As our population grows older, age-related pathologies are becoming more prevalent. Deterioration of skeletal muscle and the immune system manifests as sarcopenia and immune senescence respectively. ...The disease burden of these pathologies emphasizes the need for a better understanding of the underlying mechanisms. Skeletal muscle has emerged as a potent regulator of immune system function. As such, skeletal muscle might be the central integrator between sarcopenia and immune senescence in an aging biological system. Therapeutic approaches targeting skeletal muscle might be able to restore both muscle and immune system function. In this review, we therefore outline the current - however still fragmentary - knowledge about the potential communication pathways of muscle and immune system, how they are affected by aging of skeletal muscle and discuss possible treatment strategies. The review intends to be hypothesis-generating and should thereby stimulate further research in this important scientific field.
Alemtuzumab is a humanized monoclonal antibody against CD52 (cluster of differentiation 52) and is approved for the therapy of relapsing-remitting multiple sclerosis. The application of alemtuzumab ...leads to a rapid, but long-lasting depletion predominantly of CD52-bearing B and T cells with reprogramming effects on immune cell composition resulting in the restoration of tolerogenic networks. Alemtuzumab has proven high efficacy in clinical phase II and III trials, where interferon β-1a was used as active comparator. However, alemtuzumab is associated with frequent and considerable risks. Most importantly secondary autoimmune disease affects 30%-40% of patients, predominantly impairing thyroid function. Extensive monitoring and early intervention allow for an appropriate risk management. However, new and reliable biomarkers for individual risk stratification and treatment response to improve patient selection and therapy guidance are a significant unmet need. Only a deeper understanding of the underlying mechanisms of action (MOA) will reveal such markers, maximizing the best potential risk-benefit ratio for the individual patient. This review provides and analyses the current knowledge on the MOA of alemtuzumab. Most recent data on efficacy and safety of alemtuzumab are presented and future research opportunities are discussed.
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need ...contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, using ...single cell transcriptomics, we identify a specific location-associated composition and transcriptome of CSF leukocytes. Multiple sclerosis (MS) - an autoimmune disease of the CNS - increases transcriptional diversity in blood, but increases cell type diversity in CSF including a higher abundance of cytotoxic phenotype T helper cells. An analytical approach, named cell set enrichment analysis (CSEA) identifies a cluster-independent increase of follicular (TFH) cells potentially driving the known expansion of B lineage cells in the CSF in MS. In mice, TFH cells accordingly promote B cell infiltration into the CNS and the severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate ongoing local T/B cell interaction.
The interaction of coagulation factors has been shown to go beyond their traditional roles in hemostasis and to affect the development of inflammatory diseases. Key molecular players, such as ...fibrinogen, thrombin, or factor XII have been mechanistically and epidemiologically linked to inflammatory disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), and colitis.
To systematically review the evidence for a role of coagulation factors, especially factor XII, fibrinogen, and thrombin in inflammatory disorders like MS, RA, and bowel disorders.
A systematic literature search was done in the PubMed database to identify studies about coagulation factors in inflammatory diseases. Original articles and reviews investigating the role of the kallikrein-kinin and the coagulation system in mouse and humans were included.
We identified 43 animal studies dealing with inflammatory disorders and factors of the kallikrein-kinin or the coagulation system. Different immunological influences are described and novel molecular mechanisms linking coagulation and inflammation are reported.
A number of studies have highlighted coagulation factors to tip the balance between hemostasis and thrombosis and between protection from infection and extensive inflammation. To optimize the treatment of chronic inflammatory disorders by these factors, further studies are necessary.
Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical studies delineate abnormal expression of specific cytokines over the course of disease. Preclinical ...studies using animal models of MS have yielded promising results in manipulating the activity of certain cytokines to improve the clinical outcome. However, the translation of these findings into the clinic is often disappointing. The reason for this might be the complex nature of cytokine networks and the pathogenesis of neuroinflammation, as well as an oversimplified interpretation of preclinical observations. This review presents an overview on cytokines that potentially contribute to the development of MS and provides examples of success and failure in translating basic science into clinical benefit for people with MS.
Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder of neuromuscular synaptic transmission. The clinical hallmark of MG consists of fluctuating fatigability and weakness affecting ...ocular, bulbar and (proximal) limb skeletal muscle groups. MG may either occur as an autoimmune disease with distinct immunogenetic characteristics or as a paraneoplastic syndrome associated with tumors of the thymus. Impairment of central thymic and peripheral self-tolerance mechanisms in both cases is thought to favor an autoimmune CD4
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T cell-mediated B cell activation and synthesis of pathogenic high-affinity autoantibodies of either the IgG1 and 3 or IgG4 subclass. These autoantibodies bind to the nicotinic acetylcholine receptor (AchR) itself, or muscle-specific tyrosine-kinase (MuSK), lipoprotein receptor-related protein 4 (LRP4) and agrin involved in clustering of AchRs within the postsynaptic membrane and structural maintenance of the neuromuscular synapse. This results in disturbance of neuromuscular transmission and thus clinical manifestation of the disease. Emphasizing evidence from clinical trials, we provide an updated overview on immunopathogenesis, and derived current and future treatment strategies for MG divided into: (a) symptomatic treatments facilitating neuromuscular transmission, (b) antibody-depleting treatments, and (c) immunotherapeutic treatment strategies.
Microglia play an essential role for central nervous system (CNS) development and homeostasis and have been implicated in the onset, progression, and clearance of numerous diseases affecting the CNS. ...Previous in vitro research on human microglia was restricted to post-mortem brain tissue-derived microglia, with limited availability and lack of scalability. Recently, the first protocols for the generation of microglia from human pluripotent stem cells have become available, thus enabling the implementation of powerful platforms for disease modeling, drug testing, and studies on cell transplantation. Here we give a detailed and comprehensive overview of the protocols available for generating microglia from human pluripotent stem cells, highlighting the advantages, drawbacks, and operability and placing them into the context of current knowledge of human embryonic development. We review novel insights into microglia biology and the role of microglia in neurological diseases as drawn from the new methods and provide an outlook for future lines of research involving human pluripotent stem cell-derived microglia.
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