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Editorial overview
Innate immunity Editorial overview Harvey R. Colten and Jeffrey V. Ravetch Washington
University
Sloan-Kettering
at St Louis, St Louis, Missouri
and Memorial
Cancer Center, New York, New York, USA
Current
Opinion
in Immunology
An effective host response to microbial infection and tissue injury is critically dependent on the following: a selective but not highly specific recognition system; the capacity for a rapid initial response that can be sustained by ampliiication/recruitment of effector systems to neutral ize or clear noxious products; and an orderly defervescence of the response, permitting tissue repair and a return to basal conditions. These requirements are satisfied by the ‘innate immune mechanisms’ summarized in this section. For most species, ‘innate’ immunity offers a host advantage particularly in the newly born and developing organism during which time ‘immunological experience’ is acquired. These ‘innate’ host defense mechanisms are augmented by the highly efficient adaptive immune response. The efficiency of the acquired immunity is gained by sacrificing the rapidity and broader specihcity of the innate mechanisms. Innate immunity is frequently contrasted with acquired immunity to highlight the differences between these two host defense systems. It is becoming increasingly dilh cult, however, to differentiate these two components of immunity, as our knowledge of each expands. In this section, we have attempted to focus on recent developments in our understanding of the mechanisms of innate immunity. In doing so, the interactions between innate immunity and acquired immunity are brought into sharper focus. Although it has long been appreciated that coupling of antigen-driven responses to effector mechanisms is critical to adaptive immune responses, several contributions point out the direct linkage of cell-surface recognition complexes in these systems. For example, natural killer (NK) cells recognize MHC molecules and Fc receptors share subunits with clonotypic T-cell receptors. Similarly, the exquisite specificity of antigen-driven systems is emerging as a more important theme for immune responses driven by cells of the innate response. Among the most primitive of the innate host defenses are the antibacterial peptides summarized in the review by Zasloff (pp 3-7). He emphasizes characteristics generally applicable to innate immunity such as phylogenetic antiquity (these inducible antimicrobial peptides are expressed in insects and other invertebrates as well as in higher species including mammals). These peptides
1992, 4:1-2
are elaborated at critical sites (epithelial surfaces) and their expression is regulated in response to appropriate stimuli (bacterial products, tissue injury). They function as membrane-active agents and demonstrate a surprising degree of specificity for microbes over host cells, pointing to the importance of lipid compositions as a determinant of recognition. Moreover, recent studies are cited that suggest much more is still to be learned in this important and interesting area. Recent developments in understanding a somewhat more complex humoral natural host defense system, the complement system and complement receptors, is detailed in the review by Ktych et al. (pp S-13) and the microbial strategies that have evolved to subvert complementdependent host defenses are described in the review by Frank (pp 14-19). Considerable progress has been made in this area as a result of the application of molecular biological methods to the subject during the past decade. Hence, the detailed structures and structure-function relationships of the complement receptors, signal transduction pathways activated by these receptors, the complement proteins that serve as ligands, and some of the microbial products that mimic these host defenses have been revealed. In the review by Ktych et al. are cited applications of our knowledge for control of inflammation that suggest potential therapies for many diseases. Portnoy (pp 20-24) has focused on L&end monocy togenes, long considered a paradigm of T-cell-mediated immunity. However, as he points out, T-cell-independent pathways represent a signilicant mechanism for host resistance to infection. Thus, direct lysis of infected cells by neutrophils, NK cells or mediators such as tumor necrosis factor is effective in limiting growth of the bacteria. Granuloma formation can be viewed as an effective means of limiting intracellular spreading of the organism. Innate mechanisms, however, are not totally effective and the sterilizing immunity usually seen with listeria requires the participation of CD8+ T cells. The broader role of cells such as macrophages, neutrophils and M( cells in innate immunity is covered in reviews by Gordon et al. (pp 25-32) Ryan and Worthington (pp 33-37) and Ianier and Phillips (pp 3842). Gordon’s contribution indicates the selective role of
Abbreviations MHC-major
histocompatibility complex; NK-natural
@ Current Biology Ltd ISSN 0952-7915
killer
2
Innate immunity
macrophages in diEerent tissue mIcroenvironments. The increasing sophistication brought to the understanding of these important cells by the application of molecular and cellular approaches have helped define the multiple roles attributed to these cells. The rapid advances in cell-cell contact are covered in the Ryan and Worthington review. The molecules responsible for binding, extravasation and triggering of monocytes, neutrophils and platelets with endothelial cells illustrate the Importance of considering dynamic events in these processes. Lanier and Phillips consider the expanding role of NK cells in immunity. Although much progress has been reported in the isolation of receptors involved in antibody-dependent cytotoxicity, the existence of multiple NK-cell receptor systems that distinguish between self and non-self are convincingly argued. NK cells have the capacity to recognize tumor targets in the absence of antibody or MHC class I and can also distinguish cells lacking class I as specific targets for lysis. The molecular basis for NK-cell specikity is likely to be an active area of investigation. Rapid progress has been reported over the past year in the isolation and characterization of specific receptor systems Involved in innate immunity. The overlapping activities found for these receptors suggests the importance of these effector responses in immunity. For example, phagocytosis is mediated by complement, man nose and Fc receptors by as yet unknown mechanisms. These three systems are presented in this section. Kinet (pp 43-48) has focused on the complexity of the Fc receptor system, where heterogeneity of receptors determines the speciiicity of cellular responses to immune complexes. Surprisingly, a set of common subunits have been found to be shared by Fc receptors for IgG, IgE and the TCR-03 complex, mediating assembly and signal
transduction. Stahl (pp 49-52) surveys the mannose and lectin receptors of macrophages. These molecules have taken advantage of the structural variability of complex carbohydrates for specilic and selective interactions with target cells. Cloning of many of these receptors has offered a glimpse of the complexity we can expect in this category of recognition molecules. Finally, although discussion of mediators of Innate immunity could occupy a separate section, the recent advances in one of these mediators, reactive oxygen, is summarized by Gallin et al. (pp 53-56). The study of chronic granulomatous disease of childhood has yielded Important new insights into the complexity of the components of the phagocyte NADPH ox&se system. New cytokines defined in the preceding year include the steel factor, interleukin-11 and natural killer stimulatory factor. The cloning of many cytokine receptors has revealed recurring motifs, indicative of a large family of such molecules. Signal transduction by these molecules is emerging as an active area of investigation, likely to yield important insights. The importance of the innate immune system is reflected in the complexity of their Interactions and their biological consequences. The contributions in this section represent a sampling of the progress in this field and illustrate the variety of molecules and mechanisms that combine to mediate innate immunity.
H Colten, Department of Pediatrics, Washington University School of Medicine, 400 Kingshighway, St Louis, Missouri 63110, USA J Ravetch, Laboratory of Biochemical Genetics, Memorial Sloaw Kettering Cancer Center, 1275 York Avenue, New York New York, 10021, USA
University
Sloan-Kettering
at St Louis, St Louis, Missouri
and Memorial
Cancer Center, New York, New York, USA
Current
Opinion
in Immunology
An effective host response to microbial infection and tissue injury is critically dependent on the following: a selective but not highly specific recognition system; the capacity for a rapid initial response that can be sustained by ampliiication/recruitment of effector systems to neutral ize or clear noxious products; and an orderly defervescence of the response, permitting tissue repair and a return to basal conditions. These requirements are satisfied by the ‘innate immune mechanisms’ summarized in this section. For most species, ‘innate’ immunity offers a host advantage particularly in the newly born and developing organism during which time ‘immunological experience’ is acquired. These ‘innate’ host defense mechanisms are augmented by the highly efficient adaptive immune response. The efficiency of the acquired immunity is gained by sacrificing the rapidity and broader specihcity of the innate mechanisms. Innate immunity is frequently contrasted with acquired immunity to highlight the differences between these two host defense systems. It is becoming increasingly dilh cult, however, to differentiate these two components of immunity, as our knowledge of each expands. In this section, we have attempted to focus on recent developments in our understanding of the mechanisms of innate immunity. In doing so, the interactions between innate immunity and acquired immunity are brought into sharper focus. Although it has long been appreciated that coupling of antigen-driven responses to effector mechanisms is critical to adaptive immune responses, several contributions point out the direct linkage of cell-surface recognition complexes in these systems. For example, natural killer (NK) cells recognize MHC molecules and Fc receptors share subunits with clonotypic T-cell receptors. Similarly, the exquisite specificity of antigen-driven systems is emerging as a more important theme for immune responses driven by cells of the innate response. Among the most primitive of the innate host defenses are the antibacterial peptides summarized in the review by Zasloff (pp 3-7). He emphasizes characteristics generally applicable to innate immunity such as phylogenetic antiquity (these inducible antimicrobial peptides are expressed in insects and other invertebrates as well as in higher species including mammals). These peptides
1992, 4:1-2
are elaborated at critical sites (epithelial surfaces) and their expression is regulated in response to appropriate stimuli (bacterial products, tissue injury). They function as membrane-active agents and demonstrate a surprising degree of specificity for microbes over host cells, pointing to the importance of lipid compositions as a determinant of recognition. Moreover, recent studies are cited that suggest much more is still to be learned in this important and interesting area. Recent developments in understanding a somewhat more complex humoral natural host defense system, the complement system and complement receptors, is detailed in the review by Ktych et al. (pp S-13) and the microbial strategies that have evolved to subvert complementdependent host defenses are described in the review by Frank (pp 14-19). Considerable progress has been made in this area as a result of the application of molecular biological methods to the subject during the past decade. Hence, the detailed structures and structure-function relationships of the complement receptors, signal transduction pathways activated by these receptors, the complement proteins that serve as ligands, and some of the microbial products that mimic these host defenses have been revealed. In the review by Ktych et al. are cited applications of our knowledge for control of inflammation that suggest potential therapies for many diseases. Portnoy (pp 20-24) has focused on L&end monocy togenes, long considered a paradigm of T-cell-mediated immunity. However, as he points out, T-cell-independent pathways represent a signilicant mechanism for host resistance to infection. Thus, direct lysis of infected cells by neutrophils, NK cells or mediators such as tumor necrosis factor is effective in limiting growth of the bacteria. Granuloma formation can be viewed as an effective means of limiting intracellular spreading of the organism. Innate mechanisms, however, are not totally effective and the sterilizing immunity usually seen with listeria requires the participation of CD8+ T cells. The broader role of cells such as macrophages, neutrophils and M( cells in innate immunity is covered in reviews by Gordon et al. (pp 25-32) Ryan and Worthington (pp 33-37) and Ianier and Phillips (pp 3842). Gordon’s contribution indicates the selective role of
Abbreviations MHC-major
histocompatibility complex; NK-natural
@ Current Biology Ltd ISSN 0952-7915
killer
2
Innate immunity
macrophages in diEerent tissue mIcroenvironments. The increasing sophistication brought to the understanding of these important cells by the application of molecular and cellular approaches have helped define the multiple roles attributed to these cells. The rapid advances in cell-cell contact are covered in the Ryan and Worthington review. The molecules responsible for binding, extravasation and triggering of monocytes, neutrophils and platelets with endothelial cells illustrate the Importance of considering dynamic events in these processes. Lanier and Phillips consider the expanding role of NK cells in immunity. Although much progress has been reported in the isolation of receptors involved in antibody-dependent cytotoxicity, the existence of multiple NK-cell receptor systems that distinguish between self and non-self are convincingly argued. NK cells have the capacity to recognize tumor targets in the absence of antibody or MHC class I and can also distinguish cells lacking class I as specific targets for lysis. The molecular basis for NK-cell specikity is likely to be an active area of investigation. Rapid progress has been reported over the past year in the isolation and characterization of specific receptor systems Involved in innate immunity. The overlapping activities found for these receptors suggests the importance of these effector responses in immunity. For example, phagocytosis is mediated by complement, man nose and Fc receptors by as yet unknown mechanisms. These three systems are presented in this section. Kinet (pp 43-48) has focused on the complexity of the Fc receptor system, where heterogeneity of receptors determines the speciiicity of cellular responses to immune complexes. Surprisingly, a set of common subunits have been found to be shared by Fc receptors for IgG, IgE and the TCR-03 complex, mediating assembly and signal
transduction. Stahl (pp 49-52) surveys the mannose and lectin receptors of macrophages. These molecules have taken advantage of the structural variability of complex carbohydrates for specilic and selective interactions with target cells. Cloning of many of these receptors has offered a glimpse of the complexity we can expect in this category of recognition molecules. Finally, although discussion of mediators of Innate immunity could occupy a separate section, the recent advances in one of these mediators, reactive oxygen, is summarized by Gallin et al. (pp 53-56). The study of chronic granulomatous disease of childhood has yielded Important new insights into the complexity of the components of the phagocyte NADPH ox&se system. New cytokines defined in the preceding year include the steel factor, interleukin-11 and natural killer stimulatory factor. The cloning of many cytokine receptors has revealed recurring motifs, indicative of a large family of such molecules. Signal transduction by these molecules is emerging as an active area of investigation, likely to yield important insights. The importance of the innate immune system is reflected in the complexity of their Interactions and their biological consequences. The contributions in this section represent a sampling of the progress in this field and illustrate the variety of molecules and mechanisms that combine to mediate innate immunity.
H Colten, Department of Pediatrics, Washington University School of Medicine, 400 Kingshighway, St Louis, Missouri 63110, USA J Ravetch, Laboratory of Biochemical Genetics, Memorial Sloaw Kettering Cancer Center, 1275 York Avenue, New York New York, 10021, USA