Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Saxena, Amit; Martin‐Blondel, Guillaume; Mars, Lennart T.; Liblau, Roland

doi:10.1016/j.febslet.2011.08.047

Cited by 64 publications

(39 citation statements)

References 101 publications

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“…Although many studies have focused on the role of CD4 + cell populations in EAE and MS, CD8 + cells are also important (Saxena et al, 2011). Antigen-specific CD8 + cells infiltrate the CNS, causing inflammatory lesions in the optic nerve, brain and spinal cord, with focal loss of oligodendrocytes and axonal damage (Saxena et al, 2011). In our experiments we found a twofold reduction in CNS CD8 + cells from infected EAE mice compared to the Broth/EAE group.…”

Section: Discussionsupporting

confidence: 60%

“…We anticipate that these dramatic changes in the immune cell populations are responsible for the difference in EAE clinical scores. Although many studies have focused on the role of CD4 + cell populations in EAE and MS, CD8 + cells are also important (Saxena et al, 2011). Antigen-specific CD8 + cells infiltrate the CNS, causing inflammatory lesions in the optic nerve, brain and spinal cord, with focal loss of oligodendrocytes and axonal damage (Saxena et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis

Gran

Crooks

Cook³

et al. 2015

Journal of the Neurological Sciences

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Recent research has demonstrated that infection with the bacterial pathogen Helicobacter pylori is less common amongst patients with multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). We aimed to compare the prevalence of H. pylori amongst MS patients and healthy controls, and also investigated the impact of this infection on an animal model for MS, experimental autoimmune encephalomyelitis (EAE). The H. pylori status of 71 MS patients and 42 healthy controls was determined by serology. Groups of C57BL/6 mice were infected with H. pylori, or given diluent alone as a placebo, prior to inducing EAE. Clinical scores were assessed for all mice, and spleens and spinal cord tissue were harvested. CD4 + T cell subsets were quantified by flow cytometry, and T cell proliferation assays were performed. In MS patients the seroprevalence of H. pylori was half that of healthy controls (p = 0.018). Over three independent experiments, prior H. pylori infection had a moderate effect in reducing the severity of EAE (p = 0.012). In line with this, the antigen-specific T cell proliferative responses of infected animals were significantly reduced (p = 0.001), and there was a fourfold reduction in the number of CD4 + cells in the CNS. CD4 + populations in both the CNS and the spleens of infected mice also contained greatly reduced proportions of IFNγ + , IL-17 + ,T-bet + , and RORγt + cells, but the proportions of Foxp3 + cells were equivalent.There were no differences in the frequency of splenic CD4 + cells expressing markers of apoptosis between infected and uninfected animals. H. pylori was less prevalent amongst MS patients. In mice, the infection exerted some protection against EAE, inhibiting both Th1 and Th17 responses. This could not be explained by the presence of increased numbers of Foxp3 + regulatory T cells, or T cell apoptosis. This is the first direct experimental evidence showing that H. pylori may provide protection against inflammatory demyelination in the CNS.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis

Gran

Crooks

Cook³

et al. 2015

Journal of the Neurological Sciences

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“…However, because the administration of IFN-g worsened MS in a previous clinical trial (13), the role of Th1 cells in MS needs to be analyzed further. In addition, increasing evidence suggest a pathogenic role for cytotoxic effector T cells in MS (14,15). Moreover, a recent clinical trial of anti-IL12p40 Ab to block IL-12/IL-23 signaling failed to modulate MS (16), making it difficult to portray a complete picture of MS (9).…”

Section: Ultiple Sclerosis (Ms) Is An Inflammatory Demyelinating DImentioning

confidence: 99%

CCR2+CCR5+ T Cells Produce Matrix Metalloproteinase-9 and Osteopontin in the Pathogenesis of Multiple Sclerosis

Sato

Tomita

Ichikawa

et al. 2012

The Journal of Immunology

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Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4+ autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS. In this article, we report that CCR2+CCR5+ T cells constitute a unique population selectively enriched in the cerebrospinal fluid of MS patients during relapse but not in patients with other neurologic diseases. After polyclonal stimulation, the CCR2+CCR5+ T cells exhibited a distinct ability to produce matrix metalloproteinase-9 and osteopontin, which are involved in the CNS pathology of MS. Furthermore, after TCR stimulation, the CCR2+CCR5+ T cells showed a higher invasive potential across an in vitro blood–brain barrier model compared with other T cells. Of note, the CCR2+CCR5+ T cells from MS patients in relapse are reactive to myelin basic protein, as assessed by production of IFN-γ. We also demonstrated that the CCR6−, but not the CCR6+, population within CCR2+CCR5+ T cells was highly enriched in the cerebrospinal fluid during MS relapse (p < 0.0005) and expressed higher levels of IFN-γ and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2+CCR5+CCR6− Th1 cells play a crucial role in the pathogenesis of MS.

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“…Interestingly, ... a significant up-regulation of natural killer receptor protein la/CD 161 as well as increased numbers of CD 161high CD8 T cells is seen in the peripheral blood of MS patients (25), and CD8+ T cells , and in particular CD8+ CD 161+ cells can express IL-22 and play an important role in the pathogenesis of autoimmunity (26). As all circulating Tc 17 cells are contained within the CD 161high subset, it is tempting to speculate that Tc do play a pathogenic role in MS (27) possibly togeth er with other cells, including neutrophils (28). IL-6-expressing monocyte/ma crophages (MM) were significantly augmented as well in all patients.…”

Section: Hementioning

confidence: 99%

TH17-Driven Inflammation is Present in All Clinical Forms of Multiple Sclerosis; Disease Quiescence is Associated with Gata3-Expressing Cells

et al. 2013

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Multiple Sclerosis (MS) presents in a variety of clinical forms associated with a diverse grade of neurological impairment, different prognosis and, possibly, multiple pathogenic mechanisms. Thus, whereas relapsing-remitting (RR) MS appears to be largely driven by inflammatory processes, neurodegeneration, partially independent from inflammation, drives primary progressive (PP) and secondary progressive (SP) MS. An extensive analysis of neuroinflammation in the different forms of MS was performed by evaluating immunophenotypic and functional parameters in MBP-stimulated T lymphocytes of 103 MS patients (26 benign (BE) MS, 30 RRMS, 33 SPMS and 14 PPMS) and 40 healthy controls (HC). Results showed that: i) IL-17-producing and RORC/yt-expressing CD4+ T cells (THI7 lymphocytes), as well as IL-6 expressing CDI4+ cell were augmented in all patients; ii) IL-22-expressing cells were increased in all forms of MS with the exception of PPMS; iii) TGF-p-expressing B cells were increased only in RRMS; and iv) GATA3-, NFATc-l, IL-13-, and IL-25-expressing cells (TH2 lymphocytes) were augmented in RRMS and BEMS patients alone. Data herein indicate a pivotal pathogenic role of THl7-driven inflammation in all clinical forms of MS and suggest that control over disease (RRMS and BEMS) is associated not with lack of inflammation per se, but rather with the activation of immune-mediated anti-inflammatory mechanisms. These results could help the design of novel diagnostic and therapeutic approaches.Multiple sclerosis (MS), a demyelinating autoimmune disease ofthe central nervous system, is triggered by molecular mimicry with cross-reacting and yet undefined epitopes and is associated with the activation of CD4+ TH I and TH I7 lymphocytes, CD8+ T lymphocytes, and B lymphocytes, as well as myeloid dendritic cells. The activation of these cells drives the neuroinflammation that plays an important role in damaging the myelin sheath (I, 2).The most common clinical phenotype ofMS is the relapsing-remitting (RR) form, which is characterized by an acute onset of symptoms and signs suggestive of neurological dysfunction, followed by complete or partial recovery. The long-term prognosis of RRMS is usually unfavorable, since patients enter the so-called secondary progressive (SP) phase of

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Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Cited by 64 publications

References 101 publications

Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis

Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis

CCR2+CCR5+ T Cells Produce Matrix Metalloproteinase-9 and Osteopontin in the Pathogenesis of Multiple Sclerosis

TH17-Driven Inflammation is Present in All Clinical Forms of Multiple Sclerosis; Disease Quiescence is Associated with Gata3-Expressing Cells

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