Anti-Integrin Therapy for Multiple Sclerosis

Kawamoto, Eiji; Nakahashi, Susumu; Okamoto, Takayuki; Imai, Hiroshi; Shimaoka, Motomu

doi:10.1155/2012/357101

Cited by 30 publications

(30 citation statements)

References 48 publications

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“…Multiple sclerosis (MS) is a devastating autoimmune disease that is characterized by inflammation in the central nervous system (CNS), and also known as a multifocal chronic inflammatory perivascular demyelinating disease (Frohman et al, 2006;Kawamoto et al, 2012;Trapp & Nave, 2008). It is thought that self-reactive lymphocytes pervade the CNS through the blood-brain barrier (BBB), and together with the resident microglia and/or dendritic cells (DCs), generate local CNS inflammation and cause damage to oligodendrocytes and demyelination (Stasiolek et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

Ramroodi

Khani

Ganjali

et al. 2015

Immunological Investigations

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

Ramroodi

Khani

Ganjali

et al. 2015

Immunological Investigations

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“…before the infection. CD49d is expressed by these cells and is involved in the transendothelial migration of leukocytes into tissues that are undergoing inflammation (24,25). CD49d antibody prevents the interaction of immune cells and endothelial cells, thereby reducing their translocation (24).…”

Section: Resultsmentioning

confidence: 99%

Impaired learning resulting from Respiratory Syncytial Virus infection

Espinoza

Böhmwald

Céspedes

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

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Respiratory syncytial virus (RSV) is the major cause of respiratory illness in infants worldwide. Neurologic alterations, such as seizures and ataxia, have been associated with RSV infection. We demonstrate the presence of RSV proteins and RNA in zones of the brainsuch as the hippocampus, ventromedial hypothalamic nucleus, and brainstem-of infected mice. One month after disease resolution, rodents showed behavioral and cognitive impairment in marble burying (MB) and Morris water maze (MWM) tests. Our data indicate that the learning impairment caused by RSV is a result of a deficient induction of long-term potentiation in the hippocampus of infected animals. In addition, immunization with recombinant bacillus Calmette-Guérin (BCG) expressing RSV nucleoprotein prevented behavioral disorders, corroborating the specific effect of RSV infection over the central nervous system. Our findings provide evidence that RSV can spread from the airways to the central nervous system and cause functional alterations to the brain, both of which can be prevented by proper immunization against RSV.espiratory syncytial virus (RSV) is an enveloped virus with a negative-sensed, single-stranded RNA genome that encodes 11 proteins (1, 2). RSV is the most prevalent pathogen of the Paramyxoviridae family and is the leading cause of lower respiratory tract infection in infants worldwide. RSV infects more than 70% of children in the first year of life, and 100% of children by age 2 years (3, 4). Although most symptoms of RSV infection, such as bronchiolitis and pneumonia, are related to airway inflammation, several central nervous system (CNS) manifestations have been reported in ∼2% of patients with RSVassociated bronchiolitis (5), including seizures, central apnea, lethargy, feeding or swallowing difficulties, muscular tone or strabismus abnormalities, cerebrospinal fluid (CSF) abnormalities, and encephalopathy (6-8). Recently, there has been an increase in the number of case reports on RSV-caused encephalopathy, highlighting the importance of these symptoms (9).Previous clinical studies have suggested an association between neurological symptoms and RSV infection (6,8,10), and other studies have documented the presence of RSV and RSV-specific antibodies in the CSF of patients suffering from severe bronchiolitis (11, 12). However, the pathophysiological mechanism responsible for RSV-caused encephalopathy remains undefined.Despite evidence demonstrating the presence of RSV in the CSF of infected children and CNS alterations resulting from severe respiratory infection by this virus, several aspects of RSV biology regarding the CNS, such as the entrance mechanism, localization, and spreading of RSV in the CNS and its associated tissues, remain obscure. Here, we evaluated whether RSV was able to access the CNS and cause cognitive sequelae using BALB/c mice and Sprague-Dawley rats. Immunofluorescence and quantitative real-time RT-PCR assays revealed the presence of both RSV nucleoprotein (N) and genetic material in the brains of infected anima...

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“…In particular, individuals with multiple sclerosis (MS) who are receiving the biological therapy natalizumab have a 1:500 chance of developing PML (25, 26). Natalizumab is an anti-VLA-4 (α4β1 integrin) antibody that blocks extravasation of VLA-4 + T and B lymphocytes to the brain, where they normally bind to endothelial cells (27). Therefore, while this treatment prevents the movement of lymphocytes to the brain, thus protecting the brain of an MS patient from attack, the lack of immune surveillance can also result in increased spread of JCPyV to the brain and thus increase the chances of developing PML (25).…”

Section: Introductionmentioning

confidence: 99%

Progressive Multifocal Leukoencephalopathy-Associated Mutations in the JC Polyomavirus Capsid Disrupt Lactoseries Tetrasaccharide c Binding

Maginnis

Stroh

Gee

et al. 2013

mBio

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The human JC polyomavirus (JCPyV) is the causative agent of the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML). The Mad-1 prototype strain of JCPyV uses the glycan lactoseries tetrasaccharide c (LSTc) and serotonin receptor 5-HT2A to attach to and enter into host cells, respectively. Specific residues in the viral capsid protein VP1 are responsible for direct interactions with the α2,6-linked sialic acid of LSTc. Viral isolates from individuals with PML often contain mutations in the sialic acid-binding pocket of VP1 that are hypothesized to arise from positive selection. We reconstituted these mutations in the Mad-1 strain of JCPyV and found that they were not capable of growth. The mutations were then introduced into recombinant VP1 and reconstituted as pentamers in order to conduct binding studies and structural analyses. VP1 pentamers carrying PML-associated mutations were not capable of binding to permissive cells. High-resolution structure determination revealed that these pentamers are well folded but no longer bind to LSTc due to steric clashes in the sialic acid-binding site. Reconstitution of the mutations into JCPyV pseudoviruses allowed us to directly quantify the infectivity of the mutants in several cell lines. The JCPyV pseudoviruses with PML-associated mutations were not infectious, nor were they able to engage sialic acid as measured by hemagglutination of human red blood cells. These results demonstrate that viruses from PML patients with single point mutations in VP1 disrupt binding to sialic acid motifs and render these viruses noninfectious.

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Anti-Integrin Therapy for Multiple Sclerosis

Cited by 30 publications

References 48 publications

RETRACTED ARTICLE: Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

RETRACTED ARTICLE: Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

Impaired learning resulting from Respiratory Syncytial Virus infection

Progressive Multifocal Leukoencephalopathy-Associated Mutations in the JC Polyomavirus Capsid Disrupt Lactoseries Tetrasaccharide c Binding

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