Innate immunity

Editorial overview

Innate immunity: 50 ways to kill a microbe

Eric Brown, John P Atkinson and Douglas T Fearon

Washington University School of Medicine, St Louis, USA and University of Cambridge, Cambridge, UK

Current Opinion in Immunology 1994, 6:73-74

In the absence of an immune system, multicellu- lar organisms cannot survive attack from the more rapidly growing, more easily adaptable members of the prokaryotic and eukaryotic kingdoms. Innate immu- nity is the foundation of host defense in multicellular organisms and can be defined as the collected func- tions of cells, serum proteins, cytokines and other bar- riers to infection in the absence of specific, or antigen- driven, immunity. Neutrophils, macrophages and nat- ural killer cells are recognized as the primary effector cells of innate immunity; the complement cascade, and a variety of lectins and lipid binding proteins such as mannose-binding protein, C-reactive protein and lipo- polysaccharide (Ll?S)-binding protein are some of the major serum effecters in this pathway. Innate immu- nity is phylogenetically older than antigen-specific im- munity, and its recognition mechanisms may underlie the self/non-self discrimination that has so exquisitely developed in specific immunity [I]. Of course innate immunity has evolved in concert with specific immu- nity, and therefore these are not separate and uncon- nected mechanisms of host defense. For example, the complement system is both part of innate immunity and an effector arm of the humoral immune system [21. Should natural antibody be thought of as part of innate or of specific immunity? Cytokines that markedly affect T- and B-cell function are produced by macrophages and also by natural killer (NK) cells, mast cells and eosinophils. T and B cells, by direct interaction or by producing cytokines and antibodies, can affect the functions of all the cells involved in innate immunity. Thus it is not possible to unravel completely innate from antigen-specific immunity in a functioning im- mune system. Because of its essential role in immunity, and its importance in pathology and pathogenesis of various diseases, and because of the increasing number of severely immunocompromised hosts encountered in clinical medicine, the study of antigen-independent host defense has become increasingly important.

Major advances have occurred in the past few years in understanding the molecular and cell biology of the innate immune system. An increasingly detailed

understanding of cell-cell interactions in inflammation has refocused attention on innate immunity. For ex- ample, Ca*+-binding lectins known as selectins, ex- pressed on both endothelial cells and leukocytes, are necessary for early events in leukocyte extravasation to sites of inflammation. This has led to an intense search for the specific ligands for these selectins, which is reviewed in this issue by McEver(pp 75-84). Stud- ies of NK cells, eosinophils and mast cells have re- vealed they can be major sources of cytokines that in- fluence immune function. NK cells make inteferon-‘y, which can enhance the ability of both macrophages and neutrophils to eliminate invading pathogens. The studies on cytokine production by eosinophils and mast cells as well as an update on the contents of their granules are reviewed in this issue by Weller (pp 85-90) and Schwartz (pp 91-97). Basophils pro- duce interleukin (IL)-4 and IL-~, and eosinophils syn- thesize a plethora of cytokines, including granulocyte- macrophage colony-stimulating factor, IL-3 and IL-5, which regulate their own proliferation, and IL-6, IL- 8 and tumor necrosis factor-a, which can influence other aspects of the immune response. Despite these advances, the true roles for these cells in immunity are not understood, and future studies will be directed at elucidation of this aspect of the biology of these cells.

The study of the molecular mechanisms involved in innate immunity can have direct implications not only for antigen-specific immunity, but also for more broad questions in cell biology. In this sense, the tradi- tional separations between subdisciplines in biology are rapidly disappearing. This is most evident in stud- ies of signal transduction, in which pathways are em- ployed that are preserved at least in outline throughout the eukaryotic kingdom. The studies of seven-trans- membrane ‘serpentine’ receptors, reviewed by Gerard and Gerard (pp 140-145), of small GTP-binding pro- teins, reviewed by Bokoch and Knaus (pp 9%105), and of phospholipases and tyrosine kinases, reviewed by Thelen and Wirthmueller (pp 106-1121, in leuko- cyte activation have been tremendously influenced by findings in systems as diverse as yeast mating factor

Abbreviations LPS-lipopolysaccharide; IL-interleukin; NK-natural killer; NOSnitric oxide synthase; Rag-recombinase activating gene;

s&&-severe combined immunodeficient.

@Current Biology Ltd ISSN 0952-7915 73

74 Innate immunitv

secretion and Drososphila eye development. Some of the most useful models for the regulation of actin as- sembly and disassembly in chemotaxis, reviewed by Downey (pp 113-1241, come from studies of unicell- ular or primitive organisms like Dictyostelium discoid- ium, Saccharomyces cerevisae and Caenorhabditis el- egans, as well as from studies of fish keratocytes and nerve growth cones. Undoubtedly, studies of signal transduction from binding of the LPS-LPS-binding pro- tein (LBP) complex to cells, reviewed in this issue by Ulevitch and Tobias (pp 125-1301, and selectin bind- ing to its ligands, reviewed by McEver, also will rely on these or other models in apparently unrelated cells as paradigms. In parallel, studies of leukocyte activa- tion have provided new insights into signal transduc- tion, which are relevant throughout the phylogenetic tree. Moreover, while these models provide valuable insights and speed progress in studies of leukocyte ac- tivation, it is important ultimately to understand leuko- cyte activation specifically. These activation pathways are excellent targets for pharmacological interference with the effector pathways of the immune response. A more detailed understanding of the activation path- ways would likely lead to the development of new classes of anti-inflammatory drugs for the treatment of autoimmune and other idiopathic inflammatory condi- tions. The point at which the innate immune system and antigen-specific immunity certainly converge is in the effector mechanisms for the destruction of invading pathogens. The last few years have seen the discov- ery of several mechanisms of pathogen elimination, in- cluding the purification and analysis of several classes of bacterial peptides and the recognition of the role of reactive nitrogen intermediates in killing of intra- cellular parasites. The reactive nitrogen intermediates are generated by an inducible macrophage nitric oxide synthase (NOS). What is known about nitric oxide in host defense and inflammation and its relationship with the better understood reactive oxygen metabo- lites is the subject of the review by Bastian and Hibbs (pp 131-139). While inducible NOS activity has not been reconstituted in vitro, the NADPH oxidase, a key microbicidal mechanism of phagocytes, has. The oxi- dase is a complex of at least seven gene products, whose assembly is regulated by cell activation. The as- sembly of the NADPH oxidase is discussed by Bastian

and Hibbs, and aspects of signal transduction neces- sary for association of the cytoplasmic and membrane components of the complex into an active enzyme are discussed in the reviews by Bokoch and Knaus and by Thelen and Wirthmueller.

Ultimately, these elegant studies of receptors, signal transduction, and effecters require in vivo validation. The potential for the use of severely immunodeficient mice such as scid mice, which have no functional T or B cells, for the study of innate immunity isolated from antigen-specific responses is great. Several groups have made elegant use of these mice. With targeted gene ablation, such as of the recombinase activating gene, (Rag)-1 and Rag-2 knockout mice, which are even more immunodeficient than scid mice and which do not have the problem of development of a few T and B cells with age, have been developed. These mice have even more exciting potential as experimental an- imals in which to study innate immunity. The near fu- ture will likely see further major advances in the under- standing of the role of innate immunity in host defense in vivo. The receptors, signalling pathways that they trigger, and the effector systems of the innate immune response may also be invoked by the acquired immune response. This fundamental conservation of host de- fense makes the studies reviewed in this issue relevant to the understanding of all immunological reactions.

References

1. ATKINSON JP, FARRIES T: Separation of Self from Non-Self in the Complement System. Immunol Today 1987, 8:212-215.

2. FAKHIES TC, ATKINSON JP: Evolution of the Complement Sys- tem. Immzlnol Today 1991, 12:295-300.

E I3rown, Division of Infectious Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110. USA.

JP Atkinson, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.

DT FearOn, Wellcome Trust Immunology Unit, University of Cam- bridge, School of Clinical Medicine, Hills Road, Cambridge Cl32 2SP, UK.