Interleukin 17, the double-edged sword in atherosclerosis

Cardiovascular diseases, including atherosclerosis, are the number one cause of death worldwide. These diseases have taken the place of pneumonia and other infectious diseases in the epidemiological charts. Thus, their importance should not be underestimated. Atherosclerosis is an inflammatory disease. Therefore, immunological signaling molecules and immune cells carry out a central role in its etiology. One of these signaling molecules is interleukin (IL)-17. This relatively newly discovered signaling molecule might have a dual role as acting both pro-atherogenic and anti-atherogenic depending on the situation. The majority of articles have discussed IL-17 and its action in atherosclerosis, and it may be a new target for the treatment of patients with this disease. In this review, the immunological basis of atherosclerosis with an emphasis on the role of IL-17 and a brief explanation of the role of IL-17 on atherosclerogenic disorders will be discussed.     

Hypoxia: a double-edged sword of immunity

Hypoxia is a condition of low oxygen tension that characterizes virtually every site of inflammation, tissue damage, and neoplasia. Hypoxic environment attracts infiltrating immune cells that move against oxygen gradients and respond to these demanding conditions by switching to anaerobic metabolism to maintain their energy requirements. Several lines of evidence suggest that oxygen deprivation causes opposite effects on the innate or adaptive immune responses. We will review the evidence that the hypoxic environment promotes the recruitment, activation, and survival of innate immune cells while inhibiting the adaptive immunity through downregulation of effector lymphocyte functions. This divergent regulation of the innate and adaptive immunity appears to reflect evolutionary mechanisms aimed to both guarantee tissue homeostasis and provide safeguard mechanisms against autoimmunity. Selective inhibition of hypoxic signaling pathways in myeloid versus lymphoid cells may open new therapeutic opportunities in diseases characterized by low oxygen tension.     

Manipulation of BCG vaccine: a double-edged sword

Mycobacterium bovis Bacillus Calmette–Guérin (BCG), an attenuated vaccine derived from M. bovis, is the only licensed vaccine against tuberculosis (TB). Despite its protection against TB in children, the protective efficacy in pulmonary TB is variable in adolescents and adults. In spite of the current knowledge of molecular biology, immunology and cell biology, infectious diseases such as TB and HIV/AIDS are still challenges for the scientific community. Genetic manipulation facilitates the construction of recombinant BCG (rBCG) vaccine that can be used as a highly immunogenic vaccine against TB with an improved safety profile, but, still, the manipulation of BCG vaccine to improve efficacy should be carefully considered, as it can bring in both favourable and unfavourable effects. The purpose of this review is not to comprehensively review the interaction between microorganisms and host cells in order to use rBCG expressing M. tuberculosis (Mtb) immunodominant antigens that are available in the public domain, but, rather, to also discuss the limitations of rBCG vaccine, expressing heterologous antigens, during manipulation that pave the way for a promising new vaccine approach.     

Mast cells in hemangioma: a double-edged sword

Hemangioma is a common benign vascular tumor characterized by presentation within the few weeks of life, rapid growth during the first year and spontaneous involution over a period of several years. Mast cells play an important role in immunity and angiogenesis by synthesizing and releasing a group of bioactive mediators, cytokines and chemokines. Previous study confirmed that the number of mast cells is highest during the involuting phase, lower in the involuted phase, and lowest in the proliferating phase. There is evidence that several mast cell mediators are angiogenic by regulating endothelial cell proliferation and degrading the extracellular matrix. Mast cells may also secrete antiangiogenic modulators in the involuting stage of hemangioma. It could be postulated that mast cells may play both angiogenic and antiangiogenic roles in different stage of hemangioma. The mast cell secretion may trigger the "angiogenic switch", while the angiogenic roles may function through the other potential angiogenic factors. Better understanding of the exact role of mast cells in hemangioma will contribute to build new therapeutic interventions targeting mast cells in hemangioma.     

Immune system: a double-edged sword in cancer

Objective

The objective of the review is to examine the role of innate and adaptive immune cells in cancer.

Introduction

Immune system functions as a host defensive mechanism protecting against invading pathogens and transformed cells, including cancer. However, a body of research carried out over the last few decades has disclosed the unexpected role of immune system in fostering the tumor growth.

Methods

A computer-based online search was performed in the PubMed, Scopus and Web of Science databases for articles published, concerning natural killer (NK) cells, Macrophages, CD4+ and CD8+ T cells with relevance to cancer. After finding relevant articles within these search limits, a manual search was conducted through the references from these articles.

Results and Conclusions

This review summarizes the role of immune system in Immunosurveillance and Immunoediting. It then focused mainly on role of macrophages, regulatory T cells (Treg), T_H17 cells and on the immunosuppressive mechanisms, which facilitate immune evasion of tumor cells. Our results shows that, immune cells, such as CD8+ cytotoxic T lymphocytes (CTL), CD4+ T helper (T_H)1 cells and NK cells along with their characteristic cytokine interferon (IFN)-γ, function as major antitumor effector cells. Whereas CD4+T_H2 cells, myeloid-derived suppressor cells (MDSCs) and their derived cytokines function as dominant tumor-promoting forces. In contrast to these cells, macrophages, Treg, and T_H17 cells show a dual effect in cancer. Thus, it appears that most components of the immune system are potentially endowed with dual functions i.e., promoting tumor development on the one hand and restraining tumor development on the other and hence immune system can be considered as a double-edged sword in cancer.     

IDO expression in the brain: a double-edged sword

The tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO) initiates the first and rate-limiting step of the kynurenine pathway. It is induced by proinflammatory cytokines such as interferon-beta and interferon-gamma and has established effects in the control of intracellular parasites. The recent detection of its decisive function in immune tolerance at the maternal-fetal interface stimulated various studies unraveling its regulatory effect on T cells in many pathologies. In the brain, IDO can be induced in microglia by interferon-gamma-producing T helper (Th) 1 cells, thereby initiating a negative feedback loop which downmodulates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). This protective effect could to be counteracted by the production of neurotoxic metabolites of the kynurenine pathway such as quinolinic acid, which are produced upon IDO induction. Some metabolites of the kynurenine pathway can pass the blood-brain barrier and thus could act as neurotoxins, e.g., during systemic infection. In this paper, we give a brief overview on established immune regulatory functions of IDO, review recent data on IDO expression in the brain, and propose that autoimmune neuroinflammation and the increasingly appreciated neuronal damage in MS are linked by Th1-mediated IDO induction through subsequent synthesis of toxic metabolites of tryptophan.     

The alveolar macrophages in asthma: a double-edged sword

Asthma is a complex disease of the lungs, which is characterized by airway inflammation and airway hyperresponsiveness (AHR). Alveolar macrophages (AMs), one of the prominent immune system cells found in the airways, have been implicated in the development and progression of asthma. AMs constitute a unique subset of pulmonary macrophages, which serve as a first line of defense against foreign invaders to the lung tissue. In addition, based on human and animal studies, they have also been found to regulate pro- and anti-inflammatory responses in the airways, suggesting that these cells have a critical role in asthma. In this review, our focus is to evaluate the relevance of AMs in the context of asthma, and the underlying mechanisms that regulate their functions.     

Lymphopenia and autoimmunity: A double-edged sword

Lymphopenia is strongly associated with autoimmune diseases. The molecular mechanisms that link both phenomena are still unclear, but certain key pathways have been described. Central tolerance is as important as peripheral. In the earlier, epithelial and dendritic cells play a crucial role in the selection of clones. In the latter, regulatory T cells (Tregs) rise as inductors of anergy in order to prevent the development of autoimmune pathology. In lymphopenic conditions, T cells develop the process of lymphopenia-induced proliferation (LIP). A complex interaction between the major histocompatibility complex (MHC) and the T cell receptor (TCR) makes this process possible. Furthermore, IL-7 can act synergistically or in an independent manner to promote LIP. A lack of Transforming Growth Factor-β (TGF-β) was recently described as the second hit needed to develop autoimmunity in a lymphopenic microenvironment, given its actions in Tregs and its interaction with CTLA-4. Regarding autoimmune clinical scenarios, lymphopenia is related to both, systemic and organ-specific diseases. Thus, the molecular study of such patients has been limited and needs to be widened to the pathways shown here to be involved in the development of lymphopenia and autoimmunity.     

Evolution and complexity: the double-edged sword

We attempt to provide a comprehensive answer to the question of whether, and when, an arrow of complexity emerges in Darwinian evolution. We note that this expression can be interpreted in different ways, including a passive, incidental growth, or a pervasive bias towards complexification. We argue at length that an arrow of complexity does indeed occur in evolution, which can be most reasonably interpreted as the result of a passive trend rather than a driven one. What, then, is the role of evolution in the creation of this trend, and under which conditions will it emerge? In the later sections of this article we point out that when certain proper conditions (which we attempt to formulate in a concise form) are met, Darwinian evolution predictably creates a sustained trend of increase in maximum complexity (that is, an arrow of complexity) that would not be possible without it; but if they are not, evolution will not only fail to produce an arrow of complexity, but may actually prevent any increase in complexity altogether. We conclude that, with regard to the growth of complexity, evolution is very much a double-edged sword.     

Life and death within germinal centres: a double-edged sword

Within germinal centres, B lymphocytes are destined to die by apoptosis via Fas signalling, unless they are positively rescued by antigen and by signals initiated by CD40-CD154 interactions. Thus, while the germinal centre microenvironment can become a virtual graveyard for most B lymphocytes that fail to bind antigen with high affinity, it concomitantly provides the necessary stimuli for the survival of cells that successfully accomplish affinity maturation. Such dichotomy in the physiology of germinal centre reaction that results in survival of the functional B-cell repertoire and the elimination of abnormal cells, dictates the fate towards B-cell homeostasis or disease. Consequently, the death and survival-signalling arms within germinal centres predominantly reside on the timely and controlled expression of Fas and its ligand (FasL), and CD40 and CD154, respectively. In keeping with this notion, lymphoproliferation or deficient immunity are documented landmarks of inactivation of either the Fas/FasL or CD40/CD154 signalling pathways. The present review considers two different scenarios in the control of B-cell survival and death within germinal centres. The first is an idealistic scenario, in which a discriminatory and co-ordinate signalling initiated by the CD40/CD154 and Fas/FasL pairs, respectively, leads the rescue of the functional B-cell repertoire and the elimination of the abnormal phenotype. The second is a gloomy scenario in which both the lack and the hyperexpression of either receptor/ligand pairs, are seen as equally deleterious.     

Meningeal regulation of infections: A double-edged sword

In the past 10 years, important discoveries have been made in the field of neuroimmunology, especially regarding brain borders. Indeed, meninges are protective envelopes surrounding the CNS and are currently in the spotlight, with multiple studies showing their involvement in brain infection and cognitive disorders. In this review, we describe the meningeal layers and their protective role in the CNS against bacterial, viral, fungal, and parasitic infections, by immune and nonimmune cells. Moreover, we discuss the neurological and cognitive consequences resulting from meningeal infections in neonates (e.g. infection with group B Streptococcus, cytomegalovirus, …) or adults (e.g. infection with Trypanosoma brucei, Streptococcus pneumoniae, …). We hope that this review will bring to light an integrated view of meningeal immune regulations during CNS infections and their neurological consequences.     

Viral interactions with macroautophagy: A double-edged sword

Autophagy is a conserved eukaryotic mechanism that mediates the removal of long-lived cytoplasmic macromolecules and damaged organelles via a lysosomal degradative pathway. Recently, a multitude of studies have reported that viral infections may have complex interconnections with the autophagic process. These observations strongly imply that autophagy has virus-specific roles relating to viral replication, host innate and adaptive immune responses, virus-induced cell death programs, and viral pathogenesis. Autophagy can supply internal membrane structures necessary for viral replication or may prolong cell survival during viral infections and postpone cell death. It can influence the survival of both infected and bystander cells. This process has also been linked to the recognition of viral signature molecules during innate immunity and has been suggested to help rid the cell of infection. This review discusses interactions between different viruses and the autophagy pathway, and surveys the current state of knowledge and emerging themes within this field.     

Oxidized low-density lipoprotein activates migration and degranulation of human granulocytes

Oxidized low-density lipoprotein (oxLDL) has been reported as a major participant in the pathogenesis of atherosclerosis. We hypothesized that oxLDL can also interact with granulocytes during inflammatory airway diseases, such as asthma. To test the chemotactic effect of oxLDL, isolated human peripheral granulocytes were added to the upper chambers of Transwell filters and migration in response to oxLDL was determined. Cu+2-oxidized LDL stimulated neutrophil (23.4 +/- 3.2% for 100 microg/ml oxLDL versus 2.9 +/- 1.1% for buffer, P < 0.05) and eosinophil (19.3 +/- 3.5% versus 0.6 +/- 0.02% for buffer, P < 0.05) chemotaxis in a concentration-dependent manner. The magnitude of chemotaxis was dependent on the degree of LDL oxidation. Granulocyte transmigration across IL-1beta-activated human pulmonary microvascular endothelial cell monolayers was similarly stimulated by oxLDL. OxLDL activated significant degranulation of both neutrophils (100.9 +/- 9.8 versus 49.6 +/- 8.4 ng lactoferrin released/5 x 105 neutrophils for buffer, P < 0.05) and eosinophils (342 +/- 115.4 versus 85.8 +/- 30.4 ng eosinophil-derived neurotoxin/1 x 106 eosinophils for buffer, P < 0.05). Therefore, in vivo influx and oxidation of LDL may be an important mediator for the initiation of bronchial inflammation where granulocytes are recruited to the lung.     

Natural killer cells in HIV-1 infection: a double-edged sword

In order to propagate and persist within the host, HIV-1 subverts a variety of checkpoints of innate and adaptive viral immunosurveillance. Many of these are related to natural killer cells, which bridge innate and adaptive immunity and play a major role in defeating virus infections. HIV-1 affects cytotoxicity of natural killer cells towards infected cells and natural killer cell-mediated priming of effector cells of the adaptive immune system. Moreover, a subpopulation of natural killer cells was found sensitive to infection by HIV-1. Consequently, an efficient immune response against HIV-1 cannot be mounted in most patients. The current review highlights the molecular interplay between HIV-1 and effector cells of the host immune system with a focus on natural killer cells, and summarizes strategies of HIV-1 to escape from natural killer cell immunosurveillance. A detailed knowledge of these immune escape strategies might lead to the identification of access points for intervention in order to block infection and progression to AIDS.     

Dorsal root potentials and dorsal root reflexes: a double-edged sword

 The nature of dorsal root reflexes (DRRs) and their possible role in peripheral inflammation and the consequent hyperalgesia are reviewed. The history of DRRs and the relationship of DRRs to primary afferent depolarization and presynaptic inhibition in pathways formed by both large and fine afferents are discussed. Emphasis is placed on the mechanisms underlying primary afferent depolarization, including the anatomical arrangement of the synapses involved, how depolarization can result in inhibition by decreasing transmitter release, the role of excitatory amino acids and GABA, the manner in which the equilibrium potential for chloride ions is determined in primary afferent fibers, and forms of presynaptic inhibition that do not utilize GABA_A receptors. There is then a discussion of neurogenic inflammation, including the role of the release of neuropeptides such as substance P and calcitonin gene-related peptide from sensory nerve endings. Evidence is reviewed that links DRRs to a substantial part of the swelling of the knee joint in acute experimental arthritis and to the flare reaction in the skin following intradermal injection of capsaicin. Possible mechanisms by which the level of DRR activity might be enhanced following inflammation are suggested. The consquences of this increase in DRRs may include exacerbation of hyperalgesia as well as of peripheral inflammation. The conversion of an inhibitory process, presynaptic inhibition, to an excitatory one by DRRs can thus lead to pathological consequences. Received: 16 March 1998 / Accepted: 22 September 1998