Insights into the aetiology and pathogenesis of multiple sclerosis

Ewing, Christine; Bernard, Carole

doi:10.1046/j.1440-1711.1998.00718.x

Cited by 82 publications

(48 citation statements)

References 92 publications

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“…1 Patients have detectable lesions and the perivascular cells at the sites of active demyelination consist predominantly of macrophages expressing class II molecules, some B cells, and activated CD4 + T cells secreting various cytokines. 2 Conventional therapies for MS have focused on general suppression of the inflammatory response, particularly the administration of steroids, IFN-β and glatiramer acetate.…”

Section: Introductionmentioning

confidence: 99%

TNF‐related apoptosis‐inducing ligand (TRAIL)/Apo2L suppresses experimental autoimmune encephalomyelitis in mice

et al. 2005

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SummaryStudies have suggested that endogenous TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L may suppress the induction of some autoimmune diseases in mice. Here, we show that TRAIL/Apo2L suppresses autoimmune damage in relapsing-remitting, and non-remitting models of experimental autoimmune encephalomyelitis (EAE). TRAIL/Apo2L-deficient mice and wild-type mice treated with neutralizing anti-TRAIL/Apo2L antibody displayed enhanced clinical score, increased T-cell proliferative responses to myelin oligodendrocyte glycoprotein (MOG), and increased numbers of inflammatory lesions in the spinal cord and central nervous system. TRAIL neutralization immediately before disease onset was most effective at exacerbating disease score. More importantly, therapeutic intervention with recombinant soluble TRAIL/Apo2L delayed the onset and reduced the severity of MOG-induced EAE. These data are the first to illustrate the potential therapeutic value of recombinant TRAIL/Apo2L in suppressing T-cell-mediated autoimmune diseases.

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Section: Introductionmentioning

confidence: 99%

TNF‐related apoptosis‐inducing ligand (TRAIL)/Apo2L suppresses experimental autoimmune encephalomyelitis in mice

et al. 2005

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“…1 However, the mechanisms underlying this pathology are still poorly understood. A multifactorial aetiology for MS has been suggested by epidemiological studies, implicating a complex interplay between genetic and environmental factors.…”

Section: Introductionmentioning

confidence: 99%

An investigation of NOS2A promoter polymorphisms in Australian multiple sclerosis patients

et al. 2005

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As with other major autoimmune diseases, susceptibility to multiple sclerosis (MS) is believed to result from the complex interaction of a number of genes, each with modest effect. Extensive research of experimental autoimmune encephalomyelitis in mice and several direct MS studies have implicated NOS2A, which encodes the inducible form of nitric oxide synthase, and the genetic region encoding NOS2A, 17q11.2, has been identified in a number of genome wide screens as being potentially associated with MS. We investigated four single nucleotide polymorphisms in the proximal promoter region of NOS2A, in a case -control group of 100 Australian MS patients and 100 controls and in 203 MS patients and their unaffected parents. We found a trend toward excess transmission of the À277A allele (tag for the AGCC haplotype) to HLA-DRB1*1501-positive MS patients (P (uncorrected) ¼ 0.05). We initially discovered a trend toward over-representation of the AGCC haplotype in HLA-DRB1*1501-positive compared to HLA-DRB1*1501-negative MS patients in the case-control cohort. However, when combined with the probands from the transmission disequilibrium analysis, this trend was nullified. Nonetheless, despite the lack of significant evidence of association for the NOS2A promoter polymorphisms with MS, the gene remains an interesting candidate for MS susceptibility, particularly with regard to the HLA-DRB1*1501 haplotype.

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“…It is conceivable that exposure to various agents (such as bacteria and viruses) is one of the instrumental causes in modulating the incidence, severity, or even the type of autoimmune process acquired by an individual (45)(46)(47)(48)(49)(50)(51). Likewise, this type of adventitious microbial stimulation occurring throughout the life of an individual could play an important role in establishing expanded repertoires of pathogenic/regulatory memory T cells (52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

Environmental Modulation of Autoimmune Arthritis Involves the Spontaneous Microbial Induction of T Cell Responses to Regulatory Determinants Within Heat Shock Protein 65

Moudgil

Kim

Yun³

et al. 2001

The Journal of Immunology

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Both genetic and environmental factors are believed to be involved in the induction of autoimmune diseases. Adjuvant arthritis (AA) is inducible in susceptible rat strains by injection of Mycobacterium tuberculosis, and arthritic rats raise T cell responses to the 65-kDa mycobacterial heat-shock protein (Bhsp65). We observed that Fischer 344 (F344) rats raised in a barrier facility (BF-F344) are susceptible to AA, whereas F344 rats maintained in a conventional facility (CV-F344) show significantly reduced incidence and severity of AA, despite responding well to the arthritogenic determinant within Bhsp65. The acquisition of protection from AA can be circumvented if rats are maintained on neomycin/acidified water. Strikingly, naive unimmunized CV-F344 rats but not BF-F344 rats raised T cell responses to Bhsp65 C-terminal determinants (BCTD) (we have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat); however, T cells of naive CV-F344 and BF-F344 gave a comparable level of proliferative response to a mitogen, but no response at all to an irrelevant Ag. Furthermore, adoptive transfer into naive BF-F344 rats of splenic cells of naive CV-F344 rats (restimulated with BCTD in vitro) before induction of AA resulted in a considerably reduced severity of AA. These results suggest that spontaneous (inadvertent) priming of BCTD-reactive T cells, owing to determinant mimicry between Bhsp65 and its homologues in microbial agents in the conventional environment, is involved in modulating the severity of AA in CV-F344 rats. These results have important implications in broadening understanding of the host-microbe interaction in human autoimmune diseases.

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Insights into the aetiology and pathogenesis of multiple sclerosis

Cited by 82 publications

References 92 publications

TNF‐related apoptosis‐inducing ligand (TRAIL)/Apo2L suppresses experimental autoimmune encephalomyelitis in mice

TNF‐related apoptosis‐inducing ligand (TRAIL)/Apo2L suppresses experimental autoimmune encephalomyelitis in mice

An investigation of NOS2A promoter polymorphisms in Australian multiple sclerosis patients

Environmental Modulation of Autoimmune Arthritis Involves the Spontaneous Microbial Induction of T Cell Responses to Regulatory Determinants Within Heat Shock Protein 65

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