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 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.

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 Selected Clostridia Strains from The Human Microbiota and their Metabolite, Butyrate, Improve Experimental Autoimmune Encephalomyelitis

2021 ◽  
Author(s):  
Laura Calvo-Barreiro ◽  
Herena Eixarch ◽  
Thais Cornejo ◽  
Carme Costa ◽  
Mireia Castillo ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Therapeutic Effect ◽  
Clinical Effect ◽  
Short Chain Fatty Acid ◽  
Human Gut ◽  
Autoimmune Encephalomyelitis ◽  
Gut Dysbiosis ◽  
Cns Autoimmunity ◽  
The Central Nervous System ◽  
Experimental Autoimmune

SummaryGut microbiome studies in multiple sclerosis (MS) patients are unravelling some consistent but modest patterns of gut dysbiosis. Among these, a significant decrease of Clostridia cluster IV and XIVa has been reported. In the present study, we investigated the therapeutic effect of a previously selected mixture of human gut-derived 17 Clostridia strains, which belong to Clostridia clusters IV, XIVa, and XVIII, on the clinical outcome of experimental autoimmune encephalomyelitis (EAE). The observed clinical improvement was related to lower demyelination and astrocyte reactivity as well as a tendency to lower microglia reactivity/infiltrating macrophages and axonal damage in the central nervous system (CNS), and to an enhanced immunoregulatory response of regulatory T cells in the periphery. Transcriptome studies also highlighted increased antiinflammatory responses related to interferon beta in the periphery and lower immune responses in the CNS. Since Clostridia-treated mice were found to present higher levels of the immunomodulatory short-chain fatty acid (SCFA) butyrate in the serum, we studied if this clinical effect could be reproduced by butyrate administration alone. Further EAE experiments proved its preventive but slight therapeutic impact on CNS autoimmunity. Thus, this smaller therapeutic effect highlighted that the Clostridia-induced clinical effect was not exclusively related to the SCFA and could not be reproduced by butyrate administration alone. Although it is still unknown if these Clostridia strains will have the same effect on MS patients, gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course.

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

2021 ◽  
Author(s):  
William E. Barclay ◽  
M. Elizabeth Deerhake ◽  
Makoto Inoue ◽  
Toshiaki Nonaka ◽  
Kengo Nozaki ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Animal Model ◽  
Cell Death ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

ABSTRACTInflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.SIGNIFICANCE STATEMENTInflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1β, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1β-mediated inflammation.

scholarly journals Vaccination with DNA Encoding an Immunodominant Myelin Basic Protein Peptide Targeted to Fc of Immunoglobulin G Suppresses Experimental Autoimmune Encephalomyelitis

1998 ◽  
Vol 187 (9) ◽  
pp. 1543-1548 ◽  
Author(s):  
Anna Lobell ◽  
Robert Weissert ◽  
Maria K. Storch ◽  
Cecilia Svanholm ◽  
Katrien L. de Graaf ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Cell Epitope ◽  
Interferon Γ ◽  
Dna Encoding ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

We explore here if vaccination with DNA encoding an autoantigenic peptide can suppress autoimmune disease. For this purpose we used experimental autoimmune encephalomyelitis (EAE), which is an autoaggressive disease in the central nervous system and an animal model for multiple sclerosis. Lewis rats were vaccinated with DNA encoding an encephalitogenic T cell epitope, guinea pig myelin basic protein peptide 68–85 (MBP68–85), before induction of EAE with MBP68–85 in complete Freund's adjuvant. Compared to vaccination with a control DNA construct, the vaccination suppressed clinical and histopathological signs of EAE, and reduced the interferon γ production after challenge with MBP68–85. Targeting of the gene product to Fc of IgG was essential for this effect. There were no signs of a Th2 cytokine bias. Our data suggest that DNA vaccines encoding autoantigenic peptides may be useful tools in controlling autoimmune disease.

scholarly journals Amino acid sequence of the encephalitogenic basic protein from human myelin

1971 ◽  
Vol 123 (1) ◽  
pp. 57-67 ◽  
Author(s):  
P. R. Carnegie
Keyword(s):  
Amino Acids ◽  
Central Nervous System ◽  
Nervous System ◽  
Amino Acid ◽  
Basic Protein ◽  
Structure And Function ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
And Function ◽  
Experimental Autoimmune

Myelin from the central nervous system contains an unusual basic protein, which can induce experimental autoimmune encephalomyelitis. The basic protein from human brain was digested with trypsin and other enzymes and the sequence of the 170 amino acids was determined. The localization of the encephalitogenic determinants was described. Possible roles for the protein in the structure and function of myelin are discussed.

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