The deterioration of immune function with advancing age contributes to the increased incidence of morbidity and mortality among the elderly from infectious disease and possibly cancer. The innate and adaptive arms of immunity are affected by the deleterious effects of aging, but it is adaptive immunity, and in particular T lymphocytes, that is most susceptible to these effects. The aging of the immune system, referred to as immunosenescence, is associated with a dramatic decline in responsiveness as well as functional dysregulation. Age-associated alterations in T cells are evident at all stages of its development, and it is these changes that contribute to the overall increased susceptibility to infection and possibly cancer. Although there is an enormous effort worldwide to develop vaccines, much of the research is performed with young animals. Because the immune system of the aged is different from that of the young, many of the findings cannot be extrapolated. In this review, we will discuss those differences in T cell immunity of the aged, relate how these differences influence the immune response of the aged to pathogens as well as to tumors, and describe the current approaches to rejuvenate the aged immune response. Although the majority of the conclusions on T cell immunity in the aged are based on studies in the murine model, many of these findings can be extended to the human model. Throughout this review, we have noted those findings that are specific to humans.
Lymphocyte function-associated antigen-1 (LFA-1, αLβ2, CD11a/CD18) plays a critical role in the complex and well-orchestrated molecular interactions responsible for cell adhesion events required for normal and pathologic functions of the immune system. This review focuses on the diseases from various etiologies (genetic, bacterial, viral, neoplastic, allergic, and autoimmune) that are associated to lymphocyte function-associated antigen-1 with a tremendous impact on human and animal health.
Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, αLβ2) actively contributes to the molecular interactions responsible for normal functions of the immune system but is also associated to several diseases from various etiology (genetic, bacterial, viral, neoplastic, allergic, and autoimmune). In this way, the interaction between lymphocyte function-associated antigen-1 and its major ligand intercellular adhesion molecule-1 (ICAM-1 or CD54) has been extensively studied, leading to the development of therapeutic antibodies, peptides, and small inhibitory molecules.
A wide range of age-related alterations in immune system function have been reported and are referred to as immunosenescence. Much of the decline in immunoresponsiveness seen in elderly persons is due to changes within the T cell compartment because of the involution of the thymus. For this reason, infectious diseases are more frequent and severe in elderly persons, and the efficacy of vaccinations is low. Recently, scientific evidence has accumulated that chronic cytomegalovirus (CMV) infection may accelerate the aging of the immune system and may lead to a high chronic-inflammatory background in elderly persons. This may exacerbate the functional pathology and disease course of age-related disorders, such as atherosclerosis, rheumatoid arthritis, and Alzheimer's disease. Therefore, the present article will summarize the changes that occur in the immune system of elderly persons with and without chronic CMV infection and will highlight the impact of CMV infection on the immune response and efficacy of vaccinations in old age. It will also elucidate the mechanisms CMV uses to escape immune surveillance, the basis for life-long persistence in the host. Finally, current and future immunotherapeutic strategies to fight or prevent CMV infection will be reviewed.
The β2-integrin lymphocyte function-associated antigen-1 (LFA-1, αLβ2, CD11a/CD18) is made of the association of the CD11a and CD18 subunits that each possesses a large extracellular region and short transmembrane and cytoplasmic parts. A general comparison among species enlights the importance of especially conserved functional regions, as well as their role in folding and heterodimerization. This review also focuses on providing insights into structural aspects that lead to lymphocyte function-associated antigen-1 ability, central to its critical role in the molecular interactions responsible for leukocyte adhesion and migration in the immune system, to modulate dynamically its adhesiveness through avidity (affinity and valency)-based mechanisms.
To patrol the body effectively for infectious organisms, the cells of the immune system must both circulate as nonadherent cells in the blood and lymph and, in the presence of a foreign antigen, be able to congregate in lymphoid organs, cross endothelial and basement membranes to aggregate at sites of infection, and adhere to cells bearing foreign antigen. In this context, lymphocyte function-associated antigen-1 (LFA-1, αLβ2, CD11a/CD18) plays a critical role (1) in forming stable bonds with counter receptors in the vascular walls to allow leukocytes to leave the circulation and (2) in validating the interaction between an antigen presenting cell and a T lymphocyte. Both roles are described in detail in this review.
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.
Malignant melanoma is a lethal disease for which the only curative therapy of proven benefit is complete surgical resection for early stage disease. Melanoma is a disease that is usually resistant to systemic therapy, with dacarbazine and interleukin-2 being the only 2 United States Food and Drug Administration approved drugs for advanced disease, and interferon alfa-2b the only one approved therapy for adjuvant treatment of high-risk disease. Evidence has shown that melanoma cells can be immunogenic prompting extensive basic and clinical research attempting to develop effective antimelanoma vaccine therapies. In this review, we concentrate on clinical results of vaccine trials in patients with melanoma.
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 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 up regulate 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 NF-κB, MAPK and AP-1. This transcriptional activation induces the expression of cytokines and intracellular adhesion molecules that facilitates 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.
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.
Psoriasis is a chronic, T-cell mediated autoimmune disorder that affects up to 2.5% of the population worldwide and is accompanied by substantial physical and psychosocial distress. Recent progress in understanding the mechanisms behind the efficacy of conventional treatments has transformed psoriasis from a disease of keratinocyte hyperproliferation to that of T cell pathogenesis. Current treatment options for psoriasis are limited in efficacy and are associated with a number of problems such as inconvenience, organ toxicity, and broad-band immunosuppression. Hence, there has been a demand for new therapeutic approaches that are more convenient, effective, safe, and immunologically selective. Numerous biologic agents that modulate T cell and cytokine action at various steps along the pathogenic sequence have been developed and studied in clinical trials for the treatment of psoriasis. The current review will explore these novel immunomodulatory therapies.
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.
Campylobacteriosis is a leading bacterial food-borne illness in developed countries. Guillain–Barré syndrome is the most common acute flaccid paralysis due to an autoimmune disorder in nature. A considerable number of Guillain–Barré syndrome patients present with a prior history of campylobacteriosis, and Guillain–Barré syndrome is considered a sequela of infections caused specifically by Campylobacter jejuni. Because Campylobacter is normally contracted through consumption of contaminated foods including those derived from food animals, food safety measures aimed at the disruption of oral transmission will not only reduce the prevalence of campylobacteriosis but also potentially lessen the incidence of Guillain–Barré syndrome. An emerging public health concern regarding Campylobacter is the issue of microbial food safety due to increasing numbers of antimicrobial-resistant isolates. Part of the reason to address this emerging microbial food safety concern is to institute and maintain better monitoring and control programs, which require a collective effort among public health authorities.
Viral diseases continue to pose some of the greatest challenges to modern medicine. For many viral diseases, prophylactic vaccines are unlikely to be developed in the near future. Fortunately, effective antiviral therapies have been developed for many of these viruses. In this review, I will focus on antiviral therapy for herpes simplex virus, human immunodeficiency virus, hepatitis C virus, and human papillomavirus. The development of compounds targeting these viruses illustrates many of the principles driving current antiviral development. It is likely that our increasing understanding of viral replication and the virus-host interaction will lead to more rapid development of new antivirals in the future.
The immunotherapy of patients with metastatic melanoma is currently at a crossroads. Indeed, recent results from vaccine strategies worldwide have revealed a strikingly low overall response rate in patients with stage IV melanoma. Although disappointing, we have gained valuable insight and knowledge about how vaccines interact with the host immune response and to melanoma. However, although an immunological response to therapy is often reported from various clinical trials, it does not contribute to a patient's long term survival. It has been proven time and again that an immunological response to therapy does not necessarily translate into a meaningful clinical response. This frustrating dichotomy of response continues to vex investigators, providing a glaring example of our poor understanding of the immunologic response to cancer. Thus, we remain at the crossroads of understanding and treatment. On the one hand, we have dramatically advanced the field of tumor immunology/immunotherapy over the last 20 years. On the other hand, we have made little headway in truly developing effective treatment options for patients with stage IV disease. We must realize our previous shortcomings and failures in order to learn from them and develop improved therapies. The future of immunotherapy remains a bright ray of hope for everyone, with the road to success paved with the previous hard work of thousands of clinicians and researchers everywhere. Towards this end, this review hopes to provide the reader with the current state of affairs for the immunotherapy of melanoma as well as a primer of where we might be heading in the future.
Over the last decade there have been some profound changes in the way we treat inflammatory arthritis. In the late 1980's and early 1990's, a significant philosophy change that had been underway for at least a decade was formalized with the concept of “inverting the pyramid”, which was to treat patients early and aggressively to prevent joint damage. In the late 1990's the biologic agents became available and these played into this concept of early aggressive therapy with their ability to affect inflammation rapidly and prevent joint damage. Currently the use of the biologic agents is undergoing some “fine tuning” as we add their power to older disease modifying agents such as methotrexate. New biologic agents are on the horizon that will hopefully add to the ability to diminish the impact of inflammatory arthritis. Cost and unknown long-term side effects add caution to the use of these agents. Rheumatologists finally have therapies that we do not need statisticians to tell us that they work; our patients demonstrate their efficacy to us daily.
The technique of observing fluorescence resonance energy transfer (FRET) between a cyan fluorescent protein (CFP) fusion protein and a yellow fluorescent protein (YFP) fusion protein has been used in numerous studies as a reliable indicator of protein–protein interaction. Moreover, because CFP and YFP fusions generally retain activity and maintain their normal subcellular localizations, the detection of CFP–YFP FRET in live cells typically reflects the steady-state association of functional proteins in their native states. Although CFP–YFP FRET can also be monitored by fluorimetry and fluorescence microscopy, the ability of flow cytometry to rapidly acquire multiparameter fluorescence data on a large number of individual cells provides several important advantages. The analysis of CFP–YFP FRET on a cell-by-cell basis allows for a sensitive and highly rigorous assessment of protein interaction, and the large number of cells that can be examined by flow cytometry provides for a high degree of statistical confidence. In addition, simple, yet stringent, gating-based analyses of FRET can be performed on a flow cytometer simultaneously with data collection, allowing FRET-based cell sorting that can be used in high-throughput screens to identify interacting proteins. As a brief review of flow cytometric CFP–YFP FRET analysis, this article outlines a typical instrument configuration, describes the required controls, explains how gating is performed, and discusses the basic physical principles behind FRET as they relate to the successful design and interpretation of protein interaction experiments.
Multiple sclerosis (MS) remains a leading cause of neurologic disability among young adults. Clinical manifestations of the disease result from immune-mediated demyelination of the central nervous system. Most patients experience new symptoms in a relapsing-remitting pattern, although the course is highly variable from person to person and even in the same individual over time.
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.
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.
