Anoctamin 2 identified as an autoimmune target in multiple sclerosis

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.

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GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis

Science Translational Medicine ◽

10.1126/scitranslmed.aat4301 ◽

2018 ◽

Vol 10 (462) ◽

pp. eaat4301 ◽

Cited By ~ 19

Author(s):

Raquel Planas ◽

Radleigh Santos ◽

Paula Tomas-Ojer ◽

Carolina Cruciani ◽

Andreas Lutterotti ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

Cell Clone ◽

Autoimmune Response ◽

Guanosine Diphosphate ◽

Immune Mediated ◽

T Cell Clone ◽

Positional Scanning ◽

The Central Nervous System

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.

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Impact of Exercise on Immunometabolism in Multiple Sclerosis

Journal of Clinical Medicine ◽

10.3390/jcm9093038 ◽

2020 ◽

Vol 9 (9) ◽

pp. 3038 ◽

Cited By ~ 1

Author(s):

Remsha Afzal ◽

Jennifer K Dowling ◽

Claire E McCoy

Keyword(s):

Multiple Sclerosis ◽

Cell Function ◽

Immune Cell ◽

Therapeutic Benefits ◽

Demyelinating Lesions ◽

Inflammatory State ◽

Autoimmune Condition ◽

The Central Nervous System ◽

Axonal Degradation

Multiple Sclerosis (MS) is a chronic, autoimmune condition characterized by demyelinating lesions and axonal degradation. Even though the cause of MS is heterogeneous, it is known that peripheral immune invasion in the central nervous system (CNS) drives pathology at least in the most common form of MS, relapse-remitting MS (RRMS). The more progressive forms’ mechanisms of action remain more elusive yet an innate immune dysfunction combined with neurodegeneration are likely drivers. Recently, increasing studies have focused on the influence of metabolism in regulating immune cell function. In this regard, exercise has long been known to regulate metabolism, and has emerged as a promising therapy for management of autoimmune disorders. Hence, in this review, we inspect the role of key immunometabolic pathways specifically dysregulated in MS and highlight potential therapeutic benefits of exercise in modulating those pathways to harness an anti-inflammatory state. Finally, we touch upon current challenges and future directions for the field of exercise and immunometabolism in MS.

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IFN-β treatment modulates the CD28/CTLA-4-mediated pathway for IL-2 production in patients with relapsing -remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1094oa ◽

2004 ◽

Vol 10 (6) ◽

pp. 630-635 ◽

Cited By ~ 4

Author(s):

C Espejo ◽

L Brieva ◽

G Ruggiero ◽

J Río ◽

X Montalban ◽

...

Keyword(s):

Multiple Sclerosis ◽

Chronic Inflammatory Disease ◽

Autoimmune Response ◽

T Cell Proliferation ◽

Immunomodulatory Effects ◽

Cd25 Expression ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Relapsing Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system probably mediated by Th1 lymphocytes. IFN-b is an established therapy for relapsing MS patients, although the mechanisms underlying its efficacy are yet to be well characterized. We determined IL-2 production, CD25 expression and T-cell proliferation from relapsing -remitting MS patients before and three months after starting therapy. A decrease in the percentage of CD80-induced IL-2-producing cells was observed after in vivo IFN-b treatment. These data support that one of the immunomodulatory effects of IFN-b treatment in MS may be a limitation of the autoimmune response modifying the CD80:CD28/CTLA-4 pathway.

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Role of Gut Microbiota in Multiple Sclerosis and Potential Therapeutic Implications

Current Neuropharmacology ◽

10.2174/1570159x19666210629145351 ◽

2021 ◽

Vol 19 ◽

Author(s):

Xu Wang ◽

Zhen Liang ◽

Shengnan Wang ◽

Di Ma ◽

Mingqin Zhu ◽

...

Keyword(s):

Multiple Sclerosis ◽

Gut Microbiota ◽

Demyelinating Disease ◽

Inflammatory Diseases ◽

Intestinal Barrier ◽

Autoimmune Response ◽

Therapeutic Implications ◽

The Central Nervous System ◽

Underlying Mechanisms

: The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on the gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota has also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.

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Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

Frontiers in Immunology ◽

10.3389/fimmu.2021.724108 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guan Yang ◽

Luc Van Kaer

Keyword(s):

Multiple Sclerosis ◽

Immune Cell ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Nerve Fibers ◽

Therapeutic Approaches ◽

Autoimmune Encephalomyelitis ◽

Autoimmune And Inflammatory Diseases ◽

The Central Nervous System

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding nerve fibers that project from neurons. The pathological hallmark of MS is multiple areas of myelin loss accompanied by inflammation within the CNS, resulting in loss of cognitive function that ultimately leads to paralysis. Recent studies in MS have focused on autophagy, a cellular self-eating process, as a potential target for MS treatment. Here, we review the contribution of immune cell autophagy to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS. A better understanding of the role of autophagy in different immune cells to EAE might inform the development of novel therapeutic approaches in MS and other autoimmune and inflammatory diseases.

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Metal Imbalance in Neurodegenerative Diseases with a Specific Concern to the Brain of Multiple Sclerosis Patients

International Journal of Molecular Sciences ◽

10.3390/ijms21239105 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9105

Author(s):

Jean-Philippe Dales ◽

Sophie Desplat-Jégo

Keyword(s):

Multiple Sclerosis ◽

Neurodegenerative Diseases ◽

Drug Targets ◽

Chronic Inflammatory Disease ◽

Autoimmune Reaction ◽

Candidate Drug ◽

The Central Nervous System ◽

Multiple Sclerosis Patients ◽

The Brain

There is increasing evidence that deregulation of metals contributes to a vast range of neurodegenerative diseases including multiple sclerosis (MS). MS is a chronic inflammatory disease of the central nervous system (CNS) manifesting disability and neurological symptoms. The precise origin of MS is unknown, but the disease is characterized by focal inflammatory lesions in the CNS associated with an autoimmune reaction against myelin. The treatment of this disease has mainly been based on the prescription of immunosuppressive and immune-modulating agents. However, the rate of progressive disability and early mortality is still worrisome. Metals may represent new diagnostic and predictive markers of severity and disability as well as innovative candidate drug targets for future therapies. In this review, we describe the recent advances in our understanding on the role of metals in brain disorders of neurodegenerative diseases and MS patients.

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Potential Role of Trace Elements (Al, Cu, Zn, and Se) in Multiple Sclerosis Physiopathology

NeuroImmunoModulation ◽

10.1159/000511308 ◽

2020 ◽

Vol 27 (4) ◽

pp. 163-177

Author(s):

Mohammad Sadegh Hesamian ◽

Nahid Eskandari

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Trace Elements ◽

Plasma Cells ◽

Peripheral Tolerance ◽

The Central Nervous System ◽

Living Organisms ◽

Tolerance Breakdown ◽

Peripheral Immune Cells

Multiple sclerosis (MS) is an unpredictable disease of the central nervous system. The cause of MS is not known completely, and pathology is specified by involved demyelinated areas in the white and gray matter of the brain and spinal cord. Inflammation and peripheral tolerance breakdown due to Treg cell defects and/or effector cell resistance are present at all stages of the disease. Several invading peripheral immune cells are included in the process of the disease such as macrophages, CD8+ T cells, CD4+ T cells, B cells, and plasma cells. Trace elements are known as elements found in soil, plants, and living organisms in small quantities. Some of them (e.g., Al, Cu, Zn, Mn, and Se) are essential for the body’s functions like catalysts in enzyme systems, energy metabolism, etc. Al toxicity and Cu, Zn, and Se toxicity and deficiency can affect the immune system and following neuron inflammation and degeneration. These processes may result in MS pathology. Of course, factors such as lifestyle, environment, and industrialization can affect levels of trace elements in the human body.

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Validation and cross-cultural adaptation of sexual dysfunction modified scale in multiple sclerosis for Brazilian population

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20150078 ◽

2015 ◽

Vol 73 (8) ◽

pp. 681-687 ◽

Cited By ~ 6

Author(s):

Raquel Ataíde Peres da Silva ◽

Guilherme Sciascia do Olival ◽

Lívia Palma Stievano ◽

Vania Balardin Toller ◽

Sergio Semeraro Jordy ◽

...

Keyword(s):

Multiple Sclerosis ◽

Sexual Dysfunction ◽

Cultural Adaptation ◽

Chronic Inflammatory Disease ◽

Cross Cultural ◽

Brazilian Population ◽

Control Group ◽

Cross Cultural Adaptation ◽

The Central Nervous System ◽

The Impact

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). These patients suffer from various comorbidities, including sexual dysfunction (SD). The lesions of MS may affect regions of the CNS along the pathway of sexual response. The Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19) is a scale that assesses sexual dysfunction. Adapt and validate the MSISQ-19 to Brazilian patients with MS. 204 individuals were evaluated, 134 patients with MS and 70 healthy persons for the control group. It was determined reproducibility, validity, internal consistency and sensitivity of the MSISQ-19-BR. Among patients with MS, 54.3% of male and 71.7% of female presented some kind of SD. In the control group the results were 12.5% and 19.5%, respectively. The MSISQ-19-BR is reproducible, reliable and valid for the Brazilian population and may be used as a tool for assessing the impact of sexual dysfunction in patients with MS.

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Multiple Sclerosis and Obesity: Possible Roles of Adipokines

Mediators of Inflammation ◽

10.1155/2016/4036232 ◽

2016 ◽

Vol 2016 ◽

pp. 1-24 ◽

Cited By ~ 36

Author(s):

José de Jesús Guerrero-García ◽

Lucrecia Carrera-Quintanar ◽

Rocío Ivette López-Roa ◽

Ana Laura Márquez-Aguirre ◽

Argelia Esperanza Rojas-Mayorquín ◽

...

Keyword(s):

Multiple Sclerosis ◽

Early Life ◽

Neural Tissue ◽

Autoimmune Disorder ◽

Susceptibility Factor ◽

Related Risk ◽

Inflammatory State ◽

The Central Nervous System ◽

Ms Pathogenesis

Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS.

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