Annual review of immunology
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A fundamental property of cells of the innate immune system is their ability to elicit a transcriptional response to a microbial stimulus or danger signal with a high degree of cell type and stimulus specificity. The selective response activates effector pathways to control the insult and plays a central role in regulating adaptive immunity through the differential regulation of cytokine genes. ⋯ Chromatin also participates in innate memory mechanisms that can promote tolerance to a stimulus or prime cells for a more robust response. These findings have generated interest in the capacity to modulate chromatin regulators with small-molecule compounds for the treatment of diseases associated with innate or adaptive immunity.
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Neutrophils are the most abundant white blood cells in circulation, and patients with congenital neutrophil deficiencies suffer from severe infections that are often fatal, underscoring the importance of these cells in immune defense. In spite of neutrophils' relevance in immunity, research on these cells has been hampered by their experimentally intractable nature. Here, we present a survey of basic neutrophil biology, with an emphasis on examples that highlight the function of neutrophils not only as professional killers, but also as instructors of the immune system in the context of infection and inflammatory disease. We focus on emerging issues in the field of neutrophil biology, address questions in this area that remain unanswered, and critically examine the experimental basis for common assumptions found in neutrophil literature.
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The significance of type I interferons (IFN-alpha/beta) in biology and medicine renders research on their activities continuously relevant to our understanding of normal and abnormal (auto) immune responses. This relevance is bolstered by discoveries that unambiguously establish IFN-alpha/beta, among the multitude of cytokines, as dominant in defining qualitative and quantitative characteristics of innate and adaptive immune processes. Recent advances elucidating the biology of these key cytokines include better definition of their complex signaling pathways, determination of their importance in modifying the effects of other cytokines, the role of Toll-like receptors in their induction, their major cellular producers, and their broad and diverse impact on both cellular and humoral immune responses. Consequently, the role of IFN-alpha/beta in the pathogenesis of autoimmunity remains at the forefront of scientific inquiry and has begun to illuminate the mechanisms by which these molecules promote or inhibit systemic and organ-specific autoimmune diseases.
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Annu. Rev. Immunol. · Jan 2001
ReviewAnti-TNF alpha therapy of rheumatoid arthritis: what have we learned?
Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNF alpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNF alpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNF alpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. ⋯ Clinical investigations in which the activity of TNF alpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNF alpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.
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Annu. Rev. Immunol. · Jan 2001
ReviewThe design of vaccines against Helicobacter pylori and their development.
Helicobacter pylori is a gram negative, spiral, microaerophylic bacterium that infects the stomach of more than 50% of the human population worldwide. It is mostly acquired during childhood and, if not treated, persists chronically, causing chronic gastritis, peptic ulcer disease, and in some individuals, gastric adenocarcinoma and gastric B cell lymphoma. The current therapy, based on the use of a proton-pump inhibitor and antibiotics, is efficacious but faces problems such as patient compliance, antibiotic resistance, and possible recurrence of infection. ⋯ The exact effector mechanisms of protection induced after immunization are still poorly understood. The next couple of years will be crucial for the development of vaccines against H. pylori. Several trials are foreseen in humans, and expectations are that most of the questions being asked now on the host-microbe interactions will be answered.