Q J Med 1999; 92: 235-237
© 1999 Association of Physicians
Editorial |
Innate immunity and the biological relevance of the acquired immune response
University of Cambridge
Innate immunity has been considered to be a semi-obsolescent hold-over from invertebrate immunity that had been largely superseded by the acquired (adaptive) immune system of vertebrates. Recently, however, it has become apparent that innate immunity collaborates with acquired immunity to create an effective anti-microbial immune response. This realization may enhance our understanding of host–pathogen interactions and auto-immune disease, and facilitate the development of vaccines. This editorial reviews some of the findings that have led to this new perspective on innate immunity.
The immune system of vertebrates has been conceptually divided into two parts, innate and acquired immunity. There are many distinguishing features of the two systems, but the essential difference is genetic. The recognition proteins of the former are encoded in the germline, having evolved in invertebrates for the purpose of host defence against infection. They have been selected for their ability to recognize micro-organisms that pose risks to the host, and to initiate appropriate defensive reactions. In short, innate immunity provides evolutionary information on the biological correlates of structures with which its receptors interact; that is, these structures are likely to be associated with infectious organisms. However, innate immunity has the drawbacks of being able to recognize only the relatively few microbial structures that are highly conserved, and of being unable to evolve as rapidly as do micro-organisms.
The receptors of acquired immunity, which are the antigen receptors of T and B lymphocytes, have overcome these problems by not being encoded in the germline. Rather, they are products of somatically rearranging elements, the V, D and J segments of T-cell receptor and antibody genes. This remarkable capability, which occurred suddenly with the evolution of vertebrates approximately 400 million years ago, creates an enormous repertoire of antigen-binding structures. Yet, the somatic generation of their genes has the disadvantage of these receptors being disconnected from evolutionary selection. As a consequence, they must be subjected to somatic selection, a form of education as to which antigen receptors are biologically relevant. This process occurs in two phases, the first being positive and negative selection of developing lymphocytes, in which clones with highly self-reactive receptors are diminished or eliminated, and the second being the interaction of antigen with mature lymphocytes, leading to an effective immune response. It is in the latter reaction that innate immunity has an essential role; its recognition of infectious organisms is translated into an enhanced response by lymphocytes that are specific for antigens that are associated with these micro-organisms. This role of innate immunity in making the acquired immune response biologically relevant has only recently been explicitly recognized,1–3 although scientists and clinicians have long taken advantage of it by mixing bacterial adjuvants with antigens to elicit strong acquired immune responses, a phenomenon referred to by Janeway as `the immunologists' dirty little secret'.
Innate immunity has two means, which may be referred to as trans and cis, by which it directs the acquired immune response to microbial antigens. In a trans reaction, innate immunity promotes responses to any antigens that are in the micro-environment of an infectious process. One means by which this may occur involves dendritic cells.4–6 These cells reside in tissues in an immature state in which they are endocytically active, taking up potential antigens by macropinocytosis, receptor-mediated endocytosis, and phagocytosis. However, in this immature state they cannot serve as effective antigen-presenting cells (APCs) because they do not load peptides derived from these internalized proteins into newly synthesized MHC class II complexes, and do not express high levels of the costimulatory proteins, CD80 and CD86. Maturation to an antigen-presenting state is induced by microbial products by at least two means: lipopolysaccharide (LPS) that interacts with receptors of the Toll family, and cytokines, such as IL-1 and TNF, that are secreted by macrophages in response to microbial products. In the maturing dendritic cells, CD80 and CD87 are upregulated, and MHC class II complexes traffic to the appropriate intracellular compartments for the loading of antigen-derived peptides after which they move to the plasma membrane. At the same time, the maturing dendritic cells also turn off endocytic functions, so that they reflect the antigenic environment in which they initially encountered microbial products. Furthermore, to allow their migration to secondary lymphoid organs where they can encounter antigen-specific T cells, dendritic cells alter their expression of adhesion proteins and chemokine receptors. Thus, innate immunity, by causing the maturation of dendritic cells, biases the representation of antigens that are presented to T cells to those of microbial origin.
In a cis reaction of innate immunity, antigens are covalently `tagged' for acquired immune recognition. In one example of this process, the activation of the complement system by microbial determinants leads to the covalent binding of C3b to nearby proteins or carbohydrates. The C3b is proteolytically processed to the C3dg fragment, which uncovers the specificity that mediates binding to CD21, or CR2, the C3d receptor. CD21 is expressed on B lymphocytes and follicular dendritic cells (FDCs); such antigens, then, have been marked for interaction with cellular elements of the humoral immune response.
The biological potential of this innate immune reaction was first demonstrated approximately a quarter of a century ago when mice were depleted of C3 and shown to have an impaired IgG response to T-dependent antigens.7 More recently, experiments with genetically modified mice lacking C3 or CD21 demonstrated similarly impaired immune responses.8–12 These experiments also have found that CD21 function is required on both B lymphocytes and FDCs, and that in C3-/- or CD21-/- mice, there is an absence or marked diminution of germinal center formation. Since germinal centre reactions are required for somatic mutation of antibody genes, the generation of memory B cells, and the development of long-lived plasma cells that migrate to the bone marrow, one can conclude that innate immunity, in the form of complement, is an essential component of acquired immunity. The association of CD21 with CD19 on B lymphocytes, a membrane protein that costimulates signaling through the antigen receptor and is required for germinal centers,12–14 and the central role of FDCs in the germinal centre reaction, must be the basis for this role of complement. The potential magnitude of the effect of tagging antigen with C3d is remarkable; a recombinant antigen to which 2–3 copies of C3d had been attached was found to be 1000–10 000-fold more immunogenic than the unmodified antigen.15
The nature of the acquired immune response influences the selection of the effector mechanisms by which it controls or eliminates the infectious agent associated with the antigen to which it is directed. Innate immunity also has a role in this process. The differentiation of precursor helper T cells into Th1 or Th2 cells is governed by certain cytokines. IL-12 and IFN-
cause the development of Th1 cells, and IL-4 and IL-13 drive the differentiation of Th2 cells. The former type of response is essential for the elimination of pathogens requiring intracellular killing by macrophages, and the latter seems principally to have evolved for control of certain mucosal parasitic infections.
IL-12 was first described as promoting the function of NK cells, but it is now acknowledged as being central to the development of Th1 responses.17 Its secretion by macrophages or dendritic cells, on interaction with potential intracellular pathogens, LPS, or bacterial CpG-containing oligodeoxynucleotides, promotes the secretion by NK cells of IFN-. This cytokine, in conjunction with IL-12 and TNF, promotes the development of Th1 cells that secrete larger amounts of IFN- to up-regulate microbicidal reactions of the macrophage. These include the induction of inducible nitric oxide synthase and the generation of reactive oxygen species, both of which are required for optimal of intracellular pathogens. Impaired host defence in mice with experimentally induced mutations affecting this system, and in man with naturally occurring mutations, has shown it to be essential.18–20
The mechanism by which Th2 responses initially develop is not as well understood, but in some instances may be dependent on the production of IL-4 by mast cells. Also, certain antigens are particularly effective in causing Th2 responses, such as a fucose-containing carbohydrate from S. mansoni (Harn DA, unpublished observations), and respiratory syncytial virus. Thus, there may be uncharacterized innate immune receptors that can be engaged by these microbial structures to induce Th2 responses in a manner analogous to receptors interacting with LPS to cause Th1 responses.
From this more complete view of innate immunity, it is evident that several aspects of clinical medicine will benefit, including infectious disease and autoimmunity. It may be that with the increasing emergence of antibiotic-resistant strains of bacteria, the first applications will be an improved ability to develop immunogenic vaccines for the prevention of infection, and new pharmacological approaches directed at regulating the immune response in infected patients. This would be no mean achievement, as infectious diseases remain the greatest cause of premature mortality in the world.
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