scholarly journals IL-12 p40 monomer is different from other IL-12 family members to selectively inhibit IL-12Rβ1 internalization and suppress EAE

2020 ◽  
Vol 117 (35) ◽  
pp. 21557-21567
Author(s):  
Susanta Mondal ◽  
Madhuchhanda Kundu ◽  
Malabendu Jana ◽  
Avik Roy ◽  
Suresh B. Rangasamy ◽  
...  
Keyword(s):  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Inhibitory Effect ◽  
The Other ◽  
Healthy Controls ◽  
Specific Monoclonal Antibody ◽  
Collagen Induced Arthritis ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system. The IL-12 family of cytokines has four members, which are IL-12 (p40:p35), IL-23 (p40:p19), the p40 monomer (p40), and the p40 homodimer (p402). Since all four members contain p40 in different forms, it is important to use a specific monoclonal antibody (mAb) to characterize these molecules. Here, by using such mAbs, we describe selective loss of p40 in serum of MS patients as compared to healthy controls. Similarly, we also observed decrease in p40 and increase in IL-12, IL-23, and p402in serum of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as compared to control mice. Interestingly, weekly supplementation of mouse and human recombinant p40 ameliorated clinical symptoms and disease progression of EAE. On the other hand, IL-12, IL-23, and p402did not exhibit such inhibitory effect. In addition to EAE, p40 also suppressed collagen-induced arthritis in mice. Using IL-12Rβ1−/−, IL-12Rβ2−/−, and IL-12Rβ1+/−/IL-12Rβ2−/−mice, we observed that p40 required IL-12Rβ1, but not IL-12Rβ2, to suppress EAE. Interestingly, p40 arrested IL-12–, IL-23–, or p402-mediated internalization of IL-12Rβ1, but neither IL-12Rβ2 nor IL-23R, protected regulatory T cells, and suppressed Th1 and Th17 biasness. These studies identify p40 as an anti-autoimmune cytokine with a biological role different from IL-12, IL-23, and p402in which it attenuates autoimmune signaling via suppression of IL-12Rβ1 internalization, which may be beneficial in patients with MS and other autoimmune disorders.

scholarly journals Neuron-specific SALM5 limits inflammation in the CNS via its interaction with HVEM

2016 ◽  
Vol 2 (4) ◽  
pp. e1500637 ◽  
Author(s):  
Yuwen Zhu ◽  
Sheng Yao ◽  
Mathew M. Augustine ◽  
Haiying Xu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Clinical Symptoms ◽  
Virus Entry ◽  
Neuronal System ◽  
Specific Monoclonal Antibody ◽  
Autoimmune Encephalomyelitis ◽  
Mouse Experimental Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Functional Receptor ◽  
Experimental Autoimmune

The central nervous system (CNS) is an immune-privileged organ with the capacity to prevent excessive inflammation. Aside from the blood-brain barrier, active immunosuppressive mechanisms remain largely unknown. We report that a neuron-specific molecule, synaptic adhesion-like molecule 5 (SALM5), is a crucial contributor to CNS immune privilege. We found that SALM5 suppressed lipopolysaccharide-induced inflammatory responses in the CNS and that a SALM-specific monoclonal antibody promoted inflammation in the CNS, and thereby aggravated clinical symptoms of mouse experimental autoimmune encephalomyelitis. In addition, we identified herpes virus entry mediator as a functional receptor that mediates SALM5’s suppressive function. Our findings reveal a molecular link between the neuronal system and the immune system, and provide potential therapeutic targets for the control of CNS diseases.

scholarly journals A Pathogenic Role for Myelin-Specific Cd8+ T Cells in a Model for Multiple Sclerosis

2001 ◽  
Vol 194 (5) ◽  
pp. 669-676 ◽  
Author(s):  
Eric S. Huseby ◽  
Denny Liggitt ◽  
Thea Brabb ◽  
Bryan Schnabel ◽  
Claes Öhlén ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Autoimmune Encephalomyelitis ◽  
Effector Cells ◽  
Cns Autoimmunity ◽  
The Central Nervous System

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4+ and CD8+ T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4+ myelin-specific T cells. The role of CD8+ myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8+ T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8+ T cell–mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4+ T cell–mediated EAE. These data suggest that myelin-specific CD8+ T cells could function as effector cells in the pathogenesis of MS.

scholarly journals Combined treatment with ribavirin and tiazofurin attenuates response of glial cells in experimental autoimmune encephalomyelitis

2012 ◽  
Vol 64 (3) ◽  
pp. 843-850 ◽  
Author(s):  
Danijela Savic ◽  
Irena Lavrnja ◽  
Sanja Dacic ◽  
Ivana Bjelobaba ◽  
Nadezda Nedeljkovic ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Glial Cells ◽  
Demyelinating Disease ◽  
Combined Treatment ◽  
Nucleoside Analogues ◽  
Mononuclear Cell Infiltration ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Histological Results ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), a human inflammatory and demyelinating disease. Microglia and astrocytes are glial cells of the central nervous system (CNS) that play a dual role in MS and EAE pathology. The aim of this study was to examine the effect of combined treatment with two nucleoside analogues, ribavirin and tiazofurin, on microglia and astrocytes in actively induced EAE. Therapeutic treatment with a combination of these two nucleoside analogues reduced disease severity, mononuclear cell infiltration and demyelination. The obtained histological results indicate that ribavirin and tiazofurin changed activated microglia into an inactive type and attenuated astrocyte reactivity at the end of the treatment period. Since reduction of reactive microgliosis and astrogliosis correlated with EAE suppression, the present study also suggests that the obtained beneficial effect of ribavirin and tiazofurin could be a consequence of their action inside as well as outside the CNS.

scholarly journals Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin-11–mediated protection of regulatory T cells

2018 ◽  
Vol 11 (558) ◽  
pp. eaar8278 ◽  
Author(s):  
Susanta Mondal ◽  
Malabendu Jana ◽  
Sridevi Dasarathi ◽  
Avik Roy ◽  
Kalipada Pahan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Symptoms ◽  
Interleukin 4 ◽  
T Helper 17 ◽  
Autoimmune Encephalomyelitis ◽  
Relapsing Remitting ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a human disease that results from autoimmune T cells targeting myelin protein that is expressed within the central nervous system. In MS, the number of FoxP3-expressing regulatory T cells (Tregs) is reduced, which facilitates the activation of autoreactive T cells. Because aspirin (acetylsalicylic acid) is the most widely used nonsteroidal anti-inflammatory drug, we examined its immunomodulatory effect in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found that low-dose aspirin suppressed the clinical symptoms of EAE in mouse models of both relapsing-remitting and chronic disease. Aspirin reduced the development of EAE driven by myelin basic protein (MBP)–specific T cells and the associated perivascular cuffing, inflammation, and demyelination. The effects of aspirin required the presence of CD25+FoxP3+ Tregs. Aspirin increased the amounts of Foxp3 and interleukin-4 (IL-4) in T cells and suppressed the differentiation of naïve T cells into T helper 17 (TH17) and TH1 cells. Aspirin also increased the transcription of Il11 mediated by the transcription factor CREB, which was necessary for the generation of Tregs. Neutralization of IL-11 negated the effects of aspirin on Treg development and exacerbated EAE. Furthermore, we found that IL-11 alone was sufficient to maintain the percentage of FoxP3+ Tregs and protect mice from EAE. These results identify a previously uncharacterized mode of action of aspirin.

scholarly journals Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Ramona Gerhards ◽  
Lena Kristina Pfeffer ◽  
Jessica Lorenz ◽  
Laura Starost ◽  
Luise Nowack ◽  
...  
Keyword(s):  
Acute Disseminated Encephalomyelitis ◽  
Autoimmune Response ◽  
Healthy Controls ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Novel Target ◽  
Actual Target ◽  
T Cell Help ◽  
Oligodendrocyte Myelin Glycoprotein ◽  
Experimental Autoimmune

AbstractAutoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the actual target of their autoimmune response is unknown. Here we investigated oligodendrocyte myelin glycoprotein (OMGP) as autoimmune target, because OMGP is expressed specifically in the CNS and there on oligodendrocytes and neurons. Using a stringent cell-based assay, we detected autoantibodies to OMGP in serum of 8/352 patients with multiple sclerosis, 1/28 children with acute disseminated encephalomyelitis and unexpectedly, also in one patient with psychosis, but in none of 114 healthy controls. Since OMGP is GPI-anchored, we validated its recognition also in GPI-anchored form. The autoantibodies to OMGP were largely IgG1 with a contribution of IgG4, indicating cognate T cell help. We found high levels of soluble OMGP in human spinal fluid, presumably due to shedding of the GPI-linked OMGP. Analyzing the pathogenic relevance of autoimmunity to OMGP in an animal model, we found that OMGP-specific T cells induce a novel type of experimental autoimmune encephalomyelitis dominated by meningitis above the cortical convexities. This unusual localization may be directed by intrathecal uptake and presentation of OMGP by meningeal phagocytes. Together, OMGP-directed autoimmunity provides a new element of heterogeneity, helping to improve the stratification of patients for diagnostic and therapeutic purposes.

scholarly journals Gliotoxin Aggravates Experimental Autoimmune Encephalomyelitis by Triggering Neuroinflammation

Toxins ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 443 ◽  
Author(s):  
Thais Fernanda de Campos Fraga-Silva ◽  
Luiza Ayumi Nishiyama Mimura ◽  
Laysla de Campos Toledo Leite ◽  
Patrícia Aparecida Borim ◽  
Larissa Lumi Watanabe Ishikawa ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Symptoms ◽  
Fungal Infections ◽  
Neurological Diseases ◽  
Direct Interaction ◽  
Experimental Models ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Dose Dependent ◽  
Experimental Autoimmune

Gliotoxin (GTX) is the major and the most potent mycotoxin that is secreted by Aspergillus fumigatus, which is capable of injuring and killing microglial cells, astrocytes, and oligodendrocytes. During the last years, studies with patients and experimental models of multiple sclerosis (MS), which is an autoimmune disease of the central nervous system (CNS), suggested that fungal infections are among the possible initiators or aggravators of this pathology. The deleterious effect can occur through a direct interaction of the fungus with the CNS or by the toxin release from a non-neurological site. In the present work, we investigated the effect of GTX on experimental autoimmune encephalomyelitis (EAE) development. Female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein and then intraperitoneally injected with three doses of GTX (1 mg/kg b.w., each) on days 4, 7, and 10. GTX aggravated clinical symptoms of the disease in a dose-dependent way and this outcome was concomitant with an increased neuroinflammation. CNS analyses revealed that GTX locally increased the relative expression of inflammatory genes and the cytokine production. Our results indicate that GTX administered in a non-neuronal site was able to increase neuroinflammation in EAE. Other mycotoxins could also be deleterious to many neurological diseases by similar mechanisms.

scholarly journals Animal models of multiple sclerosis: From rodents to zebrafish

2018 ◽  
Vol 25 (3) ◽  
pp. 306-324 ◽  
Author(s):  
David John Burrows ◽  
Alexander McGown ◽  
Saurabh A Jain ◽  
Milena De Felice ◽  
Tennore M Ramesh ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Animal Models ◽  
Demyelinating Disease ◽  
Genetic Manipulation ◽  
Rapid Development ◽  
Disease Course ◽  
Autoimmune Encephalomyelitis ◽  
Immune Mediated ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system. Animal models of MS have been critical for elucidating MS pathological mechanisms and how they may be targeted for therapeutic intervention. Here we review the most commonly used animal models of MS. Although these animal models cannot fully replicate the MS disease course, a number of models have been developed to recapitulate certain stages. Experimental autoimmune encephalomyelitis (EAE) has been used to explore neuroinflammatory mechanisms and toxin-induced demyelinating models to further our understanding of oligodendrocyte biology, demyelination and remyelination. Zebrafish models of MS are emerging as a useful research tool to validate potential therapeutic candidates due to their rapid development and amenability to genetic manipulation.

T-1237C polymorphism of TLR9 gene is not associated with multiple sclerosis in the Portuguese population

2008 ◽  
Vol 14 (4) ◽  
pp. 550-552 ◽  
Author(s):  
A. Carvalho ◽  
M. Santos ◽  
P. Maciel ◽  
F. Rodrigues
Keyword(s):  
Multiple Sclerosis ◽  
Age Of Onset ◽  
Promoter Polymorphism ◽  
Healthy Controls ◽  
Autoimmune Encephalomyelitis ◽  
Portuguese Population ◽  
Disease Subtype ◽  
Tlr9 Gene ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, with disturbances of the immunological balance. As TLR9-null mice showed increased resistance to experimental autoimmune encephalomyelitis and recent genetic investigations showed that T-1237C promoter polymorphism of TLR9, commonly implicated in autoimmune diseases, induces a deregulation of its expression, we performed an association study in a Portuguese population of 165 MS patients and unrelated healthy controls. Our results show no significant association with MS and no protective effect of T-1237C concerning age of onset, disease severity or disease subtype in MS patients. Multiple Sclerosis 2008; 14 : 550—552. http://msj.sagepub.com

scholarly journals Therapeutic Potential of Pien Tze Huang on Experimental Autoimmune Encephalomyelitis Rat

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xuemei Qiu ◽  
Hui Luo ◽  
Xue Liu ◽  
Qingqing Guo ◽  
Kang Zheng ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Therapeutic Potential ◽  
Clinical Severity ◽  
Therapeutic Effects ◽  
Autoimmune Encephalomyelitis ◽  
Cytokines And Chemokines ◽  
Pien Tze Huang ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). There is still lack of commercially viable treatment currently. Pien Tze Huang (PZH), a traditional Chinese medicine, has been proved to have anti-inflammatory, neuroprotective, and immunoregulatory effects. This study investigated the possible therapeutic effects of PZH on experimental autoimmune encephalomyelitis (EAE) rats, a classic animal model of MS. Male Lewis rats were immunized with myelin basic protein (MBP) peptide to establish an EAE model and then treated with three doses of PZH. Clinical symptoms, organ coefficient, histopathological features, levels of proinflammatory cytokines, and chemokines as well as MBP and Olig2 were analyzed. The results indicated that PZH ameliorated the clinical severity of EAE rats. It also remarkably reduced inflammatory cell infiltration in the CNS of EAE rats. Furthermore, the levels of IL-17A, IL-23, CCL3, and CCL5 in serum and the CNS were significantly decreased; the p-P65 and p-STAT3 levels were also downregulated in the CNS, while MBP and Olig2 in the CNS of EAE rats had a distinct improvement after PZH treatment. In addition, PZH has no obvious toxicity at the concentration of 0.486 g/kg/d. This study demonstrated that PZH could be used to treat MS.

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