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[1] A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model.

Arima Y, Kamimura D, Atsumi T et al.

Hokkaido University, Sapporo, Japan.

  Elife 2015;4:e08733.

[2] Role of T cell–glial cell interactions in creating and amplifying central nervous system inflammation and multiple sclerosis disease symptoms.

Huseby ES, Kamimura D, Arima Y et al.

University of Massachusetts Medical School, Worcester, MA, USA.

 Front Cell Neurosci 2015;9:295.

Cris Constantinescu’s review: The immune system-related pathogenesis of multiple sclerosis (MS) is incompletely understood, but many advances in the understanding of this complex disease have been made viaappropriate analogies with the animal model, experimental autoimmune encephalomyelitis (EAE). While it is recognized that both of these diseases are primarily mediated by CD4+ T helper type (Th) cells, many of which have the Th17 phenotype that produces interleukin-17 (IL-17) and its associated cytokines, the mechanisms that lead to relapses in MS are not well understood. Moreover, although many patients with MS experience neuropathic pain, the relationship between pain signaling activation and relapse activity is unclear.

The first of these two publications concerns a sophisticated study of the EAE model, in which Arima and colleagues showed that pain-mediated signals can exacerbate EAE [1]. Following an intricate series of experiments, they propose four steps for this process. The initial step is pain-induced sensory nerve activation, which was prevented in the study by blocking specific sensory neurons via inhibition of the voltage-gated sodium channel Xa subunit (SCNIOA, also called Nav1.8) or the transient receptor potential cation channel V1 (TRPV1). The next step is sympathetic nerve activation and upregulation of chemokine (C-X3-C) ligand 1 (CX3CL1) followed by accumulation of major histocompatibility complex (MHC) class II-positive, CD11b-positive cells in the fifth lumbar cord ventral blood vessels. Sympathetic nerve blockade suppressed this step and the authors showed that this was not a response to general stress but was specifically caused by pain-mediated noradrenergic activation. The third step is accumulation of pathogenic T cells (e.g. CD4+ T cells in this study) and continuing local antigen presentation; this was blocked via local interference of antigen presentation and T cell activation. In the fourth step, CD4+ T cells produce proinflammatory cytokines, such as IL-17 or IL-6, or chemokine (CC motif) ligand 20 (CCL20), leading to relapse and tissue damage that were prevented by antibodies against these cytokines.

In short, the authors propose a novel and interesting mechanism linking pain pathway activation with neuroinflammatory disease relapse. The extent to which this mechanism can be extrapolated to neuropathic pain and relapses in MS remains to be determined, but the work provides a rationale for further investigation of this link.

The second publication is by the same group of investigators and consists of an interesting review of T cell-mediated pathogenesis in MS and a commentary on the inflammation amplifier concept in the development of MS lesions [2]. The review focuses on the role of T cells, which are indisputably the pivotal cell type mediating the pathology of MS. In the EAE model, myelin-reactive activated T cells are necessary and sufficient to induce disease that resembles clinical MS. The authors review the evidence for this and discuss how the transfer of CD4+ T cells that react against different myelin antigens results in differential localization of lesions and, thus, different clinical disease phenotypes.

Unlike other reviews of MS pathogenesis, the role of CD8+ T cells is discussed in detail. This cell type is, in fact, the predominant T cell type found in MS lesions and the evidence suggests that there are not only a pathogenic role for myelin- reactive CD8+ T cells in EAE but also a protective role, indicating that there is effector and regulatory roles for the CD8+ as well as for the CD4+ subtype. The authors discuss how certain CD8+ T cells may react against antigens present in cell types other than oligodendrocytes (the myelin-producing cells); in particular, glial fibrillary acidic protein (GFAP)-reactive T cells. After establishing the peptide specificity of the GFAP-reactive CD8+ cells in the context of MHC class I, the authors describe their own work in generating transgenic mice expressing a GFAP peptide-specific dominant CD8+ clone. Overall, 50% of mice harboring this clone developed spontaneous central nervous system autoimmunity, which was more prominent in recombination activating gene 1 (Rag1)-knockout or B cell-deficientmice. This suggests that autoreactive CD8+ T cells are subject to regulatory mechanisms that may be, at least in part, B cell-dependent. The authors propose a model whereby myelin-reactive T cells cooperate with glial cell-reactive T cells and contribute to an inflammation amplifier – simultaneous activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription factor 1 (STAT1) transcription factors.This is an interesting review of an important, albeit less frequently studied, mechanism of disease in MS that may explain the genesis of inflammatory lesions, particularly those found in gray matter and in astrocyte-abundant areas.


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