Begell House Inc.
Onco Therapeutics
OT
2694-4642
6
3-4
2015
Preface: Microvesicles in Human Diseases and their Role in Intercellular Communication and Signaling
v
10.1615/ForumImmunDisTher.2016016930
Federica
Vannini
Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy; Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
Francesco
Russo
Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics (IIT) and Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy; Department of Computer Science, University of Pisa, Pisa, Italy; University of Sannio, Department of Engineering, Piazza Roma, 21, 82100 Benevento, Italy
Extracellular Vesicles as Potential Mediators of Epigenetic Reprogramming
133-141
10.1615/ForumImmunDisTher.2016016526
Anna Lewandowska
Ronnegren
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels vag 16, Box 280, SE 171-77 Stockholm, Sweden
cancer
cellular communication
DNA methylation
epigenetic
exosomes
Extracellular vesicles
histone modification
microRNA
microvesicles
Epigenetic machinery has the ability to affect tissue-specific gene expression and is essential for normal development. A heritable chromatin structure change can be the consequence of intracellular processes; however, there is a very high probability of its mediation with cellular communication. The information transfer can be obtained with many different strategies; nonetheless, extracellular vesicles (EVs) play a pivotal role in the regulation of physiological and pathological states. It has been widely proven that factors identified within exosomes and microvesicles, like non-coding RNA or proteins, have the ability to directly or indirectly affect post-translational modifications (PTM) of histones or DNA methylation. The phenotypic change driven by these molecules contributes to the regulation of cell identity, and disruption of the epigenetic machinery can lead to altered gene function and, consequently, diseases such as cancer. Because genetically unstable cancer cells tend to secrete higher amounts of extracellular vesicles that modulate the cancer microenvironment, it is very likely that this process involves epigenetic alternations. In this review, I discuss EV-dependent epigenetic reprogramming, with particular focus on the modification driven by miRNAs as well as by enzymes involved in the regulation of DNA methylation and histone modification.
Tissue Cross-Talk and Exosomal-MicroRNAs
143-156
10.1615/ForumImmunDisTher.2016016605
Micol
Marchetti
Bristol Renal, University of Bristol, Dorothy Hocking Building, Whitson Street, BS1 3NY, Bristol, UK
Exosomes
microRNAs
prevention-tools
biomarkers
crosstalk
Over the last 10 years, the interest in microRNAs has grown rapidly, and the characterization of these short non-coding RNA sequences has become crucial due to their involvement and role in several widespread diseases such as cancer, cardiovascular diseases, kidney diseases, and diabetes, as well as developmental diseases. The increased understanding of the biology of microRNAs has triggered the development of important tools to study their function and new therapeutic opportunities to treat disease, offering a clear example of how the scientific translational approach plays a crucial role in scientific research in the 21st century. More recently, this interest in microRNAs has increased further as a result of the discovery of exosome microRNAs, microRNAs contained in endogenous vesicles isolated from biological fluids such as breast milk, blood, serum, urine, cerebrospinal fluid, and semen. MicroRNAs represent powerful potential biomarkers for the detection of diseases at an early stage, when the chances of successful treatment and outcomes (drug mediated or surgical) are higher. Furthermore, recent publications have highlighted the role of exosomal microRNAs in cell-to-cell communication, adding new information to the importance of these exosome and vesicles. Much work still needs to be done to better understand the biogenesis and loading and dispersion of exosomes and microvesicles as well to characterize the exosomal content in terms of functionality and activity, but current data already suggest that these exosomes could be potential therapeutic targets.
Extracellular Vesicle-Mediated Transfer of MicroRNAs in Atherosclerosis
157-161
10.1615/ForumImmunDisTher.2016016479
Federica
Vannini
Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy; Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
Francesco
Russo
Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics (IIT) and Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy; Department of Computer Science, University of Pisa, Pisa, Italy; University of Sannio, Department of Engineering, Piazza Roma, 21, 82100 Benevento, Italy
atherosclerosis
biomarkers
exosomes
microRNAs
MicroRNAs (miRNAs) are the most well-characterized class of small (~22 nucleotides) non-coding RNAs (ncRNAs) responsible for post-transcriptional regulation of gene expression through their interaction with messenger RNAs (mRNAs). miRNAs are present in membrane-bound vesicles, such as exosomes, in extracellular human body fluids. Because miRNAs circulate in the bloodstream in highly stable extracellular forms, they have great potential as the next generation of blood-based biomarkers. Exosomal miRNA transfer is very important in cardiovascular systems and disease. Moreover, in the blood vessels, this transfer can modulate atherosclerosis. In this review, we describe our current knowledge of extracellular vesicle-mediated transfer of miRNAs in atherosclerosis.
Extracellular Vesicles: Evolving Contributors in Autoimmunity
163-170
10.1615/ForumImmunDisTher.2016016491
Stergios
Katsiougiannis
UCLA School of Dentistry, 10833 Le Conte Ave. 73-017 CHS, Los Angeles, CA 90095-1668
apoptotic bodies
autoimmunity
exosomes
extracellular vesicles
immunity
microvesicles
Extracellular vesicles, including microvesicles, exosomes and apoptotic bodies are recognized as carriers of pathogen-associated molecules with direct involvement in immune signaling and inflammation. Those observations have enforced the way these membranous vesicles are being considered as promising immunotherapeutic targets. In this review, we discuss the emerging roles of extracellular vesicles in autoimmunity and highlights their potential use as disease biomarkers as well as targets for the treatment and prevention of autoimmune diseases.
Exosomes, Ectosomes and the Two Together. Physiology and Pathology
171-180
10.1615/ForumImmunDisTher.2016015877
Jacopo
Meldolesi
Department of Neuroscience, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy
heterogeneity of extracellular vesicles; multivesicular bodies; plasma membrane pinch-off; luminal cargoes; markers; vesicle budding/rolling; outside/inside membrane fusion; horizontal transfer of cargoes; vesicle diagnosis; vesicle therapy
Eukaryotic cells release to the extracellular space two types of vesicles which have attracted great interest, early on for their complex generation and function, and more recently for their role in multiple diseases including cancer. Previous studies have revealed ample information about these vesicles, especially the exosomes. In this review, I report the developments that have occurred during the last few years. Small vesicles first accumulated within large endocytic cisternae and are then converted into multivesicular bodies. Upon exocytosis of the latter, the released vesicles are defined as exosomes. Ectosomes, which are known only in scant detail, are larger vesicles that pinch off rapidly from the plasma membrane. The rate of this release increases markedly upon appropriate cell stimulation. Both types of vesicle are delimited by a membrane that delimits a condensed cargo composed by proteins, mRNAs, miRNAs, and DNA, which are sorted from the cytoplasm. Several proteins, previously presented as markers of either vesicle, are common to both. Today, only a few markers are accepted. Upon their release, both exosomes and ectosomes are addressed to specific target cells, where they bind and surface roll for several seconds. Later, vesicles undergo outside/in fusion to the plasma membrane by a process analogous to the fusions of retroviruses. Fusion results in the horizontal transfer of cargoes that govern changes of the genome and of protein expression, up to the reprogramming of cell structure and function. In many physiological functions, the two types of vesicles operate together. Their mixtures play specific roles in processes such as blood coagulation, angiogenesis, innate and acquired immunity, synaptic transmission. Currently, some pathology investigations are focused on the diagnosis of diseases through recognition of specific vesicles and on preliminary therapy with targeted vesicles loaded with molecules aggressive to diseased cells.
Circular RNAs and Exosomes: The New Frontier of Cancer Diagnosis
181-186
10.1615/ForumImmunDisTher.2016016641
Flavia
Scoyni
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
Rosalba
Giugno
Department of Computer Science, University of Verona, Verona, Italy
biomarkers
cancer
circular RNAs
exosomes
noncoding RNAs
Over the last decade, the development of new technologies for genome-wide analyses of the eukaryotic transcriptome has allowed comprehensive studies of circRNA species. Although biologists identified circular transcripts more than 20 years ago, these circular molecules were long considered artefacts of aberrant splicing reactions or the prerogative of a few viral pathogens. The evidence from expression data indicates a wide range of more than thousands of endogenous circRNAs in mammalian cells, some of which are abundant, conserved, and stably accumulated within the cell. The functional analysis of these transcripts revealed that circRNAs might regulate microRNA (miRNA) function and suggest that they might act in the regulation of gene expression.
Due to their emerging role as gene expression regulators, circRNAs are very likely to become important players in cancer development and pathologies like other types of noncoding RNAs.
Moreover, they have shown a great potential as tissue-based markers for cancer classification and prognostication. Recently, it was discovered that circRNAs are secreted through exosomes vesicles; thus, the study of this class of non-coding RNAs has potential implications for therapeutic and research applications.
PREFACE: Manipulation of Macrophage Functions by Mycobacterium Tuberculosis
189
10.1615/ForumImmunDisTher.v6.i3-4.80
Magdalena
Klink
Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
Phosphorylation Signaling in Mycobacterium Tuberculosis: An Overview
191-206
10.1615/ForumImmunDisTher.v6.i3-4.90
Angela C. O.
Menegatti
Centro de Biologia Molecular Estrutural, Departamento de Bioquimica, Universidade Federal de Santa Catarina, Florianopolis, SC 88040-900, Brazil
Hernan
Terenzi
Centro de Biologia Molecular Estrutural, Departamento de Bioquimica, Universidade Federal de Santa Catarina, Florianopolis, SC 88040-900, Brazil
Mycobacterium tuberculosis
signal transduction
tyrosine phosphorylation
kinase
phosphatase
Mycobacterium tuberculosis (Mtb), as observed in other pathogenic bacteria, utilizes signal transduction pathways dependent on the protein phosphorylation−dephosphorylation events to regulate its own metabolic processes but also to modulate and surrogate its host (macrophage) signal transduction−dependent defenses. In this review, we focus on the dominant phosphorylation pathways found in Mtb that are already described at the levels of genes and proteins, as well as their catalytic activity. Many of the systems we describe are the focus of intensive medicinal chemistry approaches to identify strategies to combat tuberculosis, with a special emphasis that will be dedicated to two important phosphatases secreted by Mtb: PtpA and PtpB.
Modulations of Macrophage Immune Responses by Mycobacterial PE/PPE Family of Proteins
207-216
10.1615/ForumImmunDisTher.v6.i3-4.100
Shiny
Nair
Department of Medicine, Yale Cancer Centre, Yale School of Medicine, New Haven, CT 06520-8028
PE/PPE proteins
Mycobacterium tuberculosis pathogenesis
macrophage immune responses
immunomodulation
Mycobacterium tuberculosis (Mtb) is a very successful pathogen possessing a plethora of tactics uniquely tailored to undermine the key macrophage defense system for its own survival and multiplication. Completion of the Mtb genome revealed the presence of two unique, acid rich families of proteins called PE /PPE proteins. Owing to their high abundance and expansion in pathogenic mycobacterial species, their association with the ESAT-6 (ESX) secretion system and constituting 7% of the coding potential of the Mtb genome, they have a great potential to act as virulent factors during mycobacterial pathogenesis. Though initially speculated to play a role in antigenic variation, current assessment of the functions of PE/PPE proteins reveal important and diverse roles during mycobacterial infection. Macrophages are important sentinel cells that arbitrate innate as well as adaptive immune responses. Paradoxically, macrophage anti-mycobacterial immune responses are readily manipulated by Mtb to favor their intracellular survival. Insights into the alteration of macrophage signaling pathways by PE/PPE proteins would offer a better perspective to develop effective anti-TB immunotherapeutics and vaccines. In this review, I discuss the significance of the PE/PPE proteins in the modulation of macrophage effector responses.
Autophagy and Autophagy-Related Proteins in the Immunity against Mycobacterium Tuberculosis
217-226
10.1615/ForumImmunDisTher.v6.i3-4.110
Aïcha
Bah
Institut de Pharmacologie et de Biologie Structurale, UMR 5089 CNRS - Universite de Toulouse, 205 route de Narbonne BP64182, 31077 Toulouse France
Isabelle
Vergne
Institut de Pharmacologie et de Biologie Structurale, UMR 5089 CNRS - Universite de Toulouse, 205 route de Narbonne BP64182, 31077 Toulouse France
autophagy
immunity
lysosomes
macrophages
phagosome
tuberculosis
Autophagy is a cell-autonomous lysosomal degradative pathway implicated in various functions of the immune system. One of its key roles is the capture of intracellular pathogens and their delivery to lysosomes for elimination. Numerous in vitro studies have demonstrated that autophagy activation leads to killing of Mycobacterium tuberculosis (MTB) by infected macrophages. In this review, we summarize the functions of autophagy in MTB infection, as well as the molecular mechanisms involved in its regulation by both host and pathogen factors. The recent advances in our understanding of the role of autophagy proteins in, in vivo, control of MTB are discussed as well as the potential use of autophagy-based therapy and vaccine in the fight against tuberculosis.
Toll Like Receptor-2 Signaling in Mycobacterium Tuberculosis Infection−A Double-Edged Sword
227-235
10.1615/ForumImmunDisTher.v6.i3-4.120
Monika
Sharma
Department of Bioscience and Biotechnology, Banasthali Vidyapith (Women's University), Rajasthan, India
Sadhna
Sharma
D S Kothari Centre for Research and Innovation in Science Education and Department of Zoology, Miranda House, University of Delhi
M. tuberculosis
Toll-like receptors
Th1 immune response
Th2 immune response
Mycobacterium tuberculosis (MTB), one of the major health concerns to date, is known to survive in antigen- presenting cells including macrophages. Macrophages process the antigens where the extent of microbicidal action mainly depends on the Toll like receptor-2 (TLR2). TLR2signaling involving MyD88, NF-kβ, ERK1/2 and p38 MAPK is an integral part of the host immune response against mycobacterial infection. But it is also exploited by MTBfor immune evasion which raises a question whether TLR2 acts as a 'friend' or 'foe' to the host. The MTBcell wall is rich in components that act as TLR2agonists such as lipoproteins like LpqH, LprA, LprG, PhoSl and glycolipids like Man-LAM, LM, PIM and TDM. A number of new MTB antigens are being recognized as TLR2 agonists like PE and PPE family of proteins, secretory proteins, heat shock proteins, certain latency and resuscitation proteins like DATIN, MymA and RpfB. The engagement of TLR2 with these ligands results in the elaboration of Th1 type protective proinflammatory cytokines like TNF-α and IL-12. However, prolonged signaling of TLR2by such molecules also leads to the inhibition of phagosomal maturation, resistance to innate microbicidal mechanisms and diminished MHC Class II antigen-processing and presentation. Among these inhibiting the recognition of infected macrophages by CD4+ T cells contributes markedly to the immune evasion mechanism leading to MTB survival inside the antigen-presenting cell. Understanding the interaction between MTB and TLR2and its contribution to the immune response or to the immune evasion will help in finding new ways to eliminate MTB infection.
The Role of Homologous Recombination and Non-Homologous Ends Joining Systems in M. Tuberculosis Survival inside Macrophages
237-249
10.1615/ForumImmunDisTher.v6.i3-4.130
Izabela
Szulc-Kielbik
Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
Michal
Kielbik
Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
Magdalena
Klink
Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
HR and NHEJ systems
macrophages
M. tuberculosis
DNA double-strand breaks are extremely dangerous for the integrity of the Mycobacterium tuberculosis (Mtb) genome and, when left unrepaired, they can cause bacteria death. Such breaks are caused by some environmental factors like ultraviolet light or ionizing radiation, but they can also arise during the infection process, when Mtb is constantly exposed to the hostile conditions of the host's phagocytes. The main DNA-damaging factors generated by human macrophages are reactive oxygen and nitrogen species, including superoxide anion, hydrogen peroxide, nitric oxide, and peroxynitrite anion. However, Mtb has acquired numerous mechanisms with which to avoid being killed by macrophages, and Mtb can proliferate intracellularly inside phagocytes. To protect the integrity of its genome, Mtb possesses multiple DNA double-strand-break repair systems, such as specific for the bacterial homologous recombination system with RecA as a key protein, and less commonly in prokaryotes non-homologous end-joining system, in which the main proteins are Ku and LigD. Moreover, these Mtb proteins involved in DNA repair pathways have a potential role in the modulation of macrophage functional activity.
Role of Dendritic Cells in Host−Mycobacterium Bovis BCG Interactions
251-261
10.1615/ForumImmunDisTher.v6.i3-4.140
Magdalena
Kowalewicz-Kulbat
Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, University of Lodz, Lodz, Poland
Krzysztof
Krawczyk
Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, University of Lodz, Lodz, Poland
Wieslawa
Rudnicka
Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, University of Lodz, Lodz, Poland
dendritic cells
M. bovis BCG
vaccine
Tuberculosis (TB) remains a global problem that results in as many as 2 million deaths each year. TB infects innate immune cells patrolling the lung. A live-attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) strain is the only strain used in vaccines against tuberculosis. However, its efficacy remains controversial. Dendritic cells (DCs) are the major antigen-presenting cells in the induction of a cellular response to intracellular pathogens, such as mycobacteria. DCs possess the ability to induce both innate and adaptive immune responses. In the context of human infection, little is known about DC−BCG interaction. In this review, we focus on BCG interactions with human DCs with regard to the role of DCs receptors in BCG recognition and the significance of the pro-inflammatory cytokines produced by BCG-infected DCs, especially interferon-γ−producing cells. Insights into human DC responses to BCG are necessary for a better understanding of the lack of a protective response to the current BCG vaccine and for developing new effective anti-TB immunotherapeutics and vaccine strategies.
CONTENTS VOLUME 6, 2015
263-266
10.1615/ForumImmunDisTher.v6.i3-4.150