Science in Medicine
Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence
Abstract
Since the identification of the hepatitis C virus (HCV) 20 years ago, much progress has been made in our understanding of its life cycle and interaction with the host immune system. Much has been learned from HCV itself, which, via decades of coevolution, gained an intricate knowledge of host innate and adaptive immune responses and developed sophisticated ways to preempt, subvert, and antagonize them. This review discusses the clinical, virological, and immunological features of acute and chronic hepatitis C and the role of the immune response in spontaneous and treatment-induced HCV clearance.
Authors
Barbara Rehermann
Abstract
Holoprosencephaly (HPE), the most common human forebrain malformation, occurs in 1 in 250 fetuses and 1 in 16,000 live births. HPE is etiologically heterogeneous, and its pathology is variable. Several mouse models of HPE have been generated, and some of the molecular causes of different forms of HPE and the mechanisms underlying its variable pathology have been revealed by these models. Herein, we summarize the current knowledge on the genetic alterations that cause HPE and discuss some important questions about this disease that remain to be answered.
Authors
Xin Geng, Guillermo Oliver
Abstract
SLE, a chronic, multisystem autoimmune disorder with a broad range of symptoms, involves defective B cell selection and elimination of self-reactive B cells. B lymphocyte stimulator (BLyS), a soluble ligand of the TNF cytokine family, is a prominent factor in B cell differentiation, homeostasis, and selection. BLyS levels affect survival signals and selective apoptosis of autoantibody-producing B cells. High levels of BLyS may relax B cell selection and contribute to autoantibody production, exacerbating the SLE disease state. This review discusses the mechanism of BLyS action on B cells, its role in SLE, and specific targeting of BLyS in the treatment of SLE.
Authors
Michael P. Cancro, David P. D’Cruz, Munther A. Khamashta
Abstract
Bardet-Biedl syndrome (BBS) is a multisystemic disorder typified by developmental and progressive degenerative defects. A combination of genetic, in vitro, and in vivo studies have highlighted ciliary dysfunction as a primary cause of BBS pathology, which has in turn contributed to the improved understanding of the functions of the primary cilium in humans and other vertebrates. Here we discuss the evidence linking the clinical BBS phenotype to ciliary defects, highlight how the genetic and cellular characteristics of BBS overlap with and inform other ciliary disorders, and explore the possible mechanistic underpinnings of ciliary dysfunction.
Authors
Norann A. Zaghloul, Nicholas Katsanis
Abstract
Given the dramatic increase in skeletal size during growth, the need to preserve skeletal mass during adulthood, and the large capacity of bone to store calcium and phosphate, juxtaposed with the essential role of phosphate in energy metabolism and the adverse effects of hyperphosphatemia, it is not surprising that a complex systems biology has evolved that permits cross-talk between bone and other organs to adjust phosphate balance and bone mineralization in response to changing physiological requirements. This review examines the newly discovered signaling pathways involved in the endocrine functions of bone, such as those mediated by the phosphaturic and 1,25(OH)2D-regulating hormone FGF23, and the broader systemic effects associated with abnormalities of calcium and phosphate homeostasis.
Authors
L. Darryl Quarles
Abstract
Monocyte-derived macrophages can determine the outcome of the immune response and whether this response contributes to tissue repair or mediates tissue destruction. In addition to their important role in immune-mediated renal disease and host defense, macrophages play a fundamental role in tissue remodeling during embryonic development, acquired kidney disease, and renal allograft responses. This review summarizes macrophage phenotype and function in the orchestration of kidney repair and replacement of specialized renal cells following injury. Recent advances in our understanding of macrophage heterogeneity in response to their microenvironment raise new and exciting therapeutic possibilities to attenuate or conceivably reverse progressive renal disease in the context of fibrosis. Furthermore, parallels with pathological processes in many other organs also exist.
Authors
Sharon D. Ricardo, Harry van Goor, Allison A. Eddy
Abstract
Overconsumption of lipid-rich diets, in conjunction with physical inactivity, disables and kills staggering numbers of people worldwide. Recent advances in our molecular understanding of cholesterol and triglyceride transport from the small intestine to the rest of the body provide a detailed picture of the fed/fasted and active/sedentary states. Key surprises include the unexpected nature of many pivotal molecular mediators, as well as their dysregulation — but possible reversibility — in obesity, diabetes, inactivity, and related conditions. These mechanistic insights provide new opportunities to correct dyslipoproteinemia, accelerated atherosclerosis, insulin resistance, and other deadly sequelae of overnutrition and underexertion.
Authors
Kevin Jon Williams
Abstract
Recent investigations have suggested that it might be possible to reverse the pathology of pulmonary arterial hypertension (PAH), a disorder that can be rapidly progressive and fatal despite current treatments including i.v. prostacyclin. This review will address the cellular and molecular processes implicated in clinical, genetic, and experimental studies as underlying the pulmonary vascular abnormalities associated with PAH. Emerging treatments are aimed at inducing apoptosis of abnormal vascular cells that obstruct blood flow and at promoting regeneration of “lost” distal vasculature.
Authors
Marlene Rabinovitch
Abstract
Phagocytosis is a key component of the innate immune response and of the clearance of apoptotic bodies. Phagosome formation and subsequent maturation require extensive cytoskeletal rearrangement and precisely choreographed vesicular fusion and fission events. The objectives of this review are to highlight the functional importance of lipids in the phagocytic process, to discuss how pathogenic microorganisms can in some cases manipulate host lipid metabolism to either co-opt or disrupt phagosome maturation and promote their own survival, and to describe how defective phagosomal lipid metabolism can result in disease.
Authors
Benjamin E. Steinberg, Sergio Grinstein
Abstract
Although the impact of tumor immunology on the clinical management of most cancers is still negligible, there is increasing evidence that anticancer immune responses may contribute to the control of cancer after conventional chemotherapy. Thus, radiotherapy and some chemotherapeutic agents, in particular anthracyclines, can induce specific immune responses that result either in immunogenic cancer cell death or in immunostimulatory side effects. This anticancer immune response then helps to eliminate residual cancer cells (those that fail to be killed by chemotherapy) or maintains micrometastases in a stage of dormancy. Based on these premises, in this Review we address the question, How may it be possible to ameliorate conventional therapies by stimulating the anticancer immune response? Moreover, we discuss the rationale of clinical trials to evaluate and eventually increase the contribution of antitumor immune responses to the therapeutic management of neoplasia.
Authors
Laurence Zitvogel, Lionel Apetoh, François Ghiringhelli, Fabrice André, Antoine Tesniere, Guido Kroemer
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ISSN: 0021-9738 (print), 1558-8238 (online)