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- Volume 16, 1998
Annual Review of Immunology - Volume 16, 1998
Volume 16, 1998
- Review Articles
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DIMERIZATION AS A REGULATORY MECHANISM IN SIGNAL TRANSDUCTION
Vol. 16 (1998), pp. 569–592More Less▪ AbstractDynamic protein-protein interactions are a key component of biological regulatory networks. Dimerization events—physical interactions between related proteins—represent an important subset of protein-protein interactions and are frequently employed in transducing signals from the cell surface to the nucleus. Importantly, dimerization between different members of a protein family can generate considerable functional diversity when different protein combinations have distinct regulatory properties. A survey of processes known to be controlled by dimerization illustrates the diverse physical and biological outcomes achieved through this regulatory mechanism. These include: facilitated proximity and orientation; differential regulation by heterodimerization; generation of temporal and spatial boundaries; enhancement of specificity; and regulated monomer-to-dimer transitions. Elucidation of these mechanisms has led to the design of new approaches to study and to manipulate signal transduction pathways.
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THE IMMUNOGENETICS OF HUMAN INFECTIOUS DISEASES
Vol. 16 (1998), pp. 593–617More Less▪ AbstractTwin and adoptee studies have indicated that host genetic factors are major determinants of susceptibility to infectious diseases in humans. Twin studies have also found high heritabilities for many humoral and cellular immune responses to pathogen antigens, with most of the genetic component mapping outside of the major histocompatibility complex. Candidate gene studies have implicated several immunogenetic polymorphisms in human infectious diseases. HLA variation has been associated with susceptibility or resistance to malaria, tuberculosis, leprosy, AIDS, and hepatitis virus persistence. Variation in the tumor necrosis factor gene promoter has also been associated with several infectious diseases. Chemokine receptor polymorphism affects both susceptibility to HIV-1 infection and the rate of progression to AIDS. Inactivating mutations of the γ-interferon receptor lead to increased susceptibility to atypical mycobacteria and disseminated BCG infection in homozygous children. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor appear to be associated with differential susceptibility to several infectious diseases. NRAMP1, a macrophage gene identified by positional cloning of its murine homologue, has been implicated in susceptibility to tuberculosis in Africans. Whole genome linkage analysis of multi-case families is now being used to map and identify new loci affecting susceptibility to infectious diseases. It is likely that susceptibility to most microorganisms is determined by a large number of polymorphic genes, and identification of these should provide insights into protective and pathogenic mechanisms in infectious diseases.
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HOW DO MONOCLONAL ANTIBODIES INDUCE TOLERANCE? A Role for Infectious Tolerance?
Vol. 16 (1998), pp. 619–644More Less▪ AbstractOne of the major goals in therapeutic immunosuppression has been to achieve long-term benefit from short-term therapy. The discovery in the mid-1980s that CD4 antibodies can induce immunological tolerance without depleting CD4+ T cells has reawakened interest in the use of nondepleting monoclonal antibodies for reprogramming the immune system in autoimmunity and in transplantation. Since that time, antibodies to CD11a, CD4OL, CD25, CD3, and CTLA4-Ig have all been shown capable of facilitating tolerance. In order to apply the principle of reprogramming in the clinic, we have sought to understand the mechanisms that are involved in its induction and its maintenance. In a number of allogeneic transplant models (heart, skin, bone marrow) anti-CD4 (± CD8) antibodies can be shown to block the rejection process while selectively promoting the development of CD4+ regulatory T cells responsible for a dominant tolerance that is reflected in findings of linked suppression and infectious tolerance. In these models, T cells that have never been exposed to CD4 antibodies become tolerant to grafted antigens by experiencing antigen in the microenvironment of regulatory T cells. Dominant tolerance is not the only mechanism that can be facilitated by CD4 Mab therapy. If allogeneic marrow is given at high cell doses under the umbrella of CD4 and CD8 antibodies, then tolerance can be achieved through clonal deletion.
The mechanism by which regulatory CD4+ T cells suppress is not yet defined but could be active or passive. We have proposed the “civil service model” to explain how tolerant T cells might interfere with the responses of competent T cells in such a way as to render them tolerant.
The application of dominant infectious tolerance and linked suppression to clinical immunosuppression should not be underestimated because it suggests that tolerance acquired (through therapy) to a limited set of antigens can spread to embrace all others in the tissues under attack.
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POSITIVE VERSUS NEGATIVE SIGNALING BY LYMPHOCYTE ANTIGEN RECEPTORS
Vol. 16 (1998), pp. 645–670More Less▪ AbstractAntigen receptors on lymphocytes play a central role in immune regulation by transmitting signals that positively or negatively regulate lymphocyte survival, migration, growth, and differentiation. This review focuses on how opposing positive or negative cellular responses are brought about by antigen receptor signaling. Four types of extracellular inputs shape the response to antigen: (a) the concentration of antigen; (b) the avidity with which antigen is bound; (c) the timing and duration of antigen encounter; and (d) the association of antigen with costimuli from pathogens, the innate immune system, or other lymphocytes. Intracellular signaling by antigen receptors is not an all-or-none event, and these external variables alter both the quantity and quality of signaling. Recent findings in B lymphocytes have clearly illustrated that these external inputs affect the magnitude and duration of the intracellular calcium response, which in turn contributes to differential triggering of the transcriptional regulators NFκB, JNK, NFAT, and ERK. The regulation of calcium responses involves a network of tyrosine kinases (e.g. lyn, syk), tyrosine or lipid phosphatases (CD45, SHP-1, SHIP), and accessory molecules (CD21/CD19, CD22, FcRγ2b). Understanding the biochemistry and logic behind these integrative processes will allow development of more selective and efficient pharmaceuticals that suppress, modify, or augment immune responses in autoimmunity, transplantation, allergy, vaccines, and cancer.
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Previous Volumes
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Volume 42 (2024)
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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)