Clinical and applied immunology reviews最新文献

Chronic obstructive pulmonary disease (COPD) exacerbations are an important cause of the considerable morbidity and mortality found in COPD. COPD exacerbations increase with increasing severity of COPD, and some patients are prone to frequent exacerbations leading to hospital admission and readmission. These frequent exacerbations may have considerable impact on quality of life and activities of daily living. Factors that increase the risk for COPD exacerbations are associated with increased airway inflammation caused by common pollutants and bacterial and/or viral infections. These inflammatory responses cause mucus hypersecretion and, thereby, airway obstruction and associated exacerbations. While chronic mucus hypersecretion is a significant risk factor for frequent and severe exacerbations, patients with chronic mucus hypersecretion have a lower rate of relapse after initial treatment for acute exacerbation. The benefit of antibiotics for treatment of COPD exacerbations is small but significant. While the mechanisms of actions are not clear, mucolytic agents reduce the number of days of disability in subjects with exacerbations. Reducing mucous cell numbers in small airways could be a useful way to reduce chronic mucus hypersecretion. Our studies suggest that programmed cell death is crucial in the resolution of metaplastic mucous cells, and understanding these mechanisms may provide novel therapies to reduce the risk of COPD exacerbations.

Scleroderma is a fibrotic condition characterized by immunological abnormalities, vascular injury, and increased accumulation of matrix proteins in the skin. Although the etiology of scleroderma has not been fully elucidated, a growing body of evidence suggests that the overproduction of extracellular matrix by activated fibroblasts results from complex interactions among endothelial cells, lymphocytes, macrophages, and fibroblasts, via a number of mediators.

Cytokines, chemokines, and growth factors secreted by inflammatory cells and mesenchymal cells (fibroblasts and myofibroblasts) play an important role in the fibrotic process of scleroderma. Animal models are important tools for achieving a better understanding of the pathophysiology of scleroderma. In this review, we summarize some of the current insights into the role of cytokines in human as well as animal models of scleroderma.

There is increasing evidence that young children with severe respiratory syncytial virus (RSV)–induced bronchiolitis are at high risk of developing allergy and asthma during their later life. The determinants for this association are not well understood. Current studies suggest that both genetic backgrounds and unique characteristics of the virus play critical roles in determining the type of immune responses to RSV infection, leading to altered regulation of airway tone associated with wheezing. In susceptible subjects, RSV may either enhance the Th2 immune response or decrease the Th1 immune response. This altered Th1/Th2 cytokine response associated with RSV infection is not commonly observed among other RNA viruses, suggesting that RSV may have unique characteristics. Multiple clinical studies support the link between severe RSV bronchiolitis and the subsequent development of allergy and asthma. This link will be further tested by the ongoing large studies on the effect of early RSV intervention on the development of allergy. The administration of palivizumab, an anti-RSV monoclonal antibody, seems to be helpful for RSV prevention and treatment at early stage. There are no effective RSV vaccines available, and this is, at least in part, because of the poorly understood immunology and pathogenesis of RSV disease. The use of experimental animal models has led to a better, but not sufficient, understanding of the immunologic basis of RSV-induced disease, particularly asthma. Further studies on the immunopathology of RSV infection with animal models, including the nonhuman primate models, may help develop effective RSV vaccines.

The inhalation of cigarette smoke triggers a marked cellular influx in the lung, and this inflammation is believed to play a central role in the development of smoke-related lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Studies demonstrate that smoke-derived oxidants are a major factor in this inflammatory reaction to cigarette smoke. These oxidants can overwhelm the lung's antioxidant defenses, and they can upregulate inflammation by a number of mechanisms. Free radicals directly stimulate the production of chemotactic compounds such as 8-isoprostane. In addition, smoke-derived oxidants can activate several intracellular signaling cascades including nuclear factor kappa B, mitogen-activated protein kinase, and AP-1. This transcriptional activation induces the expression of cytokines and intracellular adhesion molecules that facilitate the trafficking of neutrophils, macrophages, and lymphocytes into the lung. Moreover, oxidants can promote chromatin remodeling that facilitates the expression of proinflammatory genes by stimulating the acetylation of histone residues in the nucleosome. This leads to conformational changes that enhance expression by rendering the gene more accessible to binding to transcriptional factors. Thus, the oxidant–antioxidant imbalance generated by cigarette smoke can promote inflammation, which is critical to the functional decline that occurs in both asthma and COPD patients. Future research is needed to better define the effects of smoke-derived oxidants on lung inflammation and to determine the most efficacious strategies for generating significant antioxidant protection in the lung.

Sensitization to antigens of the HLA and ABO system has been the biggest barrier to access in renal transplantation and, increasingly, in transplantation of other organs. Additionally, antibody to donor antigens has been shown to result in injury to the graft ranging from catastrophic, irreversible hyperacute rejection to the slower, more insidious, chronic form of rejection. The problem of access has been recognized globally and has been the incentive for measures to overcome the disadvantage experienced by the sensitized patient. However, early attempts to reduce sensitization achieved only transient success. Newer immunosuppressive agents that affect B-cell function or viability have permitted the development of treatment protocols to eliminate and, potentially, downregulate donor-specific antibodies. The use of these protocols has achieved successful transplants that were HLA and/or ABO incompatible prior to treatment and, as such, has provided some patients with their only opportunity for transplantation.

Immunosuppressants are used in posttransplantation patient care and autoimmune disease therapy. Because of their narrow therapeutic ranges and high variations of the interindividual pharmacokinetics, therapeutic drug monitoring (TDM) of immunosuppressants is critical. The most common methods used in the clinical laboratories for measurement of immunosuppressants are immunoassays and liquid chromatography coupled with ultraviolet detection, which are subject to interference by the metabolites formed in vivo. Liquid chromatography coupled with mass spectrometry (LC/MS) is a powerful analytical tool that provides high specificity and sensitivity in TDM of the immunosuppressants. In this article, the recent development of LC/MS application in measurement of the immunosuppressants is reviewed, and its benefits and pitfalls are critically discussed. The immunosuppressants included in this review are cyclosporine A, tacrolimus, sirolimus, everolimus, and mycophenolic acid. Because of the simplified sample preparation and the high sensitivity and specificity, LC/MS has shown great potential to be the method of choice for TDM of the immunosuppressants, especially for simultaneous multiple-drug monitoring.

Polymorphisms of human Fc gamma receptor IIA (FcγRIIA) have been described and shown to be associated with susceptibility to and severity of certain infectious diseases. Invasive Streptococcus pneumoniae infection continues to be a major cause of morbidity and mortality throughout the world and effective host defense against S. pneumoniae depends on immunoglobulin (Ig) G2–mediated phagocytosis of the bacteria by polymorphonuclear leukocytes. One of the major functions of the FcγRIIA receptor is to play a crucial role in the phagocytosis of IgG2-opsonized bacteria because it is the only receptor able to interact with IgG2 immune complexes. The FcγRIIA polymorphism (FcγRIIA-R131 vs. FcγRIIA-H131) determines the capacity of IgG2-mediated phagocytosis via this receptor. Thus, studies that have examined the direct functional role of R131 and H131 in phagocytosis of the opsonized S. pneumoniae by effector cells in clinically relevant patient groups would provide compelling evidence linking this polymorphism with disease. Here we review the role of FcγRIIA polymorphisms as a host-genetic factor influencing S. pneumoniae infection and describe the in vitro and clinical studies that support the importance of this association.

Flow cytometry is most often used in the clinical laboratory for the purpose of immunophenotyping. Here, fluorescently labeled antibodies are bound to cell surface receptors, and their presence on the cell is most often defined in bivariate terms of positive or negative, with a cutoff set relative to a nonstaining control population. It has long been recognized that the intensity of the fluorescent signal is proportional to the amount of antibody bound per cell and therefore related to the number of antigen sites expressed. This relationship makes flow cytometers, at least theoretically, capable of quantifying antigen expression in terms of molecules per cell. There were numerous obstacles to the development of such methods and clinical utilization of fluorescence intensity measures by flow cytometry has in the past been largely overlooked. The first widespread recognition of the clinical utility for fluorescence intensity measures came from laboratories where malignant phenotypes were defined by aberrant intensity of staining due to over or under expression of various cellular proteins. These semiquantitative measures were relative in nature and described staining as bright or dim compared to that normally seen in healthy individuals. Recent advances within the past decade have resulted in the development of flow cytometric methods and materials that now permit one to conduct measures of quantitative fluorescence with improved levels of control and interlaboratory precision. With these advances have come increasing interest in quantitative flow cytometry as a method to quantify the expression and activities of a variety of proteins and enzymes for diagnostic, prognostic, and therapeutic purposes. This article discusses the background and theoretical and practical considerations, as well as the current use of quantitative flow cytometry measures in the clinical laboratory.

Chronic obstructive pulmonary disease (COPD) could develop following long-term exposure of individuals to cigarette smoke, toxic gases, and particulate matter, resulting in airway flow limitation, pulmonary failure, multiple systemic effects, and, eventually, death. The disease is associated with pulmonary inflammation with its own specific characteristics, and could be exacerbated by multiple factors such as microbial infection. COPD is chronic and progressive in nature, and multiple pulmonary inflammatory cells are detected at different stages of the disease, with a possible network of interactions with parenchymal cells. The pathological changes in the lung of COPD patients are characterized by an excess of extracellular matrix deposition, yet, loss of extracellular matrix in alveoli, increased thickness of airway walls, mucus hypersecretions, and destruction of alveolar septae, resulting in narrowing of airway diameters, reduced functional lung parenchyma, and decreased elastic tethering forces to maintain airway patency. Multiple factors, such as inflammatory cytokines, proteolytic proteinases, and oxidative stress molecules are suspected to be responsible, each at some degree, for these structural changes leading to airway obstruction. Because not everyone exposed to cigarette smoke will develop the disease, it is reasonable to think that multiple risk factors are involved and that COPD could be developed along a variety of pathways. Our current understanding of pulmonary changes associated with COPD, its similarity and differences with asthma, the nature of inflammatory cells associated with the disease, and the capacity of different molecules to induce a variety of these structural alterations are discussed to advance a cellular and molecular look at the pathogenesis of COPD.