CONTENTS
Review
- Immune Balance in Critically Ill Patients
MICHAEL R. PINSKYAbstract. The systemic inflammatory response reflects the non-specific clinical expression of a profound activation of the body’s immune responsive elements. Immune activation and immune suppression coexist in the blood of patients with severe sepsis. It is their interaction and the resultant host parenchymal responses that ultimately define the course of sepsis. Importantly, neither profound immune activation (pro-inflammatory) or immune suppression (anti-inflammatory) characterize the dominant process. Rather, there is a combined low grade pro-inflammatory state associated with an immune hyporesponsiveness that defines the usual immunologic state of the patient with severe sepsis.
Keywords: inflammatory response; PMN leukocyte activation; inflammatory mediators.
- T Cell Integrin Activation by Chemokines in Inflammation
YOSHIYA TANAKAAbstract. The adhesive function of integrins is regulated through cytoplasmic signaling induced by several stimuli, whose process is designated „inside-out signaling”. A large number of lymphocytes are recruited to the sites of inflammation where they form an essential component of the response to infection, injury, autoimmune disorders, allergy, tumor invasion, atherosclerosis and so on. The recruitment of leukocytes into tissue is regulated by a sequences of interactions between the circulating leukocytes and the endothelial cells. Leukocyte integrins play a pivotal role in leukocyte adhesion to endothelial cells. During the process, the activation of integrins by chemokines, is essential for integrin-mediated adhesion in which a signal transduced to the leukocyte converts the functionally inactive integrin to an active adhesive configuration. The present review documents the relevance of cytoplasmic signaling and cytoskeletal assembly to integrin-mediated adhesion induced by chemokines during inflammatory processes.
Keywords: T lymphocytes; recirculation/recruitment; adhesion molecules; integrins; chemokines; inflammation.
- T Cell Chemokine Receptor Expression in Human Th1- and Th2-Associated Diseases
J. DARREN CAMPBELL and KENT T. HAYGLASSAbstract. The interaction between chemokines and their receptors is an important step in the control of leukocyte migration into sites of inflammation. Chemokines also mediate a variety of effects independent of chemotaxis, including induction and enhancement of Th1- and Th2—associated cytokine responses. Recent studies have shown that human Th1 and Th2 clones, activated under polarizing conditions with polyclonal stimuli in vitro, display distinct patterns of chemokine receptor expression: Th1 clones preferentially express CCR5 and CXCR3 while many Th2 clones express CCR4, CCR8 and, to a lesser extent, CCR3. These differential patterns of chemokine receptor expression suggest a mechanism for selective induction of migration and activation of Th1- and Th2-type cells during inflammation and, perhaps, normal immune homoeostasis. Studies have begun to examine T cell chemokine receptor expression in vivo to determine the relevance of these in vitro observations to human Th1 and Th2-associated diseases. In this review, we critically examine recent reports of T cell chemokine receptor expression in human autoimmune disorders (multiple sclerosis and rheumatoid arthritis) and atopic disorders (allergic rhinitis and asthma) which are believed to arise from inappropriate Th1- and Th2-dominated responses, respectively.
Keywords: multiple sclerosis; rheumatoid arthritis; atopy; chemokines; chemokine receptors; T cells.
- Interleukin 15: Its Role in Inflammation and Immunity
LIYANAGE P. PERERAAbstract. Interleukin-15 (IL-15) is a 14-15 kDa polypeptide that belongs to the four alpha-helix bundle family of cytokines and was originally discovered due to its T cell proliferative activity. It utilizes the signal transducing b/g polypeptides of the IL-2 receptor complex thus sharing many biological activities with IL-2, in addition to its high affinity private receptor subunit IL-15Ra. Accumulating evidence indicates that the biological relevance of IL-15 may not solely be confined to T lymphocytes, but to a variety of cell populations within the immune system as well as outside the immune system of the host. The expression of both IL-15 and its high affinity receptor component, IL-15Ra are readily demonstrable in a wide variety of tissues and appear to be augmented in response to environmental/stress stimuli and infectious agents. There is increasing evidence to suggest that IL-15 may play an important role in protective immune responses, allograft rejection and the pathogenesis of autoimmune diseases where mononuclear cell infiltration is a hallmark feature. Herein, the effects of IL-15 on cells associated with host defense, immunity and inflammation are reviewed and support a central role for this cytokine in orchestrating multiple aspects of effector functions in immunity and inflammation.
Keywords: interleukin 15; natural killer cells; monocytes; dendritic cells.
- Cytokines and Costimulatory Molecules: Positive and Negative Regulation of the Immune Response to Cryptococcus neoformans
ANNA VECCHIARELLIAbstract. Cytokines are small proteins or glycoproteins that transmit information from one cell to another. Most cells in the body secrete and respond to cytokines and their effects have been described on a myriad of cellular functions. Cytokine interactions may not be linear, thus making the system extremely intricate and with unpredictable features. Therefore, each model of disease may be unique with its own mechanism of autoregulation dictated by positive and negative feedback involving cytokines and costimulatory molecules. The emergence of some cytokines over others in the course of C. neoformans infection may characterize a positive or negative outcome of cryptococcosis. Much less is known about the influence of costimulatory molecules in regulating C. neoformans immune response. The available information indicates a critical role for proinflammatory cytokines such as tumor necrosis factor-a and interleukin (IL)-12. The positive role of interferon-g in infected tissue as an inducer of antimicrobial function of innate immune cells and as positive feedback for IL-12 induction appears to be indisputable. In vitro studies indicate that costimulatory molecule expression appears to be regulated on antigen presenting cells by C. neoformans and increased expression of B7-1 and CD40 on these cells may promote a protective response. These studies await confirmation in an in vivo system. The interplay between cytokines and costimulatory molecules has been scarcely explored, and additional details are needed to better understand how they convey positive and negative information to immune cells in response to C. neoformans.
Keywords: C. neoformans; cytokines; costimulatory molecules.
- Prostaglandins and Inflammation: the Cyclooxygenase Controversy
OLIVIER MORTEAUAbstract. Prostaglandins (PGs) are arachidonic acid metabolites produced by the action of the enzyme cyclooxygenase (COX). Although PGs are important mediators of inflammation in various diseases, they also are key factors in the physiological regulation of gastrointestinal and renal homeostasis. The finding that two distinct COX isoforms are responsible for PG synthesis has provided basis to the opposite actions of PGs in inflammation and homeostasis regulation. COX-1-derived PGs are thought to mediate cytoprotective actions on the gastrointestinal mucosa, whereas COX-2-derived PGs are assumed to display pro-inflammatory properties. This dichotomy has led to the development of selective inhibitors of COX-2 activity which are safer for the gastrointestinal mucosa than the classic inhibitors of both COX isoforms. However, some COX-2 antiinflammatory properties have been recently demonstrated in several experimental models of inflammation. These studies have raised some concern about the potential adverse effects of COX-2 selective inhibitors. In addition, there is evidence that COX-1 displays pro-inflammatory properties, depending on the organ and on the stage of the inflammatory response. This review will focus on the roles of COX-1 and COX-2 in inflammation, based on studies involving pharmacologic COX inhibitors as well as COX knockout mice, with a particular emphasis on the gastrointestinal tract.
Keywords: prostaglandins; cyclooxygenase; NSAIDs; inflammation; colitis.
- Nuclear Import of Arachidonate 5-Lipoxygenase
THOMAS G. BROCK and ANNETTE M. HEALYAbstract. Leukotrienes are lipid messenger molecules that are secreted by leukocytes to orchestrate a rapid and prolonged immune response. The enzyme 5-lipoxygnease catalyzes the rate-limiting first two steps in the synthesis of leukotrienes from arachidonic acid. Although it has long been known that 5-lipoxygenase moves from the cytoplasm to a membrane following activation, it has only recently been recognized that the enzyme may shuttle into and out of the nucleus before activation. The regulation of this movement of soluble 5-lipoxygenase between the cytoplasm and the nucleoplasm, as well as its impact on 5-lipoxygenase action, leukotriene synthesis and cell function, is only now being elucidated. This review details the state of our understanding of the nuclear import of 5-lipoxygenase and its potential importance in immunity.
Keywords: leukotrienes; 5-lipoxygenase; nuclear import.
- Suppression of Mast Cell Activation by Glucocorticoid
HIDESHI YOSHIKAWA and KACHIO TASAKAAbstract. Mast cells play a critical role in allergic diseases. When mast cells are activated by cross-linking of their high affinity IgE receptors by the antigen and IgE antibodies, release of chemical mediators is followed by secretion of multiple cytokines. We report that IL-3-dependent mucosal-type mast cells undergo apoptosis when IL-3 is withdrawn. In addition, cross-linking of high affinityIgE receptors prevents apoptosis of mast cells by paractine mechanisms, producing IL-3, IL-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF). However, the secretion of endogenous growth factors are not enough for cell survival, whereas IL-4 induces cell aggregation by expressing adhesion molecules such as leukocyte function-associated antigen 1 (LFA-1), and makes it reactive to endogenous growth factors by contact cell to cell interaction. On the other hand, dexamethazone down-regulates the expression of intracellular adhesion molecule 1 (ICAM-1) and IL-4 in activated mast cells, by which the self-aggregation of mast cells is inhibited and poptosis is induced. Thus, glucocorticoids suppress mast cell survival by inhibiting IL-4 production and expression of adhesion molecules.
Keywords: allergy; mast cell; glucocorticoid; cytokine; adhesion molecule.
- Pathogenetic Mechanisms of Atopic Dermatitis
SAVERIA PASTORE, MARIA LAURA GIUSTIZIERI, FRANCESCA MASCIA, ALBERTO GIANNETTI and GIAMPIERO GIROLOMONIAbstract. Atopic dermatitis (AD) is a chronic inflammatory disease which results from complex interactions between genetic and environmental mechanisms. An altered lipid composition of the stratum corneum is responsible of the xerotic aspect of the skin, and determines a higher permeability to allergens and irritants. Keratinocytes of AD patients exhibit a propensity to an exaggerated production of cytokines and chemokines, a phenomenon that can have a major role in promoting and maintaining inflammation. Specific immune responses against a variety of environmental allergens are also implicated in AD pathogenesis with a bias towards Th2 immune responses. In particular, dendritic cells expressing membrane IgE receptors, play a critical role in the amplification of allergen-specific T cell responses. Cross-linkage of specific IgE receptors on dermal mast cells provokes release and synthesis of a vast series of mediators. Following their recruitment and activation into the skin, eosinophils are also thought to contribute relevantly to tissue damage. Thus, a complex network of cytokines and chemokines contributes to establish a local milieu that favors the permanence of inflammation in AD skin.
Keywords: skin; atopy; keratinocytes; dendritic cells; T lymphocytes.
- Recent Advances in Understanding How Interleukin 13 Signals Are Involved in the Pathogenesis of Bronchial Asthma
KENJI IZUHARA, RITSUKO UMESHITA, MINA AKAIWA, TARO SHIRAKAWA, KLAUS A. DEICHMANN, KAZUHIKO ARIMA, BIN YU, NAOTAKA HAMASAKI and JULIAN H. HOPKINAbstract. The prevalence of allergic disease has dramatically increased in recent decades, especially in urban and industralized areas. Allergic disease are disorders of the immune system, the results of complex interactions among various genetic and environmetal factors. Among them, the important role of interleukin 13 (IL-13), a TH2-type cytokine, has recently emerged in the pathogenesis of bronchial asthma. Based on studies using mice, great attention has been paid to the direct effects of IL-13 on bronchial tissues. In this review, we describe recent advances in understanding the signal transduction mechanism of IL-13, the infolvement of IL-13 signal-related genes as genetic factors in the pathogenesis of bronchial asthma, and the expression of IL-13 receptor on bronchial tissues. We describe potential strategies for targeting IL-13 signals to improve allergic states.
Keywords: allergy; interleukin 13; interleukin 3; bronchial asthma; receptor.
- The Inflammatory Response in M. tuberculosis Infection
ZAHRA TOOSSIAbstract. Infection with Mycobacterium tuberculosis (MTB) is accompanied by an intense local inflammatory response which may be critical to the pathogenesis of tuberculosis. Activation of components of the innate immune response, such as recruitment of polymorphonuclear (PMN) and mononuclear phagocytes and induction of pro-inflammatory cytokines, such as tumor necrosis factor a (TNF-a), by MTB occurs early after MTB infection, however, may persist as the organism establishes itself within granulomas. MTB and its protein and non-protein components are potent in induction of cytokines and chemokines from PMN and monocytes. This review focuses on the interaction of MTB and the host with regard to activation of the innate immune response. It also attempts to identify the potential impact of this early response on the subsequent pathogenesis of MTB, and its role in development and extent of tuberculosis. Insights into the initiation and persistent of the inflammatory response may allow the application of anti-inflammatory agents as adjuncts in the treatment of tuberculosis.
Keywords: polymorhonuclear; monocyte; cytokine; chemokine; tumor necrosis factor a; Mycobacterium tuberculosis; tuberculosis.
- Mechanisms of Mycobacterium avium Pathogenesis
LUIZ E. BERMUDEZ, DIRK WAGNER and DANUTA SOSNOWSKAAbstract. Infections caused by M. avium are common in AIDS patients and patients with chronic lung diseases. The bacterium can be acquired both by the intestinal route and respiratory route. M. avium is capable of invading mucosal epithelial cells and translocate across the mucosa. The bacterium can infect macrophages interfering with several functions of the host cell. The host defense against M. avium is primarily dependent on CD4+ T lymphocytes and NK cells. Activated macrophages can inhibit or kill intracellular bacteria by mechanisms that are currently unknown but M. avium can invade resting macrophages and suppress key aspects of its function by triggering the release of TGF-b and IL-10. Co-infection with HIV-1 appears to be mutually beneficial with both organisms growing faster.
Keywords: Mycobacterium avium
- The Therapeutic Potential of Interleukin 10 in Infection and Inflammation
ASHOK KUMAR and W. DAVID CREERYAbstract. Interleukin 10 (IL-10), a cytokine with inhibitory activity on inflammation and cell–mediated immune responses (CMIR), holds enormous potential for the treatment of inflammatory and autoimmune disorders. In addition, IL-10 has also been implicated in the immunopathogenesis of a number of infectious diseases through the use of IL-10 knock-out or IL-10 transgenic mouse models. In this review, we delineate infectious and inflammatory conditions in which IL-10 has shown potential for therapeutic manipulation. Specifically, we review the role of IL-10 in human endotoxemia/sepsis and in HIV infection, conditions for which preliminary phase I trials have recently been undertaken. It is suggested that the therapeutic potential of IL-10 to selectively ameliorate human infectious and inflammatory processes can be realized through a careful selection of the clinical conditions in which patients are undergoing concomitant treatment with anti-microbial regimens.
Keywords: IL-10; IL-10 knock-out mice; infectious diseases; sepsis; HIV.
- Idiopathic Pulmonary Fibrosis: Molecular Mechanisms and Possible Therapeutic Strategies
BERNT VAN DEN BLINK, HENK. M. JANSEN and MAIKEL P. PEPPELENBOSCHAbstract. Idiopathic pulmonary fibrosis (IPF) is a devastating disease with an almost universally terminal outcome. In recent years much insight has been gained into the pathogenesis of IPF from both a bleomycin mice-model as well as ex vivo human tissue studies. Alveolar damage and inflammation of unknown etiology, eventually leading to interstitial fibrosis, characterize IPF. Apoptosis has emerged as an important factor in the pathogenesis of IPF. This review will outline the current understanding of the immunological and molecular mechanisms underlying IPF, and discuss new therapeutic strategies.
Keywords: apoptosis; fibrosis; Fas; inflammation; bleomycin.
- Bacteriophage Therapy of Bacterial Infections: an Update of Our Institute`s Experience
BEATA WEBER-DĄBROWSKA, MARIAN MULCZYK and ANDRZEJ GÓRSKI
Abstract. 1307 patients with suppurative bacterial infections caused by multidrug resistant bacteria of different species were treated with specific bacteriophages (BP). BP therapy was highly effective; full recovery was noted in 1123 cases (85.9%). In 134 cases (10.9%) transient improvement was observed and only in 50 cases (3.8%) BP treatment was found to be ineffective. The results confirm the high effectiveness of BP therapy in combating bacterial infections which do not respond to treatment with all available antibiotics.
Keywords: phage therapy; drug resistance; bacterial infections .