Autoimmune diseases represent a family of at least 80 illnesses that share a common pathogenesis: an immune-mediated attack on the body's own organs. Collectively, autoimmune diseases affect some 20 ...million Americans, predominantly women. Many of these diseases are increasing in frequency in industrialized countries. Treatment of autoimmune diseases improved greatly during the second half of the 20th century but has been hampered because the diseases often progress before a clinical diagnosis is possible. Research in the 21st century is focusing on prospective prediction using the tools of systems biology.
Viral myocarditis Rose, Noel R
Current opinion in rheumatology,
2016-July, 2016-Jul, 2016-07-00, 20160701, Letnik:
28, Številka:
4
Journal Article
Odprti dostop
PURPOSE OF REVIEWThe article traces the pathways leading from viral infection of the heart by coxsackievirus B3 to autoimmune myocarditis in its various manifestations.
RECENT FINDINGSMyocarditis can ...be induced by a number of different infectious agents and represents a significant cause of death especially in young individuals. Following infection, patients may develop lymphocytic, eosinophilic, or giant cell/granulomatous myocardial inflammation. It can lead to infectious dilated cardiomyopathy, a disease frequently requiring cardiac transplantation. Although acute viral myocarditis is frequently subclinical and recovery may be spontaneous, treatment of chronic myocarditis is currently unsatisfactory. Ongoing disease may be because of persistent virus in the heart or to immunopathic attack. Depending on the cause, treatment may be antiviral or immunosuppressive. Endomyocardial biopsy is proving of value in determining cause and deciding future therapy. A great deal of information about the pathogenesis of myocarditis has been gained from experimental models in rodents using heart disease induced by infection using coxsackievirus B3 or by immunization with cardiac myosin.
SUMMARYTreatment of myocarditis is still problematic and may depend on etiologic diagnosis to distinguish infectious from immune-mediated disease. Both pathogenic mechanisms may co-occur in individual patients. In the future, treatment may depend upon endomyocardial biopsy, immunohistologic testing, improved imaging, and molecular genetic analysis for providing more precise diagnoses.
DNA methylation acts as an epigenetic modification in vertebrate DNA. Recently it has become clear that the DNA and histone lysine methylation systems are highly interrelated and rely mechanistically ...on each other for normal chromatin function in vivo. Here we examine some of the functional links between these systems, with a particular focus on several recent discoveries suggesting how lysine methylation may help to target DNA methylation during development, and vice versa. In addition, the emerging role of non-methylated DNA found in CpG islands in defining histone lysine methylation profiles at gene regulatory elements will be discussed in the context of gene regulation. This article is part of a Special Issue entitled: Methylation: A Multifaceted Modification — looking at transcription and beyond.
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•There is an emerging realisation that DNA and histone lysine methylation in mammals are highly interrelated.•Targeting of DNA methylation is mechanistically linked to H3K9 methylation.•Uhrf1 acts as a link between H3K9 methylation and maintenance methylation during DNA replication.•Targeting of Dnmt3a/b is influenced by H3K4 and H3K36 methylation.•Non-methylated DNA at CpG islands influences histone methylation through ZF-CxxC proteins.
•Cross-reactions between epitopes of an invading microorganism and similar epitopes in the host are common. Only rarely is epitope mimicry known to cause an autoimmune disease in humans.•These ...cross-reactions based on shared epitopes reflects the requirement to maintain a maximal immunologic repertoire.•Identifying epitope mimicry opens opportunities for improved treatments and prevention of autoimmune disease.
Infections often precede the onset of autoimmune disease and molecular (or epitope) mimicry is a plausible link. Cross-reacting epitopes are common between an infecting microorganism and the host because negative selection of self-reactive T-cells and B-cells is frequently incomplete. Complete eradication could lead to major voids in the immunologic repertoire. The association of an autoimmune disease with a microbial epitope may signify a causal relationship with the organism, an indirect connection through bystander effects, persistent infection or coincidence. There are well-established examples of a microbial mimic inducing a defined model of autoimmune disease in experimental animals but such instances are still relatively rare in humans. Establishing epitope mimicry as a direct cause opens opportunities for preventing the disease. Current approaches to cancer immunotherapy provides new examples of epitope mimicry between cancer antigens and normal tissue antigens.
Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac ...disease, chronic fatigue syndrome, and rheumatoid arthritis. Fatigue is multi-faceted and broadly defined, which makes understanding the cause of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases. In general, fatigue is defined by debilitating periods of exhaustion that interfere with normal activities. The severity and duration of fatigue episodes vary, but fatigue can cause difficulty for even simple tasks like climbing stairs or crossing the room. The exact mechanisms of fatigue are not well-understood, perhaps due to its broad definition. Nevertheless, physiological processes known to play a role in fatigue include oxygen/nutrient supply, metabolism, mood, motivation, and sleepiness-all which are affected by inflammation. Additionally, an important contributing element to fatigue is the central nervous system-a region impacted either directly or indirectly in numerous autoimmune and related disorders. This review describes how inflammation and the central nervous system contribute to fatigue and suggests potential mechanisms involved in fatigue that are likely exhibited in autoimmune and related diseases.
•IL6 is cardio protective during acute insult to the myocardium.•IL6 transitions to a pathogenic factor when it remains elevated chronically.•The transition is associated with specific downstream ...signaling unique to IL6.•Chronic IL6 signaling is associated with heart failure.•In myocarditis chronic IL6 signaling contributes to progression to dilated cardiomyopathy.
IL6 is a pleiotropic cytokine that is made in response to perturbations in homeostasis. IL6 becomes elevated in the acute response to host injury and can activate immune cells, direct immune cell trafficking, signal protective responses in local tissue, initial the acute phase response or initiate wound healing. In the short term this proinflammatory response is protective and limits host damage. It is when this acute response remains chronically activated that IL6 becomes pathogenic to the host. Chronically elevated IL6 levels lead to chronic inflammation and fibrotic disorders. The heart is a tissue where this temporal regulation of IL6 is very apparent. Studies from myocardial infarction show how short-term IL6 signaling can protect and preserve the heart tissue in response to acute damage, where long term IL6 signaling or an over-production of IL6R protein plays a causal role in cardiovascular disease. Thus, IL6 can be both protective and pathogenic, depending on the kinetics of the host response.
In cooperation with the Core Outcome Measures in Effectiveness Trials (COMET) initiative, the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) initiative aimed ...to develop a guideline on how to select outcome measurement instruments for outcomes (i.e., constructs or domains) included in a "Core Outcome Set" (COS). A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population.
Informed by a literature review to identify potentially relevant tasks on outcome measurement instrument selection, a Delphi study was performed among a panel of international experts, representing diverse stakeholders. In three consecutive rounds, panelists were asked to rate the importance of different tasks in the selection of outcome measurement instruments, to justify their choices, and to add other relevant tasks. Consensus was defined as being achieved when 70 % or more of the panelists agreed and when fewer than 15 % of the panelists disagreed.
Of the 481 invited experts, 120 agreed to participate of whom 95 (79 %) completed the first Delphi questionnaire. We reached consensus on four main steps in the selection of outcome measurement instruments for COS: Step 1, conceptual considerations; Step 2, finding existing outcome measurement instruments, by means of a systematic review and/or a literature search; Step 3, quality assessment of outcome measurement instruments, by means of the evaluation of the measurement properties and feasibility aspects of outcome measurement instruments; and Step 4, generic recommendations on the selection of outcome measurement instruments for outcomes included in a COS (consensus ranged from 70 to 99 %).
This study resulted in a consensus-based guideline on the methods for selecting outcome measurement instruments for outcomes included in a COS. This guideline can be used by COS developers in defining how to measure core outcomes.
The vertebrate brain has an exceptionally high energy need. During ischemia, intracellular ATP concentrations decline rapidly, resulting in the breakdown of ion gradients and cellular damage. Here, ...we employed the nanosensor ATeam1.03YEMK to analyse the pathways driving the loss of ATP upon transient metabolic inhibition in neurons and astrocytes of the mouse neocortex. We demonstrate that brief chemical ischemia, induced by combined inhibition of glycolysis and oxidative phosphorylation, results in a transient decrease in intracellular ATP. Neurons experienced a larger relative decline and showed less ability to recover from prolonged (>5 min) metabolic inhibition than astrocytes. Blocking voltage‐gated Na+ channels or NMDA receptors ameliorated the ATP decline in neurons and astrocytes, while blocking glutamate uptake aggravated the overall reduction in neuronal ATP, confirming the central role of excitatory neuronal activity in the cellular energy loss. Unexpectedly, pharmacological inhibition of transient receptor potential vanilloid 4 (TRPV4) channels significantly reduced the ischemia‐induced decline in ATP in both cell types. Imaging with Na+‐sensitive indicator dye ING‐2 furthermore showed that TRPV4 inhibition also reduced ischemia‐induced increases in intracellular Na+. Altogether, our results demonstrate that neurons exhibit a higher vulnerability to brief metabolic inhibition than astrocytes. Moreover, they reveal an unexpected strong contribution of TRPV4 channels to the loss of cellular ATP and suggest that the demonstrated TRPV4‐related ATP consumption is most likely a direct consequence of Na+ influx. Activation of TRPV4 channels thus provides a hitherto unacknowledged contribution to the cellular energy loss during energy failure, generating a significant metabolic cost in ischemic conditions.
Key points
In the ischemic brain, cellular ATP concentrations decline rapidly, which results in the collapse of ion gradients and promotes cellular damage and death.
We analysed the pathways driving the loss of ATP upon transient metabolic inhibition in neurons and astrocytes of the mouse neocortex.
Our results confirm the central role of excitatory neuronal activity in the cellular energy loss and demonstrate that neurons experience a larger decline in ATP and are more vulnerable to brief metabolic stress than astrocytes.
Our study also reveals a new, previously unknown involvement of osmotically activated transient receptor potential vanilloid 4 (TRPV4) channels to the reduction in cellular ATP in both cell types and indicates that this is a consequence of TRPV4‐mediated Na+ influx.
We conclude that activation of TRPV4 channels provides a considerable contribution to the cellular energy loss, thereby generating a significant metabolic cost in ischemic conditions.
figure legend We show that brief chemical ischemia, induced by combined inhibition of glycolysis and oxidative phosphorylation results in a transient decrease in cellular ATP of neurons and astrocytes of the murine neocortex. The decline in ATP is promoted by activation of NMDA receptors (NMDA‐R), of voltage‐gated Na+ channels (Nav) in neurons and of excitatory amino acid transporters (EAATs) in astrocytes. In addition, our study reveals that transient receptor potential vanilloid 4 (TRPV4) channels contribute to the ischemia‐induced ATP decline in both cell types. Our data furthermore suggests that the TRPV4‐related decline in cellular ATP is caused by TRPV4‐related Na+ influx.
The application of nanotechnology to regenerative medicine has increased over recent decades. The development of materials that can influence biology at the nanoscale has gained interest as our ...understanding of the interactions between cells and biomaterials at the nanoscale has grown. Materials that are either nanostructured or influence the nanostructure of the cellular microenvironment have been developed and shown to have advantages over their microscale counterparts. There are several reviews which have been published that discuss how nanomaterials have been used in regenerative medicine, particularly in bone regeneration. Most of these studies have explored this concept in specific areas, such as the application of glass-based nanocomposites, nanotechnology for targeted drug delivery to stimulate bone repair, and the progress in nanotechnology for the treatment of osteoporosis. In this review paper, the impact of nanotechnology in biomaterials development for bone regeneration will be discussed highlighting specifically, nanostructured materials that influence mechanical properties, biocompatibility, and osteoinductivity.
The impact of nanotechnology in biomaterials development for bone regeneration are summarised with a focus on three key areas; mechanical properties, biocompatibility, and osteoinductivity. Current challenges and future directions are also discussed.
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