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- Volume 13, 1995
Annual Review of Immunology - Volume 13, 1995
Volume 13, 1995
- Review Articles
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Choices Following Antigen Entry: Antibody Formation or Immunologic Tolerance?
Vol. 13 (1995), pp. 1–28More LessThe research briefly summarized here covers 38 years of work in cellular immunology, briefly devoted to understanding how antigen subserves the antithetical functions of stimulating antibody formation and inducing tolerance. The three interlocking themes running through the work are the development of methods to beat the problem of heterogeneity among lymphocytes by studying single cells and single clones; critical pursuit of antigen-trapping patterns within lymphoid tissues and analysis of consequent cellular events; and construction of models of tolerance that permit the detection of events subtler than direct purging of the B cell repertoire. One of the best features of this adventure has been its international character, the interaction with colleagues in many countries, and the influence that this work, despite its entirely fundamental character, has exerted in the practical world of preventive and clinical medicine.
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Hepatitis B Virus Immunopathogenesis
Vol. 13 (1995), pp. 29–60More LessApproximately 5% of the world population is infected by the hepatitis B virus (HBV) that causes a necroinflammatory liver disease of variable duration and severity. Chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. While the humoral antibody response to viral envelope antigens contributes to the clearance of circulating virus particles, the cellular immune response to the envelope, nucleocapsid, and polymerase antigens eliminates infected cells. The class I- and class II-restricted T cell responses to the virus are vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and the responses are relatively weak and more narrowly focused in chronically infected patients who do not. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been demonstrated by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg-specific CTL into HBV transgenic mice, and by the noncytolytic suppression of viral gene expression and replication in the same animals by a posttranscriptional mechanism mediated by interferon gamma, tumor necrosis factor alpha, and interleukin 2. The dominant cause of viral persistence during HBV infection is the development of a weak antiviral immune response to the viral antigens. While neonatal tolerance probably plays an important role in viral persistence in patients infected at birth, the basis for poor responsiveness in adult-onset infection is not well understood and requires further analysis. Viral evasion by epitope inactivation and T cell receptor antagonism may contribute to the worsening of viral persistence in the setting of an ineffective immune response, as can the incomplete downregulation of viral gene expression and the infection of immunologically privileged tissues. Chronic liver cell injury and the attendant inflammatory and regenerative responses create the mutagenic and mitogenic stimuli for the development of DNA damage that can cause hepatocellular carcinoma. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic and antiviral strategies to terminate chronic HBV infection and reduce the risk of its life-threatening sequellae.
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Positive Selection of Thymocytes
Vol. 13 (1995), pp. 93–126More LessDifferentiation of αβ T cell receptor (TCR)-expressing T cells involves an obligatory interaction with self-major histocompatibility complex (MHC) molecules in the thymus. This process, called positive selection, both rescues thymocytes from programmed cell death and induces their differentiation into mature T cells. Another critical event in thymic development is to prevent maturation of hazardous autoreactive T cells; thus, mechanisms exist to eliminate T cells with self-reactive receptors (negative selection). How can these two pathways be distinguished? This question, which has long taxed immunologists, is more opposite because many features of the interactions in positive and negative selection are shared: Both processes are exquisitely MHC-allele specific, they involve MHC-bound peptide recognition, and employ at least some overlapping signal transduction pathways. However, resolution of this paradox has become much more feasible with the advent of powerful systems for withdrawing and reconstituting individual components involved in positive selection. This review describes recent advances in our understanding of the cells, receptors, ligands, and signaling pathways involved in this process. A pivotal part of this puzzle is the basis for discrimination between TCR ligands that induce positive vs negative selection. Recent work suggests that the peptide/MHC ligand for positive selection may bind with low avidity to the TCR. The implications of these data for the nature of T cell recognition during positive selection are discussed below.
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Immunology of Reactive Arthritides
Vol. 13 (1995), pp. 229–250More LessReactive arthritis (ReA) and Lyme arthritis together comprise a pair of chronic inflammatory diseases of the joints. Although differing in detail, these relatively rare diseases are related in their immunopathology to the much commoner rheumatoid arthritis (RA), for which they serve as both model and control. The trigger for rheumatoid arthritis is unknown, but for these rarer diseases triggering occurs by certain well-defined bacterial infections. Arthritis is an uncommon outcome of these infections, for reasons unknown, and the development of chronic, as distinct from brief, arthritis is even rarer; again, the reasons are unknown. Not only does knowing the trigger greatly assist us in understanding these diseases, so also does knowing the contrasting pattern of Th1 versus Th2 cytokines observed in RA and ReA. ReA and Lyme arthritis are here considered in the wider setting of infections where chronic morbidity arises first from hypersensitivity, and perhaps finally from autoimmunity, such as occurs in some of the major tropical diseases. The immunology of ReA and Lyme disease is surveyed in detail, concentrating on T cells and including an update on the Lyme vaccine(s). Additional sections deal with the enigma of HLA B27, with epidemiological findings relevant to the chronicity of ReA and to the need for enlarged prospective studies of ReA in the setting of a developing country.
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Interleukin-12: A Proinflammatory Cytokine with Immunoregulatory Functions that Bridge Innate Resistance and Antigen-Specific Adaptive Immunity
Vol. 13 (1995), pp. 251–276More LessInterleukin-12 (IL-12) is a heterodimeric cytokine produced mostly by phagocytic cells in response to bacteria, bacterial products, and intracellular parasites, and to some degree by B lymphocytes. IL-12 induces cytokine production, primarily of IFN-γ, from NK and T cells, acts as a growth factor for activated NK and T cells, enhances the cytotoxic activity of NK cells, and favors cytotoxic T lymphocyte generation. In vivo IL-12 acts primarily at three stages during the innate resistance/adaptive immune response to infection: 1. Early in the infection, IL-12 is produced and induces production from NK and T cells of IFN-γ , which contributes to phagocytic cell activation and inflammation; 2. IL-12 and IL-12- induced IFN-γ favor Thl cell differentiation by priming CD4+ T cells for high IFN-γ production; and 3. IL-12 contributes to optimal IFN-γ production and to proliferation of differentiated Th l cells in response to antigen. The early preference expressed in the immune response depends on the balance between IL-12, which favors Thl responses, and IL-4, which favors Th2 responses. Thus,IL-12 represents a functional bridge between the early nonspecific innate resistance and the subsequent antigen-specific adaptive immunity.
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Principles for Adoptive T Cell Therapy of Human Viral Diseases
Vol. 13 (1995), pp. 545–586More LessThe development of successful adoptive immunotherapy for human virus infections is predicated on an understanding of the effector cells and mechanisms essential for providing the host with a protective response to acute infection and the requirements for long-term in vivo survival of transferred cells that will be necessary to provide memory responses to persistent and latent viral infections. In this review, we discuss the results of recent studies examining the effector mechanisms mediated by virus-specific αβ+ T cells and the strategies viruses have evolved to evade recognition by such T cells and/or to interfere with the expression of T cell effector functions. The evasion strategies employed by individual viruses can render T cell subsets or T cells of particular specificities less effective in eliminating virally infected cells, and consequently they are less desirable choices for use in adoptive therapy. Insights derived from described studies of the pathogenesis and immunobiology of virus infections have resulted in the development of clinical adoptive immunotherapy studies for infections with CMV, EBV, and HIV. Although the results from such studies are preliminary, the principle that virus-specific T cells can be successfully transferred and can mediate therapeutic efficacy in humans has already been affirmed. The use of recently developed methods, such as retroviral-mediated gene transfer, to genetically modify antigen-specific T cell clones provides a novel approach to overcome limitations and improve on the safety and efficacy observed in these initial studies, suggesting that more widespread use of adoptive transfer of specific T cells as a therapeutic regimen should be feasible in the near future.
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The Three-Dimensional Structure of Peptide-MHC Complexes
Vol. 13 (1995), pp. 587–622More LessThe ability of MHC molecules to present a broad spectrum of peptide antigens for T cell recognition requires a compromise between high affinity and broad specificity. Three-dimensional atomic structures of several class I and class II MHC molecules reveal a unique structural solution to this problem: Tight binding to the peptide main chain is supplemented by more or less restrictive interactions with peptide side chains. In spite of these contacts, peptide side-chain and conformational variability ensures that the resulting peptide-MHC complex presents an antigenically unique surface to T cell receptors.
Extension of this understanding to other peptide-MHC complexes, including agonist/antagonist peptides and the identification of antigenic peptides within protein sequences, however, requires a detailed analysis of the interactions that determine both peptide-MHC binding affinity and the conformations of bound peptides. While many of these interactions can be modeled by homology with known structures, their specificity can depend sensitively on subtle and long range structural effects. Structurally and immunologically important distinctions are also found between the class I and class II peptide-binding strategies. Taken together, these interactions ultimately determine the ability of an individual to respond successfully to immune challenges.
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Potassium and Calcium Channels in Lymphocytes
Vol. 13 (1995), pp. 623–653More LessOver the past decade, a variety of ion channels have been identified and characterized in lymphocytes by use of the patch-clamp technique. This review discusses biophysical and regulatory aspects of lymphocyte potassium and calcium channels with the aim of understanding the role of these channels in lymphocyte functions. Lymphocytes express both voltage-dependent potassium [K(V)] channels and calcium-activated potassium [K(Ca)] channels, and each is upregulated as cells progress toward division following mitogenic stimulation. The genes encoding two K(V) channels, Kv1.3 (type n) and Kv3.1 (type l), have cloned. Mutational analysis is revealing functionally important regions of these channel proteins. Exogenous expression studies and the use of highly specific channel blockers have helped to establish the roles of type n K(V) channels sustaining the resting membrane potential, in regulating cell volume, and in enabling lymphocyte activation. Blockade of K(V) and K(Ca) channels effectively inhibits the antigen-driven activation of lymphocytes, probably by inducing membraned epolarization and thereby diminishing calcium influx. A prolonged rise in intracellular calcium ([ Ca2+]i) is a required signal for lymphocyte activation by antigen or mitogens. Single-cell fluorescence measurements have revealed underlying [Ca2+]i oscillations that are linked closely to the opening and closing of Ca2+ and K+ channels. Sustained Ca2+ signaling and oscillations depend absolutely on plasma-membrane Ca2+ channels that are activated by the depletion of intracellular calcium stores. Under physiological conditions these channels open as a consequence of store depletion induced by inositol 1,4,5-trisphosphate (IP3), but they can also be activated experimentally by several agents that empty the stores without generating IP3, such as the microsomal Ca2+-ATPase inhibitor thapsigargin. The intricate causal relationships among ion channels, membrane potential, [Ca2+]i, and lymphokine gene expression can now be pursued at the single-cell level with patch-clamp recording, calcium-dependent dyes, reporter genes, and fluorescence video techniques. These approaches will help to clarify the essential roles of ion channels in the molecular pathways subserving activation and other lymphocyte behaviors.
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T Cell-Independent Antigens Type 2
Vol. 13 (1995), pp. 655–692More LessIn this review we have attemped to define the characteristics of TI-2 antigens that enable them to stimulate antibody production in the absence of T cell help. One of the most critical properties of this group of antigens is their ability to deliver prolonged and persistent signaling to the B cell. This by itself is not however sufficient to stimulate Ig synthesis, and they mus therefore stimulate non-T cells to interact with the B cells either directly or indirectly via cytokine production. There is evidence implicating the NK cell and T cell as playing this important role in response to TI antigens. Furthermore, we discuss the importance of cytokines such as IL-3, GMCSF and IFN-γ, which significantly enhance antibody production by these antigens. Finally, we present evidence demonstrating that B cell activation via TI stimuli does not play merely a permissive role in allowing for cell cycle entry and enhanced responsiveness to other stimuli. Rather, the nature of the B cell activating signal is critical in determining the quantitative and qualitative profile of Ig isotype production.
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Previous Volumes
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Volume 41 (2023)
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Volume 40 (2022)
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Volume 39 (2021)
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Volume 38 (2020)
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Volume 37 (2019)
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Volume 36 (2018)
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Volume 35 (2017)
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Volume 34 (2016)
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Volume 33 (2015)
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Volume 32 (2014)
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Volume 31 (2013)
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Volume 30 (2012)
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Volume 29 (2011)
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Volume 28 (2010)
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Volume 27 (2009)
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Volume 26 (2008)
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Volume 25 (2007)
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Volume 24 (2006)
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Volume 23 (2005)
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Volume 22 (2004)
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Volume 21 (2003)
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Volume 20 (2002)
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Volume 19 (2001)
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Volume 18 (2000)
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Volume 17 (1999)
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Volume 16 (1998)
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Volume 15 (1997)
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Volume 14 (1996)
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Volume 13 (1995)
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Volume 12 (1994)
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Volume 11 (1993)
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Volume 10 (1992)
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Volume 9 (1991)
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Volume 8 (1990)
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Volume 7 (1989)
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Volume 6 (1988)
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Volume 5 (1987)
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Volume 4 (1986)
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Volume 3 (1985)
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Volume 2 (1984)
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Volume 1 (1983)
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Volume 0 (1932)