The good and the bad of neuroinflammation in multiple sclerosis

Naegele, Matthias; Martin, Roland

doi:10.1016/b978-0-444-52001-2.00003-0

Cited by 64 publications

(41 citation statements)

References 311 publications

(395 reference statements)

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“…While the involvement of different CD4+ subtypes (Th1, Th17, and Th9) is one of the very initial events in MS (31), the main lymphocytes to be found in the lesions are CD8+ cells and correlate with the degree of axonal damage (32). sCD27, a marker of intrathecal inflammation secreted mainly by T cells, is elevated in PPMS (33).…”

Section: Pathological Changesmentioning

confidence: 99%

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

2017

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The focus of multiple sclerosis research has recently turned to the relatively rare and clearly more challenging condition of primary progressive multiple sclerosis (PPMS). Many risk factors such as genetic susceptibility, age, and Epstein–Barr virus (EBV) infection may interdepend on various levels, causing a complex pathophysiological cascade. Variable pathological mechanisms drive disease progression, including inflammation-associated axonal loss, continuous activation of central nervous system resident cells, such as astrocytes and microglia as well as mitochondrial dysfunction and iron accumulation. Histological studies revealed diffuse infiltration of the gray and white matter as well as of the meninges with inflammatory cells such as B-, T-, natural killer, and plasma cells. While numerous anti-inflammatory agents effective in relapsing remitting multiple sclerosis basically failed in treatment of PPMS, the B-cell-depleting monoclonal antibody ocrelizumab recently broke the dogma that PPMS cannot be treated by an anti-inflammatory approach by demonstrating efficacy in a phase 3 PPMS trial. Other treatments aiming at enhancing remyelination (MD1003) as well as EBV-directed treatment strategies may be promising agents on the horizon. In this article, we aim to summarize new advances in the understanding of risk factors, pathophysiology, and treatment of PPMS. Moreover, we introduce a novel concept to understand the nature of the disease and possible treatment strategies in the near future.

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Section: Pathological Changesmentioning

confidence: 99%

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

2017

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“…It is believed that an imbalance in glutamate homeostasis together with oxidative stress contributes to neurodegeneration [3–6]. In addition, neuroinflammation is undeniably involved in the pathogenesis of chronic neurodegeneration in MS [7]. …”

Section: Introductionmentioning

confidence: 99%

Absence of system xc − on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Merckx

Albertini

Paterka

et al. 2017

J Neuroinflammation

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BackgroundMultiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System xc − or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration.MethodsSemi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system xc −, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT−/−) mice and irradiated mice reconstituted in xCT−/− bone marrow (BM), to their proper wild type (xCT+/+) controls.ResultsxCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT+/+ mice, xCT−/− mice were equally susceptible to EAE, whereas mice transplanted with xCT−/− BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected.ConclusionsOur findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system xc − on immune cells invading the CNS participates to EAE. Since a total loss of system xc − had no net beneficial effects, these results have important implications for targeting system xc − for treatment of MS.

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“…The role of T cells on the CNS is generally considered pathologic, however there are many beneficial effects exerted on the nervous system [3–5]. Specifically, the well-known autoimmune demyelinating disease, multiple sclerosis (MS) [6], is a prototypical abnormal T cell immune-induced CNS pathology, however, CD4 + FoxP3 + regulatory T cells (Tregs) can be exploited to exert ameliorative effects in neuro-degenerative diseases, such as cerebral ischemia [7], Alzheimer's disease (AD) [8], and Parkinson's disease (PD) [9]. The CNS itself can also, in turn, induce changes in the immune system via the neuro-endocrine-immune network [10–13].…”

Section: Introductionmentioning

confidence: 99%

Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging

Coder

Wang

et al. 2016

Oncotarget

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The interaction between T cells and the central nervous system (CNS) in homeostasis and injury has been recognized being both pathogenic (CD4+ T-helper 1 - Th1, Th17 and γδT) and ameliorative (Th2 and regulatory T cells - Tregs). However, in-depth studies aimed to elucidate the precise in the aged microenvironment and the dichotomous role of Tregs have just begun and many aspects remain unclear. This is due, not only to a mutual dependency and reciprocal causation of alterations and diseases between the nervous and T cell immune systems, but also to an inconsistent aging of the two systems, which dynamically changes with CNS injury/recovery and/or aging process. Cellular immune system aging, particularly immunosenescence and T cell aging initiated by thymic involution - sources of chronic inflammation in the elderly (termed inflammaging), potentially induces an acceleration of brain aging and memory loss. In turn, aging of the brain via neuro-endocrine-immune network drives total body systemic aging, including that of the immune system. Therefore, immunotherapeutics including vaccination and “protective autoimmunity” provide promising means to rejuvenate neuro-inflammatory disorders and repair CNS acute injury and chronic neuro-degeneration. We review the current understanding and recent discoveries linking the aging immune system with CNS injury and neuro-degeneration. Additionally, we discuss potential recovery and rejuvenation strategies, focusing on targeting the aging T cell immune system in an effort to alleviate acute brain injury and chronic neuro-degeneration during aging, via the “thymus-inflammaging-neurodegeneration axis”.

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The good and the bad of neuroinflammation in multiple sclerosis

Cited by 64 publications

References 311 publications

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

Absence of system xc − on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging

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