Immune processes have a vital role in CNS homeostasis, resilience and brain reserve. Our cognitive and social abilities rely on a highly sensitive and fine-tuned equilibrium of immune responses that ...involve both innate and adaptive immunity. Autoimmunity, chronic inflammation, infection and psychosocial stress can tip the scales towards disruption of higher-order networks. However, not only classical neuroinflammatory diseases, such as multiple sclerosis and autoimmune encephalitis, are caused by immune dysregulation that affects CNS function. Recent insight indicates that similar processes are involved in psychiatric diseases such as schizophrenia, autism spectrum disorder, bipolar disorder and depression. Pathways that are common to these disorders include microglial activation, pro-inflammatory cytokines, molecular mimicry, anti-neuronal autoantibodies, self-reactive T cells and disturbance of the blood-brain barrier. These discoveries challenge our traditional classification of neurological and psychiatric diseases. New clinical paths are required to identify subgroups of neuropsychiatric disorders that are phenotypically distinct but pathogenically related and to pave the way for mechanism-based immune treatments. Combined expertise from neurologists and psychiatrists will foster translation of these paths into clinical practice. The aim of this Review is to highlight outstanding findings that have transformed our understanding of neuropsychiatric diseases and to suggest new diagnostic and therapeutic criteria for the emerging field of immunoneuropsychiatry.
Background:
Monitoring neuronal injury remains one key challenge in early relapsing-remitting multiple sclerosis (RRMS) patients. Upon axonal damage, neurofilament – a major component of the ...neuro-axonal cytoskeleton – is released into the cerebrospinal fluid (CSF) and subsequently peripheral blood.
Objective:
To investigate the relevance of serum neurofilament light chain (sNfL) for acute and chronic axonal damage in early RRMS.
Methods:
sNfL levels were determined in 74 patients (63 therapy-naive) with recently diagnosed clinically isolated syndrome (CIS) or RRMS using Single Molecule Array technology. Standardized 3 T magnetic resonance imaging (MRI) was performed at baseline and 1–3 consecutive follow-ups (42 patients; range: 6–37 months).
Results:
Baseline sNfL correlated significantly with T2 lesion volume (r = 0.555, p < 0.0001). There was no correlation between baseline sNfL and age, Expanded Disability Status Scale (EDSS) score or other calculated MRI measures. However, T2 lesion volume increased (r = 0.67, p < 0.0001) and brain parenchymal volume decreased more rapidly in patients with higher baseline sNfL (r = −0.623, p = 0.0004). Gd-enhancing lesions correlated positively with sNfL levels. Initiation of disease-modifying treatment led to a significant decrease in sNfL levels.
Conclusion:
sNfL indicates acute inflammation as demonstrated by correlation with Gd+ lesions. It is a promising biomarker for neuro-axonal damage in early multiple sclerosis (MS) patients, since higher baseline sNfL levels predicted future brain atrophy within 2 years.
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.
During early embryogenesis, microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how the tissue-resident macrophages are maintained throughout the ...organism’s lifespan still remains unclear. Here, we describe a system that allows specific, conditional ablation of microglia in adult mice. We found that the microglial compartment was reconstituted within 1 week of depletion. Microglia repopulation relied on CNS-resident cells, independent from bone-marrow-derived precursors. During repopulation, microglia formed clusters of highly proliferative cells that migrated apart once steady state was achieved. Proliferating microglia expressed high amounts of the interleukin-1 receptor (IL-1R), and treatment with an IL-1R antagonist during the repopulation phase impaired microglia proliferation. Hence, microglia have the potential for efficient self-renewal without the contribution of peripheral myeloid cells, and IL-1R signaling participates in this restorative proliferation process.
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•Microglia repopulate within 5 days of depletion•Under defined host conditions, microglia can be replaced by BM cells•Without preconditioning, they renew themselves locally by massive proliferation•IL-1R1 on microglia is involved in self-renewal and maintenance
Microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how these cells are maintained in the adult remains unclear. Waisman and colleagues show via a genetic approach that after ablation, microglia repopulation is driven by local progenitors in response to IL-1R signaling.
Background:
Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in ...treatment decisions.
Objectives:
To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS.
Methods:
This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients–Intervention–Comparator–Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique.
Results:
A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus.
Conclusion:
The present guideline will enable homogeneity of treatment decisions across Europe.
The latest revision of the McDonald criteria for the diagnosis of multiple sclerosis (MS) was published online in 2017. New features of the criteria, which were designed to facilitate earlier ...diagnosis of MS, include the recognition of oligoclonal bands in the cerebrospinal fluid as a possible marker of dissemination of MS pathology in time, the introduction of symptomatic lesions as a parameter to demonstrate spatial or temporal pathology dissemination, and the use of cortical lesions to demonstrate dissemination in space. In this Viewpoint, a panel of world-renowned MS specialists share their personal experiences of the new criteria to date.
Multiple sclerosis is a chronic neuroinflammatory disease with a highly heterogeneous disease course. Preventing lasting disability requires early identification of persons at risk and novel ...approaches towards patient stratification for personalized treatment decisions. In this comment, we discuss the importance of large datasets of real-world cohorts in order to address this unmet need.
The therapeutic mode of action of dimethyl fumarate (DMF), approved for treating patients with relapsing-remitting multiple sclerosis, is not fully understood. Recently, we and others demonstrated ...that Ab-independent functions of distinct B cell subsets are important in mediating multiple sclerosis (MS) relapsing disease activity. Our objective was to test whether and how DMF influences both the phenotype and functional responses of disease-implicated B cell subsets in patients with MS. High-quality PBMC were obtained from relapsing-remitting MS patients prior to and serially after initiation of DMF treatment. Multiparametric flow cytometry was used to monitor the phenotype and functional response-profiles of distinct B cell subsets. Total B cell counts decreased following DMF treatment, largely reflecting losses of circulating mature/differentiated (but not of immature transitional) B cells. Within the mature B cell pool, DMF had a greater impact on memory than naive B cells. In keeping with these in vivo effects, DMF treatment in vitro remarkably diminished mature (but not transitional B cell) survival, mediated by inducing apoptotic cell death. Although DMF treatment (both in vivo and in vitro) minimally impacted B cell IL-10 expression, it strongly reduced B cell expression of GM-CSF, IL-6, and TNF-α, resulting in a significant anti-inflammatory shift of B cell response profiles. The DMF-mediated decrease in B cell proinflammatory cytokine responses was further associated with reduced phosphorylation of STAT5/6 and NF-κB in surviving B cells. Together, these data implicate novel mechanisms by which DMF may modulate MS disease activity through shifting the balance between pro- and anti-inflammatory B cell responses.
Microglia are long-living resident immune cells of the brain, which secure a stable chemical and physical microenvironment necessary for the proper functioning of the central nervous system (CNS). ...These highly dynamic cells continuously scan their environment for pathogens and possess the ability to react to damage-induced signals in order to protect the brain. Microglia, together with endothelial cells (ECs), pericytes and astrocytes, form the functional blood–brain barrier (BBB), a specialized endothelial structure that selectively separates the sensitive brain parenchyma from blood circulation. Microglia are in bidirectional and permanent communication with ECs and their perivascular localization enables them to survey the influx of blood-borne components into the CNS. Furthermore, they may stimulate the opening of the BBB, extravasation of leukocytes and angiogenesis. However, microglia functioning requires tight control as their dysregulation is implicated in the initiation and progression of numerous neurological diseases. Disruption of the BBB, changes in blood flow, introduction of pathogens in the sensitive CNS niche, insufficient nutrient supply, and abnormal secretion of cytokines or expression of endothelial receptors are reported to prime and attract microglia. Such reactive microglia have been reported to even escalate the damage of the brain parenchyma as is the case in ischemic injuries, brain tumors, multiple sclerosis, Alzheimer's and Parkinson's disease. In this review, we present the current state of the art of the causes and mechanisms of pathological interactions between microglia and blood vessels and explore the possibilities of targeting those dysfunctional interactions for the development of future therapeutics.
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