Inflammation is a primary response to injury and or infection, allowing the body to eliminate pathogens and/or damaged tissue and to initiate repair processes. Low oxygen levels, or hypoxia, is a key feature of inflamed tissue and is due to damage to the local vasculature and increased oxygen consumption by pathogens and infiltrating immune cells. In addition to being a feature of inflammation, hypoxia also induces and regulates the inflammatory response by inducing the release of inflammatory cytokines, directing immune cell infiltration, and tuning the responses of the immune cells themselves. These effects are largely mediated by a family of hypoxia-inducible transcription factors (HIFs), which serve as the master regulators of cellular responses to inadequate oxygenation and HIFs and their regulatory factors are now emerging as therapeutic targets in a number of disease states. Reviews in this series discuss the roles of hypoxia and HIFs in the regulation of inflammatory pathways, immune cell metabolism, mucosal inflammation, the tumor microenvironment, intestinal inflammation and colorectal cancer, and recovery from radiation-induced gastrointestinal toxicity. Together, these reviews identify a number of hypoxia-regulated processes that could potentially be targeted to modulate inflammation.
Published October 2016
Cell-to-cell communication is an essential component in multicellular organisms, allowing for rapid, coordinated responses to changes within the environment. Classical signaling mediators include direct cell-cell contact as well as secreted factors, such as cytokines, metabolites, and hormones. In the past decade, extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, have emerged as important mediators of intercellular communication. EVs are double-membrane vesicles containing cargoes of multiple proteins, lipids, and nucleic acids, which are derived from their cells of origin, and EV cargoes can change depending on the status of their originating cells. Importantly, EVs are found in all body fluids and can carry their cargoes to distant sites within the body as well as neighboring cells. Reviews in this series discuss the role of EV-mediated signaling in physiological and pathophysiological conditions, including infection, host immune responses, and cancer. Additionally, these reviews cover the potential clinical use of EVs as therapeutics and diagnostic biomarkers.
Published April 2016
The development of combination antiretroviral therapy (ART) in the mid-1990s initially raised hopes that HIV was a curable disease; however, further studies revealed that the virus persists, even in patients with undetectable levels of HIV in their plasma. Resting CD4+ T cells harbor stably integrated viral genomes that can produce infectious virus following T cell activation. Importantly, treatment interruption leads to a rapid recrudescence of infection from this latent reservoir, usually within 2 to 3 weeks. Several distinct areas of HIV research are now focused on the development of strategies to prevent the latent reservoir from replicating or to eliminate it entirely. Reviews in this series detail progress in our understanding of the molecular and cellular mechanisms of viral latency, efforts to accurately assess the size and composition of the latent viral reservoir, the characterization and development of HIV-targeted broadly neutralizing antibodies and cytolytic T lymphocytes, as well as animal models for the study of HIV latency and therapeutic strategies.
Published February 2016
In the mid-1800s, Rudolf Virchow noted the presence of surfeit inflammatory cells in many tumors. Roughly 50 years later, Paul Ehrlich postulated that the immune system both recognizes and protects against cancer. Since then, researchers have been trying to elucidate the relationship between cancer, inflammation, and the innate and adaptive immune systems, starting with the theory of immunosurveillance introduced by Lewis Thomas and further developed by Sir MacFarlane Burnet. We now know that tumor cells display antigens that are recognized by immune cells, but that anti-tumor immunity can be circumvented directly by tumor cells themselves via a variety of escape mechanisms. The goal of cancer immunotherapy is to mount an effective anti-tumor immune response by repairing, stimulating or, enhancing the immune system’s response to cancer cells. Reviews in this series detail progress in cancer immunoediting, immunosuppressive cells in the tumor microenvironment, cancer-associated inflammation, therapeutic cancer vaccines, genomic approaches in immunotherapy, adoptive transfer of genetically engineered T cells, and checkpoint blockade therapy.
Published September 2015
Autoimmune disease encompasses a diverse group of over 80 chronic disorders. Each of these diseases has distinct clinical manifestations that are due to the differences in the cells and organ systems involved; however, these diseases are universally characterized by a loss of self-tolerance, resulting in autoreactive immune cells, autoantibodies, and elevated levels of inflammatory cytokines. Reviews in this series examine mechanisms underlying autoimmunity, including failure of B cell tolerance checkpoints, the generation of autoantibodies, cytokine dysregulation, aberrant T cell signaling, and the loss of immune suppressive cells and functions. They also explore the influence of genetic background, environment, microRNAs, and sex-specific factors on the loss of immune homeostasis.
Published June 2015
The enteric nervous system (ENS) encompasses extrinsic and intrinsic neurons, glia, and sensory epithelial cells that are embedded throughout the gastrointestinal tract. The circuits formed by these cells are responsible for interpreting sensory information in the gut lumen in order to regulate gut motility, secretion, food intake, and immune function. The ENS communicates with the CNS in a bidirectional manner, allowing stimuli in the gut to influence mood, food intake, and other behaviors. Reviews in this series examine the mechanisms by which the ENS develops from neural crest cells, chemosensory mechanisms that allow for the detection of and response to fats and other nutrients within the gut lumen, the role of the enteric glia, regulation of ENS function by the immune system and inflammation, and the impact of surgery and the gut microbiota on ENS communication with the brain.
Published March 2015
The term autophagy, or “self-eating”, refers to the processes by which cells deliver cytoplasmic constituents to lysosomes for degradation. Autophagy provides biosynthetic precursors and energy sources to sustain metabolism and cell growth and prevent the accumulation of toxic components. These processes are invoked in response to stressors, including changing nutrient conditions, damage to organelles, intracellular pathogens, and accumulation of reactive oxygen species, among others, in order to maintain cellular homeostasis. Autophagy becomes insufficient with age and is perturbed in multiple disease states; consequently, pathogenic aberrations in autophagy have emerged as a major focus in the development of novel therapeutic strategies. Reviews in this series detail specific autophagic mechanisms; the role of autophagy in cardiovascular disease, cancer, neurodegeneration, lifespan, and the immune system; and methods to develop autophagy-centered therapeutic modalities.
Published January 2015
The human gastrointestinal tract harbors approximately one hundred trillion microbial cells, collectively known as the gut microbiome. We have been aware of these friendly bacteria for around a century, but we are only now beginning to appreciate their influence in multiple aspects of human physiology and disease. Our understanding of the gut microbiome is constantly evolving and is currently being aided by new technologies and approaches that combine ecological principles with biomedical techniques. These new studies take into account both the pathological and commensal aspects of the microbes that inhabit our bodies. Reviews in this series explore how perturbation of the microbiome not only contributes to disease, but also helps to reveal its function; the impact of the microbiome on the metabolism of therapeutics and dietary nutrients; the contributions of commensal bacteria to disease, including cancer and cardiovascular disease; and the role of the microbiome in the development and maintenance of the immune system.
Published October 2014
Nephrology encompasses the study of normal kidney function, kidney disease, and kidney replacement therapy, including kidney transplantation and dialysis. Kidney diseases are a serious public health problem, with nearly 12% of American adults suffering from chronic kidney disease (CKD). Importantly, kidney dysfunction is associated with the increasingly common conditions of obesity, diabetes, and hypertension. Recent technological advances, including genetic and epigenetic screens, metabolic profiling, new model systems, and the use of kidney biopsies for diagnosis and treatment, have created new avenues for the study of kidney pathology. Reviews in this series provide a survey of kidney pathogenesis, including hypertension, diabetic kidney disease, IgA nephropathy, idiopathic membranous nephropathy, acute kidney injury, fibrosis, and mechanisms mediating graft failure after transplantation.
Published June 2014
Significant progress in the last 15 years has transformed the field of lymphatic vasculature research into a boom area. The relatively recent identification of specific growth factors and molecular markers that distinguish endothelial cells of the lymphatic and blood vasculature lineages were pivotal for this development. Given the almost ubiquitous distribution of lymphatic vessels in most organs, it is not surprising that this type of vasculature is actively or passively involved in a large number of human diseases. The reviews in this series aim to describe a number of emerging areas in lymphatic biology, including mechanisms that mediate lymphangiogenesis, the development of mammalian lymphatic vasculature, the genetics of lymphatic anomalies, new technologies for studying the lymphatic vasculature, and the role of lymphatics in disease, including lymphedema and cancer, and physiological processes, such as inflammation and immunity. Cover image credit: K.Pichler/CeMM/MedUni Wien/Josephinum (www.josephinum.ac.at).
Published March 2014