Neuroinflammation: Role of HIF-1α and Th17 Cells. Int J Mol Sci 2023; 24:ijms24043073. [PMID: 36834484 PMCID: PMC9964721 DOI: 10.3390/ijms24043073] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/14/2022] [Accepted: 12/17/2022] [Indexed: 02/09/2023] Open
Abstract
Neuroinflammation is a common event in degenerative diseases of the central and peripheral nervous system, triggered by alterations in the immune system or inflammatory cascade. The pathophysiology of these disorders is multifactorial, whereby the therapy available has low clinical efficacy. This review propounds the relationship between the deregulation of T helper cells and hypoxia, mainly Th17 and HIF-1α molecular pathways, events that are involved in the occurrence of the neuroinflammation. The clinical expression of neuroinflammation is included in prevalent pathologies such as multiple sclerosis, Guillain-Barré syndrome, and Alzheimer's disease, among others. In addition, therapeutic targets are analyzed in relation to the pathways that induced neuroinflammation.
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Affiliation(s)
- Consuelo Arias
- Escuela de Kinesiología, Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Santiago 7500922, Chile
| | - Paulina Sepúlveda
- Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Rodrigo L. Castillo
- Departamento de Medicina Interna Oriente, Facultad de Medicina, Universidad de Chile, Santiago 7500922, Chile
| | - Luis A. Salazar
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile
- Correspondence:
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3
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Berner J, Weiss T, Sorger H, Rifatbegovic F, Kauer M, Windhager R, Dohnal A, Ambros PF, Ambros IM, Boztug K, Steinberger P, Taschner‐Mandl S. Human repair-related Schwann cells adopt functions of antigen-presenting cells in vitro. Glia 2022; 70:2361-2377. [PMID: 36054432 PMCID: PMC9804420 DOI: 10.1002/glia.24257] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/16/2022] [Accepted: 07/25/2022] [Indexed: 01/05/2023]
Abstract
The plastic potential of Schwann cells (SCs) is increasingly recognized to play a role after nerve injury and in diseases of the peripheral nervous system. Reports on the interaction between immune cells and SCs indicate their involvement in inflammatory processes. However, the immunocompetence of human SCs has been primarily deduced from neuropathies, but whether after nerve injury SCs directly regulate an adaptive immune response is unknown. Here, we performed comprehensive analysis of immunomodulatory capacities of human repair-related SCs (hrSCs), which recapitulate SC response to nerve injury in vitro. We used our well-established culture model of primary hrSCs from human peripheral nerves and analyzed the transcriptome, secretome, and cell surface proteins for pathways and markers relevant in innate and adaptive immunity, performed phagocytosis assays, and monitored T-cell subset activation in allogeneic co-cultures. Our findings show that hrSCs are phagocytic, which is in line with high MHCII expression. Furthermore, hrSCs express co-regulatory proteins, such as CD40, CD80, B7H3, CD58, CD86, and HVEM, release a plethora of chemoattractants, matrix remodeling proteins and pro- as well as anti-inflammatory cytokines, and upregulate the T-cell inhibiting PD-L1 molecule upon pro-inflammatory stimulation with IFNγ. In contrast to monocytes, hrSC alone are not sufficient to trigger allogenic CD4+ and CD8+ T-cells, but limit number and activation status of exogenously activated T-cells. This study demonstrates that hrSCs possess features and functions typical for professional antigen-presenting cells in vitro, and suggest a new role of these cells as negative regulators of T-cell immunity during nerve regeneration.
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Affiliation(s)
- Jakob Berner
- St. Anna Children's Cancer Research Institute (CCRI)ViennaAustria
- St. Anna Children's HospitalViennaAustria
| | - Tamara Weiss
- St. Anna Children's Cancer Research Institute (CCRI)ViennaAustria
- Department of Plastic, Reconstructive and Aesthetic SurgeryMedical University of Vienna
| | - Helena Sorger
- St. Anna Children's Cancer Research Institute (CCRI)ViennaAustria
| | | | - Max Kauer
- St. Anna Children's Cancer Research Institute (CCRI)ViennaAustria
| | - Reinhard Windhager
- Department of Orthopedics and Trauma SurgeryMedical University of ViennaViennaAustria
| | - Alexander Dohnal
- St. Anna Children's Cancer Research Institute (CCRI)ViennaAustria
| | - Peter F. Ambros
- St. Anna Children's Cancer Research Institute (CCRI)ViennaAustria
| | - Inge M. Ambros
- St. Anna Children's Cancer Research Institute (CCRI)ViennaAustria
| | - Kaan Boztug
- St. Anna Children's Cancer Research Institute (CCRI)ViennaAustria
- St. Anna Children's HospitalViennaAustria
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI‐RUD)ViennaAustria
- Center for Molecular Medicine (CeMM)ViennaAustria
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4
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Sharma P P, Seshagiri DV, Nagappa M, Mullapudi T, Sreenivas N, Dey S, Shivaram S, Wahatule R, Kumawat V, Binu VSN, Kamath S, Sinha S, Taly AB, Debnath M. Role of altered IL-33/ST2 immune axis in the immunobiology of Guillain-Barré syndrome. Eur J Neurol 2022; 29:2074-2083. [PMID: 35322935 DOI: 10.1111/ene.15334] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 03/17/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND IL-33/ST2 immune axis plays crucial roles in infection and immunity. A dysregulated IL-33/ST2 axis can induce autoimmune reaction and inflammatory responses. Guillain-Barré Syndrome (GBS) is an acute peripheral neuropathy, mostly caused by post-infection autoimmunity. The role of IL-33/ST2 axis is not known in GBS. This study aimed to explore the role of IL-33/ST2 axis in GBS. METHODS Three single nucleotide polymorphisms (SNPs) of Il33 gene (rs16924159; rs7044343; rs1342336) and three SNPs of Il1rl1 gene (rs10192157, rs1041973, rs10206753), coding for ST2 were genotyped in 179 GBS patients and 186 healthy controls by TaqMan Allelic Discrimination Assay. Plasma levels of IL-33 and sST2 were measured in a subset of GBS (n=80) and healthy controls (n=80) by ELISA. RESULTS The frequencies of CC genotype of rs10192157 (p=0.043) and TT genotype of rs10206753 (p=0.036) SNPs of Il1rl1 gene differed significantly between GBS patients and healthy subjects. Gene-gene interaction between Il33 and Il1rl1 genes also conferred significant risk to GBS. In addition, the plasma sST2 levels were significantly elevated in GBS patients compared to healthy subjects (24,934.31 ± 1.81 pg/ml vs. 12,518.97 ± 1.51 pg/ml, p<0.001). Plasma sST2 levels showed a significant correlation with the disability scores at the peak of neurological deficit in GBS patients. CONCLUSIONS IL-33/ST2 axis is suggested to influence the immunopathogenesis of GBS. Genetic variants of Il1rl1 gene might serve as a risk determinant of GBS and plasma sST2 levels might emerge as a biomarker of severity of GBS, if replicated further by other studies.
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Affiliation(s)
- Praveen Sharma P
- Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Doniparthi V Seshagiri
- Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Madhu Nagappa
- Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Thrinath Mullapudi
- Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Nikhitha Sreenivas
- Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Saikat Dey
- Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Sumanth Shivaram
- Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Rahul Wahatule
- Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Vijay Kumawat
- Department of Transfusion Medicine and Haematology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - V Sreekumaran Nair Binu
- Department of Biostatistics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Sriganesh Kamath
- Department of Neuroanaesthesia and Neurocritical Care, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Arun B Taly
- Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Monojit Debnath
- Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
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Nicknafs F, Ghafouri-Fard S, Omrani MD, Nazer N, Sayad A, Taheri M. Expression analysis of cytokine transcripts in inflammatory demyelinating polyradiculoneuropathy. Metab Brain Dis 2021; 36:2111-2118. [PMID: 34169408 DOI: 10.1007/s11011-021-00771-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 06/06/2021] [Indexed: 10/21/2022]
Abstract
Inflammatory demyelinating polyradiculoneuropathies are a group of peripheral nerve system disorders in which immune reactions are dysregulated. Cytokines have noticeable roles in the regulation of these responses. We compared transcript levels of nine cytokine coding genes namely IL-1B, IL-2, IL-4, IL-6, IL-8, IL-17A, IFN-G, TGF-B and TNF-A in the peripheral blood of patients with acute and chronic kinds of this condition (AIDP and CIDP) and healthy persons. Expression of IL-17A was significantly lower in female AIDP cases compared with female controls (Expression Ratio = 0.02, P value = 0.02). Expression of this cytokine was higher in female CIDP cases compared with female AIDP cases (Expression ratio = 65.69, P value = 0.02). Moreover, expression of IL-6 tended to be diminished in female AIDP cases compared with normal females (Expression Ratio = 0.06, P value = 0.05). Expression of TGF-B was lower in female AIDP cases compared with female controls (Expression Ratio = 0.06, P value = 0.01). Transcript amounts of IL-1B were lower in whole CIDP cases compared with whole controls and in female AIDP cases compared with female controls (Expression Ratios = 0.09 and 0.00; P values = 0.04 and 0.01, respectively). Expression of this gene was considerably increased in female CIDP cases compared with female AIDP cases (Expression Ratio = 764.10, P value = 0.02). Finally, expression of this gene was lower in total cases compared with total controls (Expression ratio = 0.19, P value = 0.03). Diagnostic power of IL-4 was estimated to be 0.7 in differentiating between CIDP cases and controls. IL-1B had the diagnostic power of 0.72 in distinguishing between ADP cases and controls. Finally, TNF-A had the diagnostic power of 0.71 in differentiating between AIDP cases and CIDP cases. The current results suggest the possible role of these cytokines in the pathogenesis of inflammatory demyelinating polyradiculoneuropathies.
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Affiliation(s)
- Fwad Nicknafs
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mir Davood Omrani
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Naghme Nazer
- Department of Electrical Engineering, Sharif University of Technology, Tehran, Iran
| | - Arezou Sayad
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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6
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Li Z, Huang Z, Li X, Huang C, Shen J, Li S, Zhang L, Wong SH, Chan MTV, Wu WKK. Bioinformatic analyses hinted at augmented T helper 17 cell differentiation and cytokine response as the central mechanism of COVID-19-associated Guillain-Barré syndrome. Cell Prolif 2021; 54:e13024. [PMID: 33751722 PMCID: PMC8088459 DOI: 10.1111/cpr.13024] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 12/16/2022] Open
Abstract
Objectives Guillain‐Barré syndrome (GBS) results from autoimmune attack on the peripheral nerves, causing sensory, motor and autonomic abnormalities. Emerging evidence suggests that there might be an association between COVID‐19 and GBS. Nevertheless, the underlying pathophysiological mechanism remains unclear. Materials and Methods We performed bioinformatic analyses to delineate the potential genetic crosstalk between COVID‐19 and GBS. Results COVID‐19 and GBS were associated with a similar subset of immune/inflammation regulatory genes, including TNF, CSF2, IL2RA, IL1B, IL4, IL6 and IL10. Protein‐protein interaction network analysis revealed that the combined gene set showed an increased connectivity as compared to COVID‐19 or GBS alone, particularly the potentiated interactions with CD86, IL23A, IL27, ISG20, PTGS2, HLA‐DRB1, HLA‐DQB1 and ITGAM, and these genes are related to Th17 cell differentiation. Transcriptome analysis of peripheral blood mononuclear cells from patients with COVID‐19 and GBS further demonstrated the activation of interleukin‐17 signalling in both conditions. Conclusions Augmented Th17 cell differentiation and cytokine response was identified in both COVID‐19 and GBS. PBMC transcriptome analysis also suggested the pivotal involvement of Th17 signalling pathway. In conclusion, our data suggested aberrant Th17 cell differentiation as a possible mechanism by which COVID‐19 can increase the risk of GBS.
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Affiliation(s)
- Zheng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ziheng Huang
- CUHK-Shenzhen Research Institute, Shenzhen, China
| | - Xingye Li
- Department of Orthopedic Surgery, Beijing Jishuitan Hospital, Fourth Clinical College of Peking University, Jishuitan Orthopaedic College of Tsinghua University, Beijing, China
| | - Cheng Huang
- Department of Orthopaedic Surgery, Center for Osteonecrosis and Joint Preserving & Reconstruction, China-Japan Friendship Hospital, Beijing, China
| | - Jianxiong Shen
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shugang Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Zhang
- Department of Anaesthesia and Intensive Care, Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Sunny H Wong
- State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Matthew T V Chan
- Department of Anaesthesia and Intensive Care, Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - William Ka Kei Wu
- CUHK-Shenzhen Research Institute, Shenzhen, China.,Department of Anaesthesia and Intensive Care, Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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7
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Hagen KM, Ousman SS. The Neuroimmunology of Guillain-Barré Syndrome and the Potential Role of an Aging Immune System. Front Aging Neurosci 2021; 12:613628. [PMID: 33584245 PMCID: PMC7873882 DOI: 10.3389/fnagi.2020.613628] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/11/2020] [Indexed: 12/15/2022] Open
Abstract
Guillain-Barré syndrome (GBS) is a paralyzing autoimmune condition affecting the peripheral nervous system (PNS). Within GBS there are several variants affecting different aspects of the peripheral nerve. In general, there appears to be a role for T cells, macrophages, B cells, and complement in initiating and perpetuating attacks on gangliosides of Schwann cells and axons. Of note, GBS has an increased prevalence and severity with increasing age. In addition, there are alterations in immune cell functioning that may play a role in differences in GBS with age alongside general age-related declines in reparative processes (e.g., delayed de-differentiation of Schwann cells and decline in phagocytic ability of macrophages). The present review will explore the immune response in GBS as well as in animal models of several variants of the disorder. In addition, the potential involvement of an aging immune system in contributing to the increased prevalence and severity of GBS with age will be theorized.
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Affiliation(s)
- Kathleen M. Hagen
- Department of Neuroscience, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Shalina S. Ousman
- Departments of Clinical Neurosciences and Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
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8
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Zhu JJ, Shan NN. Immunomodulatory cytokine interleukin-35 and immune thrombocytopaenia. J Int Med Res 2020; 48:300060520976477. [PMID: 33356722 PMCID: PMC7768574 DOI: 10.1177/0300060520976477] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 10/28/2020] [Indexed: 12/14/2022] Open
Abstract
Considerable attention has been paid to interleukin (IL)-35 because of its immunosuppressive effects in a variety of autoimmune diseases. IL-35, a recently identified cytokine of the IL-12 family, is a negative regulatory factor secreted by IL-35-inducible regulatory T cells (iTr35 cells) and the recently reported regulatory B cells (Breg cells). Four biological effects of IL-35 have been discovered in vitro and in vivo: (i) suppression of T cell proliferation; (ii) conversion of naive T cells into iTr35 cells; (iii) downregulation of type 17 helper T (Th17) cells; and (iv) conversion of Breg cells into a Breg subset that produces IL-35 and IL-10. IL-35 plays an important role in a variety of autoimmune diseases, such as rheumatoid arthritis, allergic asthma and systemic lupus erythematosus. Primary immune thrombocytopaenia (ITP), which is characterized by isolated thrombocytopaenia and mild mucocutaneous to life-threatening bleeding, is an autoimmune disease with complex dysregulation of the immune system. Both antibody-mediated and/or T cell-mediated platelet destruction are key processes. In addition, impairment of T cells and cytokine imbalances have now been recognized to be important. This review summarizes the immunomodulatory effects of IL-35 and its role in the pathogenesis of ITP as mediated by T and B cells.
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Affiliation(s)
- Jing-Jing Zhu
- Department of Haematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Ning-Ning Shan
- Department of Haematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
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9
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Yuan X, Wei Y, Ao T, Gong K, Sun Q, Zheng Z, Hagiwara H, Ao Q. Effects of microRNA-338 Transfection into Sciatic Nerve on Rats with Experimental Autoimmune Neuritis. J Mol Neurosci 2020; 71:713-723. [PMID: 32915416 DOI: 10.1007/s12031-020-01689-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 08/17/2020] [Indexed: 11/29/2022]
Abstract
Nerve demyelination or axonal lesions are characteristic of experimental autoimmune neuritis (EAN). Previous studies have demonstrated that microRNA-338 can regulate the differentiation and maturation of oligodendrocytes and Schwann cells and promote injured peripheral nerves in rats. In this study, we used microRNA-338 coded lentivirus vector (miR-338-LV) in a Lewis rat EAN model, in with the conjunction P0 peptide 180-199 which was injected into the footpads of animals to induce immunization. The clinical scores of miR-338-LV and intravenous immunoglobulin (IVIg) (positive drug) groups were significantly superior to those of untreated group at disease peak and disease plateau (p < 0.05). The nerve conduction velocity and the compound nerve action potential amplitude of miR-338-LV and IVIg groups increased significantly compared to those of the untreated group at disease peak (p < 0.01). At disease peak, myelin swelling, cavity formation, and lamellae separation showed improvement in miR-338-LV and IVIg groups compared to untreated group. S100 and NF200 expression in miR-338-LV and IVIg groups increased compared to that in untreated group. Iba1 and S100 co-expression in Schwann cells in miR-338-LV and IVIg groups decreased compared to that in untreated group, which was indicative of the reduced conversion of Schwann cells into inflammatory cells. Overall, miR-338-LV in sciatic nerves might improve neuromuscular function in EAN by inhibiting the conversion of Schwann cells into inflammatory cells.
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Affiliation(s)
- Xiaojing Yuan
- Department of Rehabilitation, Taian City Central Hospital, Taian, 271000, Shandong, China
| | - Yujun Wei
- College of life science, Tsinghua University, Beijing, 100084, China
| | - Tianrang Ao
- College of life science, Tsinghua University, Beijing, 100084, China
| | - Kai Gong
- College of life science, Tsinghua University, Beijing, 100084, China
| | - Qiangsan Sun
- Department of Rehabilitation, The Second Hospital, Jinan, 250033, Shandong, China
| | - Zuncheng Zheng
- Department of Rehabilitation, Taian City Central Hospital, Taian, 271000, Shandong, China.
| | - Haruo Hagiwara
- Department of Anatomy and Cell Biology, Teikyo University School of Medicine, Tokyo, Japan
| | - Qiang Ao
- Institute of Regulatory Science for Medical Device, Sichuan University, Chengdu, China. .,National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
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10
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Debnath M, Nagappa M, Dutta D, Talukdar PM, Subbanna M, Shivakumar V, Wahatule R, Sinha S, Bindu PS, Periyavan S, Umamaheswara Rao GS, Kumar MA, Taly AB. Evidence of altered Th17 pathway signatures in the cerebrospinal fluid of patients with Guillain Barré Syndrome. J Clin Neurosci 2020; 75:176-180. [PMID: 32217048 DOI: 10.1016/j.jocn.2020.03.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 03/08/2020] [Indexed: 12/17/2022]
Abstract
Data indexing the contribution of various immuno-inflammatory components in the cerebrospinal fluid (CSF) towards the pathophysiology of Guillain Barré Syndrome (GBS) are limited. Th17 pathway plays crucial role in many immune mediated disorders of the nervous system. This study was aimed at exploring the role of Th17 pathway related cytokines in the CSF of patients with GBS. Levels of multiple key cytokines of Th17 pathway in CSF of patients with GBS (N = 37) and controls (N = 37) were examined in this prospective study using Bio-plex Pro Human Th17 cytokine assays in a Multiplex Suspension Array platform. The findings were correlated with clinical features and electrophysiological subtypes. Three key cytokines of Th17 pathway (IL-6, IL-17A and IL-22) were significantly elevated in CSF of patients with GBS as compared to controls. There was a positive correlation between the levels of IL-6 and IL-17A as well as between the levels of IL-17A and IL-22 in the CSF of patients with GBS. The CSF levels of IL-6 and IL-22 were negatively correlated with the duration of symptoms of GBS. None of the studied cytokines correlated with functional disability scores at admission to hospital or with the electrophysiological subtypes. Identification of Th17 pathway signatures in CSF sheds more insights into the pathogenic role of Th17 cells in GBS. These findings complement the contemporary knowledge and tender further support towards the involvement of Th17 pathway in GBS.
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Affiliation(s)
- Monojit Debnath
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India.
| | - Madhu Nagappa
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Debprasad Dutta
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Pinku Mani Talukdar
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Manjula Subbanna
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Venkataram Shivakumar
- Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Rahul Wahatule
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Parayil Sankaran Bindu
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Sundar Periyavan
- Transfusion Medicine and Haematology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - G S Umamaheswara Rao
- Neuroanaesthesia and Neurocritical Care, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Malathi Anil Kumar
- Department of Anaesthesia, Sanjay Gandhi Institute of Trauma and Orthopaedics, Bangalore, India
| | - Arun B Taly
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
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11
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Liu S, Liu Y, Xiao Z, Pan S, Gong Q, Lu Z. Th17 cells and their cytokines serve as potential therapeutic target in experimental autoimmune neuritis. Brain Behav 2019; 9:e01478. [PMID: 31742934 PMCID: PMC6908853 DOI: 10.1002/brb3.1478] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 09/04/2019] [Accepted: 10/26/2019] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Accumulating evidence has pointed that T helper 17 cells and their cytokines are pathogenic in Guillain-Barré syndrome (GBS). However, little is known concerning the IL-17 expression change trend during the whole course of disease, and whether drugs specially targeting Th17 cells or their cytokines have potential effects on experimental autoimmune neuritis (EAN) is uncertain. METHODS We explored the IL-17 and receptor-related orphan receptor-gamma-t (RORγt) expression change trends in EAN rats to identify the stage of effect of Th17 pathway in EAN, and further, we investigated the effect of RORγt inhibitors by assessing clinical score, histological staining, and IL-17 and RORγt expression change trends in serum and tissues. RESULTS The expression level of IL-17 and RORγt in serum and tissues increased with the progression of the disease in the EAN group and decreased after the disease reaching its peak. RORγt-IN-1 treatment strikingly reduced the neurological deficits by ameliorating inflammatory cell infiltration, deceased the serum IL-17 and RORγt levels, and further downregulated the expression of IL-17 and RORγt mRNA in spleen, lymphnodes, and sciatic nerve. CONCLUSIONS Th17 cells and their cytokines are closely associated with the onset of GBS and the novel RORγt inhibitors may be prospective strategies in treating GBS.
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Affiliation(s)
- Shuping Liu
- Department of Neurology, Wuhan University, Renmin Hospital, Wuhan, China
| | - Yin Liu
- Department of Neurology, Wuhan University, Renmin Hospital, Wuhan, China
| | - Zheman Xiao
- Department of Neurology, Wuhan University, Renmin Hospital, Wuhan, China
| | - Sijia Pan
- Department of Neurology, Wuhan University, Renmin Hospital, Wuhan, China
| | - Qiaoyu Gong
- Department of Neurology, Wuhan University, Renmin Hospital, Wuhan, China
| | - Zuneng Lu
- Department of Neurology, Wuhan University, Renmin Hospital, Wuhan, China
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12
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Zhang G, Wang Q, Song Y, Cheng P, Xu R, Feng X, Li X. Intravenous immunoglobulin promotes the proliferation of CD4 +CD25 + Foxp3 + regulatory T cells and the cytokines secretion in patients with Guillain-Barré syndrome in vitro. J Neuroimmunol 2019; 336:577042. [PMID: 31479869 DOI: 10.1016/j.jneuroim.2019.577042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/24/2019] [Accepted: 08/26/2019] [Indexed: 10/26/2022]
Abstract
Intravenous immunoglobulin (IVIg) serves as the first line therapy in Guillain-Barré syndrome (GBS), however, its action mechanism remains unknown. We hereby stimulated peripheral blood mononuclear cells (PBMCs) from patients with GBS and healthy controls using IVIg and an IgG-derived natural Treg epitopes, namely Tregitopes. Our results showed that IVIg significantly promoted both the expansion of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and secretion of IL-10 and TGF-β1 while Tregitopes promoted secretion of IL-10 and TGF-β1 only. Further study is necessary to elucidate the molecular mechanism of IVIg and Tregitopes on Tregs and the secretion of IL-10 and TGF-β1 in GBS.
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Affiliation(s)
- Guorong Zhang
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Quanquan Wang
- Department of Neuromuscular Disorders, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Yan Song
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Panpan Cheng
- Department of Haemotology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Ranran Xu
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Xungang Feng
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Xiang Li
- Department of rehabilitation, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China.
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13
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Zhang Y, Wang L, Zhou X, Geng J, Li X. The immunomodulatory mechanism of brain injury induced by hyperhomocysteinemia in spontaneously hypertensive rats. J Cell Biochem 2019; 120:9421-9429. [PMID: 30681198 DOI: 10.1002/jcb.28217] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 11/15/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND Elevated plasma homocysteine (Hcy) concentration is considered as the diagnostic criteria of Hyperhomocysteinemia (HHcy), which is associated with the inflammatory response and blood-brain barrier disruption. Previous studies have proposed that HHcy with hypertension was associated with the brain injury by enhancing the cerebrovascular permeability, however, the immune mechanism remains obscure. The purpose of the study is to explore the immunomodulatory mechanism of brain injury in spontaneously hypertensive rats (SHRs) induced by HHcy. MATERIALS AND METHODS Sixty SHRs were randomly assigned to three groups: SHR-C (control group), SHR-M (methionine group) and SHR-T (treatment group). Physical examination of body weight, systolic blood pressure (SBP) and plasma Hcy content was measured every 4 weeks. Besides, T-helper cell 17 and regulatory T cells (Treg)-related inflammatory cytokines (interleukin [IL]-6, IL-17, IL-10, and transforming growth factor beta [TGF-β]) and genes (RORγt and FoxP3) were detected by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction , Western blot, and immunohistochemistry. RESULTS High methionine diet could cause weight loss, SBP rising, and plasma Hcy content significantly elevated. IL-16 and IL-17A levels in peripheral blood and in brain tissue both lifted, while IL-10 and TGF-β levels dropped; RORγt expression raised in brain, nevertheless, FoxP3 levels were the opposite. After the intervention with vitamin B6, B12, and folic acid in SHR-T group, these trends would be eased or completely changed. Furthermore, brain tissue slices showed that IL-17-positive cells tended to decrease, and IL-10-positive cells increased in SHR-T group, which was reversed in SHR-M group. CONCLUSIONS HHcy may promote inflammation that can lead to brain lesions and down-regulate immune response to protect the brain.
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Affiliation(s)
- Yu Zhang
- Department of Geriatric, the Second Hospital of Tianjin Medical University, Tianjin, China
| | - Lin Wang
- Department of Geriatric, the Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xin Zhou
- Department of Cardiovascular disease and heart center, Pingjin Hospital, Logistics university of the Chinese people's armed police forces, Tianjin, China
| | - Jie Geng
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - Xin Li
- Department of Geriatric, the Second Hospital of Tianjin Medical University, Tianjin, China
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Wang SX, Yang CL, Zhang M, Zhang P, Liu RT, Zhang N, Yang B, Li XL, Dou YC, Duan RS. Sulfatides ameliorate experimental autoimmune neuritis by suppressing Th1/Th17 cells. J Neuroimmunol 2018; 326:55-61. [PMID: 30481614 DOI: 10.1016/j.jneuroim.2018.11.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/05/2018] [Accepted: 11/13/2018] [Indexed: 12/25/2022]
Abstract
Sulfatides have immunomodulatory functions, and play protective roles in multiple autoimmune diseases. In the present study, we showed that sulfatides ameliorated experimental autoimmune neuritis in Lewis rats induced with bovine peripheral myelin, which was associated with decreased proportions of Th1 and Th17 cells. Furthermore, compared control group, cells from sulfatide-treated rats exhibited lower potential in proliferation and IL-17 secretion in the presence of BPM or ConA in vitro. Moreover, sulfatides also reduced the proportions of NK and NKT cells. In summary, our study indicated that sulfatides might become a new therapeutic agent in Guillain-Barré syndrome in the future.
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Affiliation(s)
- Shu-Xia Wang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China; Department of Neurology, The Second People's Hospital of Liaocheng, Linqing, Shandong 252600, PR China
| | - Chun-Lin Yang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Min Zhang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Peng Zhang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Ru-Tao Liu
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Na Zhang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Bing Yang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Xiao-Li Li
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Ying-Chun Dou
- College of Basic Medical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, PR China
| | - Rui-Sheng Duan
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China.
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15
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Debnath M, Nagappa M, Subbanna M, Sundaravadivel P, Talukdar PM, Shivakumar V, Wahatule R, Dutta D, Binukumar B, Sinha S, Bindu PS, Periyavan S, Umamaheswara Rao G, Taly AB. Th17 pathway signatures in a large Indian cohort of Guillain Barré syndrome. J Neuroimmunol 2018; 323:125-130. [DOI: 10.1016/j.jneuroim.2018.08.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/28/2018] [Accepted: 08/02/2018] [Indexed: 12/19/2022]
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Shi P, Qu H, Nian D, Chen Y, Liu X, Li Q, Li Q, Wang C, Ye M, Ma B. Treatment of Guillain-Barré syndrome with Bifidobacterium infantis through regulation of T helper cells subsets. Int Immunopharmacol 2018; 61:290-296. [PMID: 29908492 DOI: 10.1016/j.intimp.2018.06.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/19/2018] [Accepted: 06/06/2018] [Indexed: 11/28/2022]
Abstract
BACKGROUND Guillain-Barré syndrome (GBS) is a rare, autoimmune-mediated disease. The use of Bifidobacterium is reportedly effective in alleviating GBS since they act by regulating T helper (Th) cells. OBJECTIVES In this study, we explored the differentiation of T helper cell subsets in patients with GBS. We also evaluated the effect of GBS on Bifidobacterium levels in patients and the likely protective influence of this bacterium in alleviating the disease in an animal model. MATERIALS AND METHODS We used flow cytometry, and real-time polymerase chain reaction (PCR) to determine the T cell subsets differentiation among 30 GBS patients and 20 healthy controls (HC). The concentration of Bifidobacterium was assayed by real-time PCR. Experimental autoimmune neuritis (EAN) animal model was established to support the protective role of Bifidobacterium in GBS. RESULTS The expression of Th cells, Th2 and Th17 in the patients was significantly higher than that in the HC, while Treg cells decreased substantially. Moreover, the levels of Bifidobacterium in the GBS patients were considerably lower than those in the HC, the concentration of Bifidobacterium correlating with Th2 and Th17 subsets negatively. Treatment with Bifidobacterium significantly reduced the levels of Th2 and Th17 and promoted the levels of Treg cells. CONCLUSIONS We concluded from this study that Bifidobacterium alleviated GBS by regulating Th cells, although in-depth studies might be required to fully understand the mechanism of action.
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Affiliation(s)
- Peng Shi
- Department of Neurology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - Hongdang Qu
- Department of Neurology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China.
| | - Di Nian
- Department of Medical Examination, Bengbu Medical College, Bengbu 233030, China
| | - Yuhua Chen
- Department of Neurology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - Xiaolin Liu
- Department of Neurology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - Qiang Li
- Department of Neurology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - Qianqian Li
- Department of Neurology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - Chun Wang
- Department of Neurology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - Ming Ye
- Department of Neurology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - Bo Ma
- Department of Neurology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
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Fagone P, Mazzon E, Chikovani T, Saraceno A, Mammana S, Colletti G, Mangano K, Bramanti P, Nicoletti F. Decitabine induces regulatory T cells, inhibits the production of IFN-gamma and IL-17 and exerts preventive and therapeutic efficacy in rodent experimental autoimmune neuritis. J Neuroimmunol 2018; 321:41-48. [PMID: 29957387 DOI: 10.1016/j.jneuroim.2018.05.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/24/2018] [Accepted: 05/26/2018] [Indexed: 02/01/2023]
Abstract
Guillain-Barré syndrome (GBS) is an immune-mediated acute disorder of the peripheral nervous system. Despite treatment, there is an associated mortality and severe disability in 9 to 17% of the cases. Decitabine (DAC) is a hypomethylating drug used in myelodisplastic syndrome, that has been shown to exert immunomodulatory effects. We have evaluated the effects of DAC in two rodent models of GBS, the Experimental Allergic Neuritis (EAN). Both prophylactic and therapeutic treatment with DAC ameliorated the clinical course of EAN, increasing the numbers of thymic regulatory T cells and reducing the production of proinflammmatory cytokines. Our data suggest the possible use of decitabine for the treatment of GBS.
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Affiliation(s)
- Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi Bonino Pulejo, Stada Statale 113, C.da Casazza, 98124 Messina, Italy
| | - Tinatin Chikovani
- Department of Immunology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Andrea Saraceno
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Santa Mammana
- IRCCS Centro Neurolesi Bonino Pulejo, Stada Statale 113, C.da Casazza, 98124 Messina, Italy
| | - Giuseppe Colletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Katia Mangano
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Placido Bramanti
- IRCCS Centro Neurolesi Bonino Pulejo, Stada Statale 113, C.da Casazza, 98124 Messina, Italy
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
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18
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Class I PI3K inhibitor ZSTK474 attenuates experimental autoimmune neuritis by decreasing the frequency of Th1/Th17 cells and reducing the production of proinflammatory cytokines. Cell Immunol 2018; 329:41-49. [PMID: 29724464 DOI: 10.1016/j.cellimm.2018.04.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 04/02/2018] [Accepted: 04/25/2018] [Indexed: 12/17/2022]
Abstract
The Class I phosphatidylinositol 3-kinase inhibitor, 2-(2-difluoromethy lbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine (ZSTK474), has anti-inflammatory and immunoregulatory properties. However, whether it can be used to treat Guillain-Barré syndrome (GBS)-a neuroinflammatory disorder-is unknown. We induced experimental autoimmune neuritis (EAN) in Lewis rats, an established model of GBS. Orally administered ZSTK474 decreased neurological deficits in the GBS model, as demonstrated by diminished inflammatory cell infiltration, and ameliorated demyelination of sciatic nerves. Additionally, ZSTK474 decreased the number of Th1/Th17 cells and levels of the proinflammatory cytokines interleukin (IL)-1α, IL-1β, IL-17, IL-23, interferon-γ, and tumor necrosis factor-α. We propose that the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathway likely contributed to the neuroprotective effect of ZSTK474. ZSTK474 effectively decreases the frequency of Th1/Th17 cells, thereby reducing the production of proinflammatory cytokines and successfully alleviating the symptoms of EAN. Thus, the neuroprotective effect of ZSTK474 indicates its potential utility as anti-inflammatory therapy for GBS.
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19
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Debnath M, Nagappa M, Talukdar PM, Subbanna M, Sundaravadivel P, Shivakumar V, Dutta D, Wahatule R, Sinha S, Bindu PS, Periyavan S, Umamaheswara Rao GS, Taly AB. Comprehensive cytokine profiling provides evidence for a multi-lineage Th responses in Guillain Barré Syndrome. Cytokine 2018; 110:58-62. [PMID: 29704819 DOI: 10.1016/j.cyto.2018.04.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/03/2018] [Accepted: 04/20/2018] [Indexed: 12/21/2022]
Abstract
Guillain Barré Syndrome (GBS) is one of the commonest acquired immune-mediated neuropathies, often preceded by infections. Although cellular immune responses are shown to substantially account for the pathophysiology of GBS, the precise mechanistic basis of risk and disease course remains enigmatic till date. Cytokines are best known for their abilities to drive cellular immunity and inflammation through their co-ordinated actions. Data obtained from clinical and animal model studies suggest important implications of some of the cytokines in the progression and recovery of GBS. However, these studies were performed on few cytokines and small set of GBS patients, thereby lacking a complete understanding of the patterns of association of cytokines representing Th1, Th2, and Th17 responses with GBS. We studied 65 well-characterized GBS patients and 73 age- and sex-matched healthy controls. A panel of 15 cytokines representing Th1, Th2 and Th17 pathways was assayed using Multiplex Suspension Array platform. Plasma levels of five cytokines were found to be altered in GBS patients compared to healthy control subjects: (i) IL-1β exhibited reduced levels, and (ii) IFN-γ, IL-4, IL-21 and IL-33 were elevated in GBS patients. The most important finding of this study was up-regulated expression of IL-21 and IL-33 in patients with GBS. Given the role of IL-33 as an alarmin, the elevated level of this cytokine provides important indication about a much broader role of cytokines in GBS. This study also provides evidence towards a multi-lineage Th cells (Th1, Th2 and Th17) associated cytokine responses in the pathophysiology of GBS.
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Affiliation(s)
- Monojit Debnath
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India.
| | - Madhu Nagappa
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Pinku Mani Talukdar
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Manjula Subbanna
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - P Sundaravadivel
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Venkataram Shivakumar
- Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Debprasad Dutta
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Rahul Wahatule
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Parayil Sankaran Bindu
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Sundar Periyavan
- Department of Transfusion Medicine and Haematology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - G S Umamaheswara Rao
- Department of Neuroanaesthesia and Neurocritical Care, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Arun B Taly
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
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20
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Zhang LW, Zhou PR, Wei P, Cong X, Wu LL, Hua H. Expression of interleukin-17 in primary Sjögren's syndrome and the correlation with disease severity: A systematic review and meta-analysis. Scand J Immunol 2018; 87:e12649. [PMID: 29476557 DOI: 10.1111/sji.12649] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 02/15/2018] [Indexed: 12/26/2022]
Affiliation(s)
- L.-W. Zhang
- Department of Oral Medicine; Peking University School and Hospital of Stomatology; Beijing China
| | - P.-R. Zhou
- Department of Oral Medicine; Peking University School and Hospital of Stomatology; Beijing China
| | - P. Wei
- Department of Oral Medicine; Peking University School and Hospital of Stomatology; Beijing China
| | - X. Cong
- Department of Physiology and Pathophysiology; Peking University Health Science Center; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research; Beijing China
| | - L.-L. Wu
- Department of Physiology and Pathophysiology; Peking University Health Science Center; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research; Beijing China
| | - H. Hua
- Department of Oral Medicine; Peking University School and Hospital of Stomatology; Beijing China
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21
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IL-23/IL-17 immune axis in Guillain Barré Syndrome: Exploring newer vistas for understanding pathobiology and therapeutic implications. Cytokine 2018; 103:77-82. [DOI: 10.1016/j.cyto.2017.12.029] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 12/01/2017] [Accepted: 12/27/2017] [Indexed: 12/24/2022]
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Peng J, Zhang H, Liu P, Chen M, Xue B, Wang R, Shou J, Qian J, Zhao Z, Xing Y, Liu H. IL-23 and IL-27 Levels in Serum are Associated with the Process and the Recovery of Guillain-Barré Syndrome. Sci Rep 2018; 8:2824. [PMID: 29434217 PMCID: PMC5809385 DOI: 10.1038/s41598-018-21025-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 01/29/2018] [Indexed: 12/25/2022] Open
Abstract
IL-23 and IL-27 are believed to be involved in the pathogenesis of Guillain-Barré syndrome (GBS). However, changes in these cytokines during the dynamic pathological and recovery processes of GBS are not well described. In the present study, plasma was collected from 83 patients with various stages of GBS, 70 patients with central nervous system demyelinating diseases,70 patients with other neurological diseases (OND) and 70 age- and sex-matched healthy volunteers. Serum levels of IL-23, IL-27, and Campylobacter jejuni (CJ) IgM were assessed using enzyme linked immunosorbent assay (ELISA). We found that serum IL-23 levels of patients during the acute phase of GBS were significantly higher followed by a decreasing trend during the recovery phase of the disease. Serum IL-27 levels significantly increased during the acute phase of GBS, and gradually increased during the recovery phase. Interestingly, both the severity and subtype of GBS were closely associated with the two cytokines. IL-23 levels were positively correlated with IL-27 levels, prognosis, and other clinical parameters. Our findings confirm that IL-23 may show pro-inflammatory effects, especially at the early stage of GBS. IL-27 appears to have a dual role in GBS, with initial pro-inflammatory effects, followed by anti-inflammatory properties during recovery.
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Affiliation(s)
- Jing Peng
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Hui Zhang
- Department of Neurology, Beijing Xuanwu Hospital, Affiliated to Capital Medical University, Beijing, P.R. China
| | - Peidong Liu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, P.R. China
| | - Min Chen
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Bing Xue
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Rui Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Jifei Shou
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Juanfeng Qian
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Zhikang Zhao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Yanmeng Xing
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Hongbo Liu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China.
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Schafflick D, Kieseier BC, Wiendl H, Meyer Zu Horste G. Novel pathomechanisms in inflammatory neuropathies. J Neuroinflammation 2017; 14:232. [PMID: 29179723 PMCID: PMC5704548 DOI: 10.1186/s12974-017-1001-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 11/13/2017] [Indexed: 12/19/2022] Open
Abstract
Inflammatory neuropathies are rare autoimmune-mediated disorders affecting the peripheral nervous system. Considerable progress has recently been made in understanding pathomechanisms of these disorders which will be essential for developing novel diagnostic and therapeutic strategies in the future. Here, we summarize our current understanding of antigenic targets and the relevance of new immunological concepts for inflammatory neuropathies. In addition, we provide an overview of available animal models of acute and chronic variants and how new diagnostic tools such as magnetic resonance imaging and novel therapeutic candidates will benefit patients with inflammatory neuropathies in the future. This review thus illustrates the gap between pre-clinical and clinical findings and aims to outline future directions of development.
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Affiliation(s)
- David Schafflick
- Department of Neurology, Westfälische Wilhems-University, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Bernd C Kieseier
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Heinz Wiendl
- Department of Neurology, Westfälische Wilhems-University, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Gerd Meyer Zu Horste
- Department of Neurology, Westfälische Wilhems-University, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
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Resolvin D1 Programs Inflammation Resolution by Increasing TGF-β Expression Induced by Dying Cell Clearance in Experimental Autoimmune Neuritis. J Neurosci 2017; 36:9590-603. [PMID: 27629711 DOI: 10.1523/jneurosci.0020-16.2016] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 07/26/2016] [Indexed: 12/26/2022] Open
Abstract
UNLABELLED Experimental autoimmune neuritis (EAN) is the animal model of human acute inflammatory demyelinating polyradiculoneuropathies (AIDP), an auto-immune inflammatory demyelination disease of the peripheral nervous system (PNS) and the world's leading cause of acute autoimmune neuromuscular paralysis. EAN and AIDP are characterized by self-limitation with spontaneous recovery; however, endogenous pathways that regulate inflammation resolution in EAN and AIDP remain elusive. A pathway of endogenous mediators, especially resolvins and clearance of apoptotic cells, may be involved. Here, we determined that resolvin D1 (RvD1), its synthetic enzyme, and its receptor were greatly increased in PNS during the recovery stage of EAN. Both endogenous and exogenous RvD1 increased regulatory T (Treg) cell and anti-inflammatory macrophage counts in PNS, enhanced inflammation resolution, and promoted disease recovery in EAN rats. Moreover, RvD1 upregulated the transforming growth factor-β (TGF-β) level and pharmacologic inhibition of TGF-β signaling suppressed RvD1-induced Treg cell counts, but not anti-inflammatory macrophage counts, and RvD1-improved inflammation resolution and disease recovery in EAN rats. Mechanistically, the RvD1-enhanced macrophage phagocytosis of apoptotic T cells leading to reduced apoptotic T-cell accumulation in PNS induced TGF-β production and caused Treg cells to promote inflammation resolution and disease recovery in EAN. Therefore, these data highlight the crucial role of RvD1 as an important pro-resolving molecule in EAN and suggest its potential as a therapeutic target in human neuropathies. SIGNIFICANCE STATEMENT Experimental autoimmune neuritis (EAN) is the animal model of human acute inflammatory demyelinating polyradiculoneuropathies, an auto-immune inflammatory demyelination disease of the peripheral nervous system (PNS) and the world's leading cause of acute autoimmune neuromuscular paralysis. Here, we demonstrated that resolvin D1 (RvD1) promoted macrophage phagocytosis of apoptotic T cells in PNS, thereby upregulating transforming growth factor-β by macrophages, increased local Treg cell counts, and finally promoted inflammation resolution and disease recovery in EAN. These data highlight the crucial role of RvD1 as an important pro-resolving molecule in EAN and suggest that it has potential as a therapeutic target in human neuritis.
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25
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Santos MB, de Oliveira DT, Cazzaniga RA, Varjão CS, Dos Santos PL, Santos MLB, Correia CB, Faria DR, Simon MDV, Silva JS, Dutra WO, Reed SG, Duthie MS, de Almeida RP, de Jesus AR. Distinct Roles of Th17 and Th1 Cells in Inflammatory Responses Associated with the Presentation of Paucibacillary Leprosy and Leprosy Reactions. Scand J Immunol 2017; 86:40-49. [PMID: 28426172 DOI: 10.1111/sji.12558] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 04/13/2017] [Indexed: 01/08/2023]
Abstract
It is well established that helper T cell responses influence resistance or susceptibility to Mycobacterium leprae infection, but the role of more recently described helper T cell subsets in determining severity is less clear. To investigate the involvement of Th17 cells in the pathogenesis of leprosy, we determined the immune profile with variant presentations of leprosy. Firstly, IL-17A, IFN-γ and IL-10 were evaluated in conjunction with CD4+ T cell staining by confocal microscopy of lesion biopsies from tuberculoid (TT) and lepromatous leprosy (LL) patients. Secondly, inflammatory cytokines were measured by multiplex assay of serum samples from Multibacillary (MB, n = 28) and Paucibacillary (PB, n = 23) patients and household contacts (HHC, n = 23). Patients with leprosy were also evaluated for leprosy reaction occurrence: LR+ (n = 8) and LR- (n = 20). Finally, peripheral blood mononuclear cells were analysed by flow cytometry used to determine the phenotype of cytokine-producing cells. Lesions from TT patients were found to have more CD4+ IL-17A+ cells than those from LL patients. Higher concentrations of IL-17A and IL-1β were observed in serum from PB than MB patients. The highest serum IFN-γ concentrations were, however, detected in sera from MB patients that developed leprosy reactions (MB LR+ ). Together, these results indicate that Th1 cells were associated with both the PB presentation and also with leprosy reactions. In contrast, Th17 cells were associated with an effective inflammatory response that is present in the PB forms but were not predictive of leprosy reactions in MB patients.
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Affiliation(s)
- M B Santos
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil.,Infectious Diseases Research Institute (IDRI), Seattle, WA, USA
| | - D T de Oliveira
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil
| | - R A Cazzaniga
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil
| | - C S Varjão
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil
| | - P L Dos Santos
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil
| | - M L B Santos
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil
| | - C B Correia
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil
| | - D R Faria
- Laboratory of Biologia das Interações Celulares, Department of Morphology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - M do V Simon
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil
| | - J S Silva
- Department of Biochemistry and Immunology, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, Brazil
| | - W O Dutra
- Laboratory of Biologia das Interações Celulares, Department of Morphology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - S G Reed
- Infectious Diseases Research Institute (IDRI), Seattle, WA, USA
| | - M S Duthie
- Infectious Diseases Research Institute (IDRI), Seattle, WA, USA
| | - R P de Almeida
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil.,Departament of Medicine (UFS), Sergipe, Brazil.,Instituto de Investigacão em Imunologia, INCT, CNPq, São Paulo, Brazil
| | - A R de Jesus
- Laboratory of Molecular Biology, Universidade Federal de Sergipe (UFS), Sao Cristovao, Brazil.,Departament of Medicine (UFS), Sergipe, Brazil.,Instituto de Investigacão em Imunologia, INCT, CNPq, São Paulo, Brazil
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26
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Duffy SS, Keating BA, Perera CJ, Moalem-Taylor G. The role of regulatory T cells in nervous system pathologies. J Neurosci Res 2017; 96:951-968. [DOI: 10.1002/jnr.24073] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 03/28/2017] [Accepted: 04/06/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Samuel S. Duffy
- School of Medical Sciences; University of New South Wales UNSW; Sydney Australia
| | - Brooke A. Keating
- School of Medical Sciences; University of New South Wales UNSW; Sydney Australia
| | - Chamini J. Perera
- School of Medical Sciences; University of New South Wales UNSW; Sydney Australia
| | - Gila Moalem-Taylor
- School of Medical Sciences; University of New South Wales UNSW; Sydney Australia
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27
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Zhang M, Liu RT, Zhang P, Zhang N, Yang CL, Yue LT, Li XL, Liu Y, Li H, Du J, Duan RS. Parthenolide inhibits the initiation of experimental autoimmune neuritis. J Neuroimmunol 2017; 305:154-161. [DOI: 10.1016/j.jneuroim.2017.02.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/05/2017] [Accepted: 02/05/2017] [Indexed: 01/29/2023]
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28
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Liu H, Wan C, Ding Y, Han R, He Y, Xiao J, Hao J. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing T h17-cell differentiation and regulating cytokine production. FASEB J 2017; 31:1756-1766. [PMID: 28096232 DOI: 10.1096/fj.201601147r] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 01/03/2017] [Indexed: 12/23/2022]
Abstract
Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system. It has been replicated in an animal model of human inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome. In this study, we evaluated the therapeutic efficacy of a selective inhibitor of the immunoproteasome subunit, low-MW polypeptide 7 (PR-957) in rats with EAN. Our results showed that PR-957 significantly delayed onset day, reduced severity and shortened duration of EAN, and alleviated demyelination and inflammatory infiltration in sciatic nerves. In addition to significantly regulating expression of the cytokine profile, PR-957 treatment down-regulated the proportion of proinflammatory T-helper (Th)17 cells in sciatic nerves and spleens of rats with EAN. Data presented show the role of PR-957 in the signal transducer and activator of transcription 3 (STAT3) pathway. PR-957 not only decreased expression of IL-6 and IL-23 but also led to down-regulation of STAT3 phosphorylation in CD4+ T cells. Regulation of the STAT3 pathway led to a reduction in retinoid-related orphan nuclear receptor γ t and IL-17 production. Furthermore, reduction of STAT3 phosphorylation may have directly suppressed Th17-cell differentiation. Therefore, our study demonstrates that PR-957 could potently alleviate inflammation in rats with EAN and that it may be a likely candidate for treating Guillain-Barré syndrome.-Liu, H., Wan, C., Ding, Y., Han, R., He, Y., Xiao, J., Hao, J. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing Th17-cell differentiation and regulating cytokine production.
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Affiliation(s)
- Haijie Liu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.,Department of Physical Medicine and Rehabilitation, Tianjin Medical University General Hospital, Tianjin, China
| | - Chunxiao Wan
- Department of Physical Medicine and Rehabilitation, Tianjin Medical University General Hospital, Tianjin, China
| | - Yanan Ding
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Ranran Han
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yating He
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jinting Xiao
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Junwei Hao
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China;
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29
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Kharwar N, Prasad K, Singh K, Paliwal V, Modi D. Polymorphisms of IL-17 and ICAM-1 and their expression in Guillain–Barré syndrome. Int J Neurosci 2016; 127:680-687. [DOI: 10.1080/00207454.2016.1231186] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- N.K. Kharwar
- 1Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - K.N. Prasad
- 1Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - K. Singh
- 1Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - V.K. Paliwal
- 2Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - D.R. Modi
- 3Department of Biotechnology, Baba Saheb Bhimrao Ambedaker University, Lucknow, India
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30
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Che Y, Qiu J, Jin T, Yin F, Li M, Jiang Y. Circulating memory T follicular helper subsets, Tfh2 and Tfh17, participate in the pathogenesis of Guillain-Barré syndrome. Sci Rep 2016; 6:20963. [PMID: 26865046 PMCID: PMC4750093 DOI: 10.1038/srep20963] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 01/13/2016] [Indexed: 12/17/2022] Open
Abstract
Circulating memory T follicular helper subsets, Tfh2 and Tfh17 are found to be aberrantly regulated in many autoimmune diseases. However, their roles in the pathogenesis of GBS are still unclear. This study examined the phenotype, distribution, clinical relevance and potential function of Tfh2 and Tfh17 in 36 GBS patients (including 24 AMAN and 12 AIDP patients). We found that the absolute counts of total memory Tfh cells were significantly increased in AMAN, while no significant difference in AIDP compared with HC. Furthermore, the levels of the three subsets of memory Tfh cells, Tfh1, Tfh2 and Tfh17, were differentially altered in AMAN. The absolute counts of Tfh1, Tfh2 and Tfh17 were all increased to a higher level in AMAN. The ratio of (Tfh2+Tfh17)/Tfh1 and the percentages of ICOS+ cells in Tfh2 and Tfh17 cells were greater in AMAN when compared to AIDP and HC, and the former had a positive correlation with the severity of both AMAN and AIDP. Conversely, the percentages of PD1+ cells in Tfh2 and Tfh17 cells were lower in AMAN than in HC. Therefore, circulating memory Tfh2 and Tfh17 cells might promote the autoantibody-related immune response and serve as useful markers to evaluate the progression of AMAN.
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Affiliation(s)
- Yuanyuan Che
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Jinpeng Qiu
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Tao Jin
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Fei Yin
- Department of Neurology, The Second Hospital of Jilin University, Changchun 130021, China
| | - Man Li
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Yanfang Jiang
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun 130021, China.,Key Laboratory of Zoonoses Research, Ministry of Education, The First Hospital of Jilin University, Changchun 130021, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
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31
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Consolini R, Legitimo A, Caparello MC. The Centenary of Immune Thrombocytopenia - Part 1: Revising Nomenclature and Pathogenesis. Front Pediatr 2016; 4:102. [PMID: 27807534 PMCID: PMC5069646 DOI: 10.3389/fped.2016.00102] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 09/07/2016] [Indexed: 12/24/2022] Open
Abstract
The natural history of the immune thrombocytopenia (ITP) is interesting and intriguing because it traces different steps underlying autoimmune diseases. The review points out the main steps that have accompanied the stages of its history and the consequential changes related to its terminology. ITP is an autoimmune disease resulting from platelet antibody-mediated destruction and impaired megakaryocyte and platelet production. However, research advances highlight that a complex dysregulation of the immune system is involved in the pathogenesis of this condition. The review examines the role of the multiple immune components involved in the autoimmunity process, focusing on the more recent mechanisms, which could be new promising therapeutic targets for ITP patients.
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Affiliation(s)
- Rita Consolini
- Laboratory of Immunology, Department of Clinical and Experimental Medicine, Division of Pediatrics, University of Pisa , Pisa , Italy
| | - Annalisa Legitimo
- Laboratory of Immunology, Department of Clinical and Experimental Medicine, Division of Pediatrics, University of Pisa , Pisa , Italy
| | - Maria Costanza Caparello
- Laboratory of Immunology, Department of Clinical and Experimental Medicine, Division of Pediatrics, University of Pisa , Pisa , Italy
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32
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Wu X, Wang J, Liu K, Zhu J, Zhang HL. Are Th17 cells and their cytokines a therapeutic target in Guillain–Barré syndrome? Expert Opin Ther Targets 2015; 20:209-22. [DOI: 10.1517/14728222.2016.1086751] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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33
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Ye X, Zhang L, Wang H, Chen Y, Zhang W, Zhu R, Fang C, Deng A, Qian B. The role of IL-23/Th17 pathway in patients with primary immune thrombocytopenia. PLoS One 2015; 10:e0117704. [PMID: 25621490 PMCID: PMC4306550 DOI: 10.1371/journal.pone.0117704] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 12/30/2014] [Indexed: 02/07/2023] Open
Abstract
Background Primary immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with an unclear etiology. This study aims to investigate the role of IL-23/Th17 pathway in patients with ITP. Method The gene expressions of IL-17, IL-23 and their receptors in ITP patients and healthy controls were analyzed by quantitative real-time PCR. ELISA was used to test the IL-17 and IL-23 levels in plasma. Flow cytometry was used to detect the frequency of Th17 cells. The correlation between plasma IL-23 and IL-17 levels, Th17 cells, platelets were analyzed. The level of Th17-related cytokines was measured by ELISA following stimulation with IL-23. Subsequently, the IL-23 and IL-17 levels were measured in patients post-treatment. Results The PBMCs of ITP patients showed increased mRNA expression levels in each of the following: IL-23p19, IL-12p40, IL-23R, IL-12Rβ1, IL-17A, IL-17F, and RORC. In addition, elevated Th17 cells and plasma IL-17, IL-23 levels were also observed in these ITP patients. Furthermore, it was found that IL-23 levels in plasma are positively correlated with IL-17 levels and Th17 cells, yet negatively correlated with platelet count. Following IL-23 stimulation in vitro, IL-17 levels showed significant elevation. Furthermore, both IL-23 and IL-17 levels decreased after effective treatment. Conclusion The IL-23/Th17 pathway may be involved in the pathogenesis of ITP through enhancement of the Th17 response. Moreover, our results suggest that the IL-23/Th17 pathway is a potential therapeutic target in future attempts of ITP treatment.
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Affiliation(s)
- Xin Ye
- Department of Transfusion Medicine, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Lei Zhang
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Hui Wang
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Yan Chen
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Weiwei Zhang
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Rongrong Zhu
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Chaoping Fang
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Anmei Deng
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China
- * E-mail: (AMD); (BHQ)
| | - Baohua Qian
- Department of Transfusion Medicine, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China
- * E-mail: (AMD); (BHQ)
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34
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Li LJ, Gong C, Zhao MH, Feng BS. Role of interleukin-22 in inflammatory bowel disease. World J Gastroenterol 2014; 20:18177-88. [PMID: 25561785 PMCID: PMC4277955 DOI: 10.3748/wjg.v20.i48.18177] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 06/21/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by the microbiota of the intestinal lumen and inappropriate immune responses. Aberrant immune responses can cause secretion of harmful cytokines that destroy the epithelium of the gastrointestinal tract, leading to further inflammation. Interleukin (IL)-22 is a member of the IL-10 family of cytokines that was recently discovered to be mainly produced by both adaptive and innate immune cells. Several cytokines and many of the transcriptional factors and T regulatory cells are known to regulate IL-22 expression through activation of signal transducer and activator of transcription 3 signaling cascades. This cytokine induces antimicrobial molecules and proliferative and antiapoptotic pathways, which help prevent tissue damage and aid in its repair. All of these processes play a beneficial role in IBD by enhancing intestinal barrier integrity and epithelial innate immunity. In this review, we discuss recent progress in the involvement of IL-22 in the pathogenesis of IBD, as well as its therapeutic potential.
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35
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Meyer zu Hörste G, Cordes S, Mausberg AK, Zozulya AL, Wessig C, Sparwasser T, Mathys C, Wiendl H, Hartung HP, Kieseier BC. FoxP3+ regulatory T cells determine disease severity in rodent models of inflammatory neuropathies. PLoS One 2014; 9:e108756. [PMID: 25286182 PMCID: PMC4186754 DOI: 10.1371/journal.pone.0108756] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 08/25/2014] [Indexed: 01/17/2023] Open
Abstract
Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.
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Affiliation(s)
- Gerd Meyer zu Hörste
- Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
- * E-mail:
| | - Steffen Cordes
- Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
| | - Anne K. Mausberg
- Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
| | - Alla L. Zozulya
- Department of Neurology, Julius-Maximilians-University, Würzburg, Germany
| | - Carsten Wessig
- Department of Neurology, Julius-Maximilians-University, Würzburg, Germany
| | - Tim Sparwasser
- Institute for Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research, Hannover, Germany
| | - Christian Mathys
- Department of Diagnostic and Interventional Radiology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
| | - Heinz Wiendl
- Department of Neurology, University of Münster, Münster, Germany
| | - Hans-Peter Hartung
- Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
| | - Bernd C. Kieseier
- Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
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