Disease relevance of MS

• Multiple sclerosis (MS), an inflammatory autoimmune demyelinating disorder of the central nervous system, is the most common cause of acquired neurological dysfunction arising in the second to fourth decades of life [1].
• Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development less compared with their contribution to disorders such as insulin-dependent diabetes mellitus [2].
• Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS [2].
• Its pro-inflammatory ligands, S100-calgranulins, are upregulated in MS and in the related rodent model, experimental autoimmune encephalomyelitis (EAE) [3].
• Multiple sclerosis (MS) may be an autoimmune disease mediated by T cells specific for a myelin protein [4].

Psychiatry related information on MS

• Thus, antibodies containing a cross-reactive Id are present preferentially in the CSF of patients with MS compared with those with other neurological diseases [5].
• Proinflammatory cytokines and chemokines are often detected in brain tissue of patients with neurological diseases such as multiple sclerosis (MS), HIV-associated dementia (HAD) and Alzheimer's disease (AD) [6].
• Previous studies have described altered expression of metallothioneins (MTs) in neurodegenerative diseases like multiple sclerosis (MS), Down syndrome, and Alzheimer's disease (AD) [7].
• Aim: to identify and compare the needs for supportive care/palliative care services of people in Australia with Motor Neurone Disease (MND), Multiple Sclerosis (MS), Huntington's Disease (HD) and Parkinson's Disease (PD) and the needs of their carers [8].
• Control groups included HIV-1 negative patients with degenerative and/or vascular dementia, chronic multiple sclerosis (MS) and individuals without any sign of neurological or cognitive disturbances [9].

High impact information on MS

• It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future [10].
• Both HLA and TCR genes have been linked to susceptibility for MS which is widely believed to be mediated by T cells that recognize an as yet unidentified autoantigen [11].
• The major human demyelinating disease affecting the central nervous system is multiple sclerosis (MS) [11].
• Because of the advances in the understanding and treatment of EAE, recent research in MS has been focused on the characterization of cellular immune responses against myelin components [11].
• Overall, we observed no evidence of genetic association between the PTPRC polymorphism and MS susceptibility or disease course [12].

Chemical compound and disease context of MS

• OBJECTIVE: Potassium (K(+)) channels on immune cells have gained attention recently as promising targets of therapy for immune-mediated neurological diseases such as multiple sclerosis (MS) [13].
• Mitoxantrone (MX) has demonstrated efficacy in multiple sclerosis (MS), but its immunologic mechanisms of action are poorly understood [14].
• We have previously reported increased anti-CD3-induced IL-4 secretion by T cells in progressive MS patients treated with cyclophosphamide plus methylprednisolone (CY/MP) which was associated with eosinophilia [15].
• Reduction in cationicity of MBP, especially due to conversion of positively charged arginine residues to uncharged citrulline (Cit), has been found to be associated with multiple sclerosis (MS) [16].
• Recently we have shown that DNase, RNase, and polysaccharide-hydrolyzing activities are associated with IgGs from the sera of patients with multiple sclerosis (MS) [17].

Biological context of MS

• Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined, except for major histocompatibility (MHC) genes [2].
• In the association analysis, the allele frequencies between MS patients and controls differed significantly, p = 0.000049), the difference being attributable mainly to a higher frequency of a 1.27 kb allele among patients [18].
• This establishes molecular mimicry between a common viral pathogen, such as this human coronavirus, and myelin as a possible immunopathological mechanism in MS and is consistent with the possible involvement of more than one infectious pathogen as an environmental trigger of disease [19].
• Multiple sclerosis (MS) is a common and severe neurological disorder associated with an autoimmune response directed against myelin components within the CNS [20].
• The common marmoset Callithrix jacchus (C. jacchus) is an outbred species characterized by a naturally occurring bone marrow chimerism and susceptibility to a form of experimental autoimmune encephalomyelitis (EAE) resembling multiple sclerosis (MS) [21].

Anatomical context of MS

• Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells [2].
• Although an autoimmune pathogenesis has been suggested, there are no conclusive data on the number of T cells autoreactive with myelin antigens in MS compared to controls [22].
• Circulating lymphocyte populations were examined in 85 patients with multiple sclerosis (MS), 26 of whom showed exacerbations; 48 patients with other neurological diseases (OND); 14 patients suffering from psychiatric disorders; and 2 normal subjects [23].
• We examined K(+) channels on dendritic cells (DCs), which infiltrate the brain in MS and may impact disease course [13].
• Several studies have shown that demyelination in MS is caused by proinflammatory mediators which are released by perivascular infiltrates and/or activated glial cells [24].

Associations of MS with chemical compounds

• In this study, the fine specificity of 29 CD4+ cytotoxic, long term, and limiting dilution TCL that had been generated against whole MBP and were derived from four MS patients and two healthy relatives was dissected using truncated and alanine-substituted peptides for the 87-106 peptide [25].
• Immunological studies of mitoxantrone in primary progressive MS [14].
• Administration of cytokines, including IFN-beta and Copaxone, may be important in stem cell transplantation therapies and perhaps important in the efficacy of existing MS therapies [26].
• The mechanisms by which urinary p-cresol sulfate, possibly derived from tyrosine-SO(4), reflects progressive worsening that is disabling in MS are unknown [27].
• Isolated cells were cultured unstimulated or stimulated with phytohemagglutinin A (PHA), lipopolysaccharide (LPS) and myelin basic protein (MBP)--a hypothetical autoantigen for MS [28].

Physical interactions of MS

• This electron microscopical study has identified that, in vitro, the less cationic Marburg MBP isomer forms a more extended protein-lipid complex than MBP from healthy or chronic MS-afflicted individuals [29].
• We observed a statistically significant increase in the CC genotype of IL-10 -819 and -592 SNPs coupled with a decreased frequency of the TGF-beta +915 CG genotype in our MS patients (Pc<0.05) [30].
• In the present work, paralleling a previous one on T-cell TNF-alpha binding, we studied the effect of interferon (IFN)-beta-1b treatment on T-lymphocyte IL-6 binding in patients with relapsing-remitting MS [31].
• The aim of the present study was to evaluate IFN-gamma binding on peripheral blood T-lymphocytes from MS patients, compared with those from healthy subjects [32].
• In direct contrast to ferritin binding, transferrin binding in the MS tissue is present in the white matter tracts, but only in the periplaque region [33].

Enzymatic interactions of MS

• In contrast to homogeneous IgGs of healthy individuals, Abs of MS patients effectively hydrolyzed human myelin basic protein (MBP) [34].
• Cerebrospinal fluid samples from controls and patients with multiple sclerosis (MS) were split and sent to laboratories with different experiences for the detection of Chlamydia pneumoniae by polymerase chain reaction [35].

Co-localisations of MS

• Native LDL, epitopes of MDA-LDL, peptides of myelin basic protein and neutral lipid oil red O (ORO) staining were found to be co-localized within foamy macrophages in early and actively demyelinating MS plaques [36].
• High level expression of CD1b in MS lesions was found to colocalize with the presence of GM-CSF in astrocytes [37].

Regulatory relationships of MS

• Neither OKT3-stimulated T cells of healthy donors nor myelin basic protein (MBP)-specific T cells of patients with multiple sclerosis (MS) were suppressed by autologous IDO DCs [38].
• Overall, 29% of T-cell lines from MS patients (10 donors) but only 1.3% of T-cell lines from normal control subjects (2 donors) showed an HLA-DR-restricted cross-reactive pattern of antigen activation after in vitro selection with either myelin basic protein or human coronavirus strain 229E antigens [19].
• Lymphotoxin-alpha (LT-alpha) and tumour necrosis factor-alpha (TNF-alpha) promote inflammation in autoimmune diseases and have been detected in the multiple sclerosis (MS) brain lesions and blood, suggesting these cytokines are also present in the cerebrospinal fluid (CSF) [39].
• These results suggest that TNF-alpha but not LT is overproduced by PBMC during MS relapse [28].
• Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner [40].

Other interactions of MS

• The variable (V) region of the T cell receptor (TCR) beta chain was examined among 83 T cell lines from both MS patients and healthy subjects that were reactive with the immunodominant region of human MBP (residues 84 to 102) or with a second immunodominant region of MBP (143 to 168) [4].
• CD4 and HLA-DRalpha transcripts were dramatically increased in MS as compared with controls [20].
• Nevertheless, brief amino acid motifs are shared among marmoset clones and CDR3 sequences from MS samples [21].
• In the same population, serum antibody responses to recombinant myelin oligodendrocyte glycoprotein were comparable in MS patients and HD [41].
• In active MS lesions, CXCL12 levels were high on astrocytes throughout lesion areas and on some monocytes/macrophages within vessels and perivascular cuffs, with lesser staining on EC [42].

Analytical, diagnostic and therapeutic context of MS

• Such TCR structures may be used as targets for specific immunotherapy in MS [4].
• Here we performed transcriptional profiling of 56 relevant genes in brain specimens from eight MS patients and eight normal controls by kinetic RT-PCR [20].
• Isolated myelin from the brains of controls and patients with MS were incubated with purified Igs eluted from the brains of patients with MS or controls and degradation of MBP was assessed by quantitative electroimmunoblotting [43].
• These findings may have important implications for understanding the pathogenesis of MS and how irradiation of potentially pathogenic T cells produces a reagent with possible therapeutic effects in T-cell vaccination (TCV) [44].
• Based on elegant experiments in an animal model of MS, experimental allergic encephalomyelitis (EAE), a number of myelin proteins and peptides derived from these can induce inflammatory demyelinating lesions [45].

References