For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or ...to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases. Moreover, it is now understood that the barriers of the brain are not uniform in their interactions with the circulating immune cells. The implications of these new findings to the basic understanding of CNS repair processes, brain aging, and a wide spectrum of CNS disorders, including acute injuries, Rett syndrome, Alzheimer's disease, and multiple sclerosis, will be discussed.
Multiple sclerosis is a complex and heterogeneous, most likely autoimmune, demyelinating disease of the central nervous system (CNS). Although a number of histological classification systems for CNS ...lesions have been used by different groups in recent years, no uniform classification exists. In this paper, we propose a simple and unifying classification of MS lesions incorporating many elements of earlier histological systems that aims to provide guidelines for neuropathologists and researchers studying MS lesions to allow for better comparison of different studies performed with MS tissue, and to aid in understanding the pathogenesis of the disease. Based on the presence/absence and distribution of macrophages/microglia (inflammatory activity) and the presence/absence of ongoing demyelination (demyelinating activity), we suggest differentiating between active, mixed active/inactive, and inactive lesions with or without ongoing demyelination. Active lesions are characterized by macrophages/microglia throughout the lesion area, whereas mixed active/inactive lesions have a hypocellular lesion center with macrophages/microglia limited to the lesion border. Inactive lesions are almost completely lacking macrophages/microglia. Active and mixed active/inactive lesions can be further subdivided into lesions with ongoing myelin destruction (demyelinating lesions) and lesions in which the destruction of myelin has ceased, but macrophages are still present (post-demyelinating lesions). This distinction is based on the presence or absence of myelin degradation products within the cytoplasm of macrophages/microglia. For this classification of MS lesions, identification of myelin with histological stains such as luxol fast blue-PAS or by immunohistochemistry using antibodies against myelin basic-protein (MBP) or proteolipid-protein (PLP), as well as, detection of macrophages/microglia by, e.g., anti-CD68 is sufficient. Active and demyelinating lesions may be further subdivided into the early and late demyelinating lesions. The former is defined by the presence in macrophages of major and small molecular weight myelin proteins, such as cyclic nucleotide diphosphoesterase (CNP), myelin oligodendrocyte glycoprotein (MOG), or myelin-associated protein (MAG), whereas macrophages in the latter demonstrate merely the presence of the major myelin proteins MBP or PLP. We discuss the histological features and staining techniques required to classify MS lesions, and, in addition, describe the histological hallmarks of cortical pathology and diffuse white matter changes, as well as of remyelination.
Multiple sclerosis (MS) affects approximately 1 million persons in the United States, and is the leading cause of neurological disability in young adults. The concept of precision medicine is now ...being applied to MS and has the promise of improved care. MS patients experience a variety of neurological symptoms, and disease severity ranges from mild to severe, and the biological underpinnings of these phenotypes are now starting to be elucidated. Precision medicine involves the classification of disease subtypes based on the underlying biology, rather than clinical phenotypes alone, and may govern disease course and treatment response. Over 18 disease-modifying drugs have been approved for the treatment of MS, and several biomarkers of treatment response are emerging. This article provides an overview of the concepts of precision medicine and emerging biological markers and their evolving role in decision-making in MS management.
The presence of the blood–brain barrier (BBB) restricts the movement of soluble mediators and leukocytes from the periphery to the central nervous system (CNS). Leukocyte entry into the CNS is ...nonetheless an early event in multiple sclerosis (MS), an inflammatory disorder of the CNS. Whether BBB dysfunction precedes immune cell infiltration or is the consequence of perivascular leukocyte accumulation remains enigmatic, but leukocyte migration modifies BBB permeability. Immune cells of MS subjects express inflammatory cytokines, reactive oxygen species (ROS) and enzymes that can facilitate their migration to the CNS by influencing BBB function, either directly or indirectly. In this review, we describe how immune cells from the peripheral blood overcome the BBB and promote CNS inflammation in MS through BBB disruption.
The delicate microenvironment of the central nervous system (CNS) is protected by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCB). These barriers function in distinct ...CNS compartments and their anatomical basis lay on the junctional proteins present in endothelial cells for the BBB and in the choroidal epithelium for the BCB. During neuroinflammatory conditions like multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE), activation or damage of the various cellular components of these barriers facilitate leukocyte infiltration leading to oligodendrocyte death, axonal damage, demyelination and lesion development. This manuscript will review in detail the features of these barriers under physiological and pathological conditions, particularly when focal immune activation promotes the loss of the BBB and BCB phenotype, the upregulation of cell adhesion molecules (CAMs) and the recruitment of immune cells.
Prevention of progression in neurological diseases, particularly in multiple sclerosis (MS) but also in neurodegenerative diseases, remains a significant challenge. MS patients switch from a ...relapsing-remitting to a progressive disease course, but it is not understood why and how this conversion occurs and why some patients never experience disease progression. Do aging and accumulation of neuronal damage induce progression, or do cognitive symptoms and accelerated grey matter (GM) atrophy point to distinct processes affecting networks? This review weighs accepted dogma against real data on the secondary progressive phase of the disease, highlighting current challenges in this important field and directions towards development of treatment strategies to slow or prevent progression of disability.
Tumor-associated macrophages (TAMs) play an important role in the immune response to cancer, but the mechanisms by which the tumor microenvironment controls TAMs and T cell immunity are not ...completely understood. Here we report that kynurenine produced by glioblastoma cells activates aryl hydrocarbon receptor (AHR) in TAMs to modulate their function and T cell immunity. AHR promotes CCR2 expression, driving TAM recruitment in response to CCL2. AHR also drives the expression of KLF4 and suppresses NF-κB activation in TAMs. Finally, AHR drives the expression of the ectonucleotidase CD39 in TAMs, which promotes CD8
T cell dysfunction by producing adenosine in cooperation with CD73. In humans, the expression of AHR and CD39 was highest in grade 4 glioma, and high AHR expression was associated with poor prognosis. In summary, AHR and CD39 expressed in TAMs participate in the regulation of the immune response in glioblastoma and constitute potential targets for immunotherapy.
High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy ...therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4–6 years after disease onset.
In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0–2 years (early) or 4–6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0–10, with higher scores indicating increased disability), at 6–10 years after disease onset, assessed with a linear mixed-effects model.
We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7–8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 SD 1·8 vs 3·5 SD 2·1; p<0·0001), with a difference between groups of −0·98 (95% CI −1·51 to −0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6–10 year follow-up period.
High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6–10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.
National Health and Medical Research Council Australia and MS Society UK.
Neurodegeneration occurring in multiple sclerosis (MS) contributes to the progression of disability. It is therefore important to identify and neutralize the mechanisms that promote neurodegeneration ...in MS. Here, we report that oxidized phosphatidylcholines (OxPCs) found in MS lesions, previously identified as end-product markers of oxidative stress, are potent drivers of neurodegeneration. Cultured neurons and oligodendrocytes were killed by OxPCs, and this was ameliorated by microglia. After OxPC injection, mouse spinal cords developed focal demyelinating lesions with prominent axonal loss. The depletion of microglia that accumulated in OxPC lesions exacerbated neurodegeneration. Single-cell RNA sequencing of lesioned spinal cords identified unique subsets of TREM2
mouse microglia responding to OxPC deposition. TREM2 was detected in human MS lesions, and TREM2
mice exhibited worsened OxPC lesions. These results identify OxPCs as potent neurotoxins and suggest that enhancing microglia-mediated OxPC clearance via TREM2 could help prevent neurodegeneration in MS.
Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in ...astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.
PDF
