Clinical Viral Infections and Multiple Sclerosis

Sibley, W. A.; Bamford, Colin R.; Clark, Katherine

doi:10.1016/s0140-6736(85)92801-6

Cited by 538 publications

(323 citation statements)

References 8 publications

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“…Based on these findings we posed the hypothesis that APC-activating agents could disrupt endogenous immunoregulatory processes, thereby allowing tolerized autoreactive T cells to regain their biological functions and mediate autoimmune disease. This concept is intriguing in light of the fact that autoimmune diseases such as MS are more likely to relapse in the setting of infectious illness, which is typically associated with APC activation (22)(23)(24)(25)(26)(27)(28). According to our theory, APCs that bear autoantigenic peptides (or molecular mimics) and are activated by "danger signals" in the course of an infection could mediate the conversion of bystander autoreactive T cells from a tolerized into an effector phenotype.…”

Section: Activation Of Apcsmentioning

confidence: 99%

Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

Ichikawa

Williams

Segal

2002

The Journal of Immunology

131

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Some autoreactive T cells normally escape thymic selection and persist in the periphery. This is true of myelin-reactive CD4+ T cells, the effectors of experimental autoimmune encephalomyelitis (EAE) in laboratory animals and the presumed mediators of multiple sclerosis in humans. Nonetheless, most individuals do not succumb to autoimmune disease. There is growing evidence that while peripheral APCs stimulate immune responses against foreign Ags in the setting of tissue destruction and “danger,” they actually maintain tolerance against self Ags under steady state conditions. We hypothesized that tolerance against candidate autoantigens could be reversed by activation of APCs via CD40 or Toll-like receptor 9 signaling. Adult SJL mice injected i.p. with a peptide fragment of proteolipid protein (a candidate autoantigen in multiple sclerosis) emulsified in IFA fail to mount lymphoproliferative or cytokine responses and are protected from EAE upon subsequent challenge with the Ag combined with adjuvants. Here we report that tolerized proteolipid protein-specific lymph node cells regain the ability to divide, differentiate along a Th1 lineage, and transfer EAE when reactivated in the presence of agonistic Abs against CD40 or CpG oligonucleotides. The effects of both anti-CD40 and CpG oligonucleotides are dependent upon induction of IL-12. Our findings suggest two mechanisms to explain the well-documented association between infectious illnesses and flare-ups of multiple sclerosis. Microbial pathogens could 1) release molecules that bind Toll-like receptors, and/or 2) stimulate microbe-specific T cells to express CD40 ligand, thereby licensing APCs that bear both microbial and autoantigens to break tolerance.

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Section: Activation Of Apcsmentioning

confidence: 99%

Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

Ichikawa

Williams

Segal

2002

The Journal of Immunology

131

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“…3,4 Emerging evidence suggests that MS patients exposed to infections have a significantly greater risk of relapse. 3,4 Clinically, it has been shown that a significant number of MS relapses are preceded by a viral infection 5 or bacterial infection. 6,7 However, no simple relationship between these processes has emerged.…”

Section: Introductionmentioning

confidence: 99%

Magnetic Resonance Imaging Reveals Therapeutic Effects of Interferon-Beta on Cytokine-Induced Reactivation of Rat Model of Multiple Sclerosis

Serres

Bristow

Pablos

et al. 2013

J Cereb Blood Flow Metab

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Interferon-b (IFN-b) drugs are considered to derive their beneficial effects on multiple sclerosis (MS) progression via their antiinflammatory properties, but the precise mechanism of action remains unclear. Here, we sought to discover how IFN-b impacts on inflammation-associated aggravation of MS-like lesions in rat. Animals with dormant focal experimental allergic encephalomyelitis (EAE) lesions were challenged intravenously with a replication-deficient adenovirus vector carrying interleukin (IL)-1b cDNA (AdIL-1b). Aggravation of inflammation and demyelination within the focal EAE lesion was observed after AdIL-1b injection with associated changes in tissue structure detected by diffusion and magnetization transfer imaging. Postgadolinium-DTPA T 1 -weighted images revealed contrast enhancement in the ipsilateral meninges, indicating breakdown of the blood-cerebrospinal fluid barrier, and increased left/right regional cerebral blood volume ratio was also observed after AdIL-1b injection. To determine the role of IFN-b on reactivation of the EAE lesion, rats were treated with therapeutic doses of IFN-b and focal EAE lesions showed significantly reduced reactivation in response to systemic AdIL-1b injection. In conclusion, these findings indicate a central role for peripheral IL-1b expression in the mechanism of MS lesion reactivation and that the therapeutic effects of IFN-b may, at least in part, reflect suppression of the effects of peripheral inflammation on MS lesion pathogenesis.

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“…However, there is growing evidence that there may be a link between infection and relapse (Buljevac et al, 2002). A number of studies have shown that approximately one-third of MS relapses are preceded by a viral infection (Sibley et al, 1985;Andersen et al, 1993;Panitch, 1994;Edwards et al, 1998;Buljevac et al, 2002). Relapse in individuals with MS has also been associated with bacterial infections, such as those of the urinary tract, which appear to trigger relapse in as many as 30% of MS patients (Rapp et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Systemic Inflammatory Response Reactivates Immune-Mediated Lesions in Rat Brain

Serres¹,

Anthony²,

Jiang³

et al. 2009

J. Neurosci.

107

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The potential association between microbial infection and reactivation of a multiple sclerosis (MS) lesion is an important issue that remains unresolved, primarily because of the absence of suitable animal models and imaging techniques. Here, we have evaluated this question in an empirical manner using immunohistochemistry and magnetic resonance imaging (MRI), before and after the induction of a systemic inflammatory response in two distinct models of MS. In a pattern-II-type focal myelin oligodendrocyte glycoproteinexperimental autoimmune encephalomyelitis model, systemic endotoxin injection caused an increase in regional cerebral blood volume (rCBV) around the lesion site after 6 h, together with a reduction in the magnetization transfer ratio of the lesioned corpus callosum. These changes were followed by an increase in the diffusion of tissue water within the lesion 24 h after endotoxin challenge and new leukocyte recruitment as revealed both immunohistochemically and by MRI tracking of ultrasmall superparamagnetic iron oxidelabeled macrophages. Importantly, we detected in vivo expression of E-and P-selectin in quiescent lesions by MRI-detectable glyconanoparticles conjugated to sialyl Lewis X . This finding may explain, at least in part, the ability of quiescent MS lesions to rapidly reinitiate the cell recruitment processes. In a pattern-I-type delayed-type hypersensitivity response model, a similar effect of endotoxin challenge on rCBV was observed, together with delayed breakdown of the blood-brain barrier, showing that systemic infection can alter the pathogenesis of MS-like lesions regardless of lesion etiology. These findings will have important implications for the management and monitoring of individuals with MS.

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Clinical Viral Infections and Multiple Sclerosis

Cited by 538 publications

References 8 publications

Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

Magnetic Resonance Imaging Reveals Therapeutic Effects of Interferon-Beta on Cytokine-Induced Reactivation of Rat Model of Multiple Sclerosis

Systemic Inflammatory Response Reactivates Immune-Mediated Lesions in Rat Brain

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