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Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.

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Immunobiology: The Immune System in Health and Disease. 5th edition.

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Evolution of the innate immune system

The innate immune system is well developed in the fruit fly Drosophila melanogaster, a favorite model organism for many aspects of biological research, and in many other invertebrates, including the nematode worm, Caenorhabditis elegans. What these organisms share in common with the vertebrates are the genes that encode intracellular signaling pathways leading from the cell surface to the activation of the transcription factor NFκB (see Chapter 6). Each organism has a cassette of genes that encode the proteins of this pathway. That makes us believe that the activation of NFκB is the original and central signaling pathway of activation in innate immunity, leading in turn to the activation of a set of genes that depend on NFκB for their transcription. This pathway is a universal pathway that leads to activation in all host defense systems, as we will learn in this part of the chapter.

Innate immunity has its origins in early eukaryotes such as the amoeba

Many of us grew up marveling at the amoeba's abundance in pond water; if you look at amoebas under a high-power lens, you can see them wandering around on the slide, but you will also see that they are feeding on micro-organisms, just like a culture of macrophages. It seems as if the amoeba is the earliest form of macrophage, and perhaps gave rise, by an unknown evolutionary pathway, to the modern macrophage. Innate immunity in eukaryotes can be thought of as arising from the need of a unicellular microorganism such as an amoeba to discriminate between food and other amoebas. If you think about it, any amoeba that could not make this distinction would be bound to consume itself and vanish from the face of the Earth. Therefore, we can infer a specific surface receptor on amoebas that acts to discriminate between food, which can eagerly be engulfed, from what is another amoeba, or even another part of the same amoeba. The nature of this presumed receptor is not yet known, but it must be highly specific and must discriminate self from nonself, which is one of the most basic functions of the immune system.

Like macrophages, amoebas move around under the microscope seemingly at random, unless exposed to a chemoattractant. Then, they all head in the same direction. In this respect also, amoebas behave like macrophages, and may well have occupied the coelomic cavity of early multicellular organisms as useful passengers. All vertebrates and many invertebrates have a population of phagocytic cells that patrol their blood vessels and tissues, as described in Chapter 2, and which have much in common with amoebas. It is possible that such phagocytic cells, the probable ancestors of macrophages, could derive from a population of cells within the multicellular organism that retained an ancestral, unicellular morphology—a form of evolutionary neoteny—the expression of primitive traits—in which the ontogeny of the macrophage would recapitulate its phylogeny.

One further mystery about macrophages is whether evolutionarily they are the source of dendritic cells and lymphocytes. The origin of lymphocytes, which we will deal with later, is a mystery in itself. But the origin of dendritic cells, which appear to have no other function than to present antigen to T cells, and therefore must have arisen after the evolution of the T lymphocyte, is also curious. Did they evolve simultaneously as antigen-presenting cells with their target, the thymus-derived T cell, and what is their function in the absence of T cells? These questions also seem important to me.

Sophisticated means of host defense were hard-wired in the genome by the time organisms diverged into plants and animals

Genomic analysis of plants and animals provides evidence that a sophisticated mechanism of host defense was in existence by the time the ancestors of plants and animals diverged. This system, shared by plants and animals, is the Toll pathway of NFκB activation of gene function. This pathway has been demonstrated conclusively in fruit flies such as Drosophila and in vertebrates such as mice and humans, and is also believed to occur in plants, where the evidence for it is less direct. The necessary DNA sequences are, however, found in all three classes of organisms—invertebrates, vertebrates, and plants. More compellingly, there is evidence in all three groups that the products of these shared genes interact in similar pathways with a role in host defense. In the fruit fly, where this genetic module was discovered as the organizer of the dorsal-ventral axis during embryonic development, it was subsequently shown also to be essential for host defense. We will discuss Drosophila in the next section, as it provides the most complete story. For now, we will take it as the foundation of host defense in all organisms except prokaryotes.

When the molecules of the Toll pathway were looked for in the mouse, they were relatively easy to identify. On searching a library of mouse expressed sequence tags (ESTs), several fragments of a gene for mouse Toll were isolated, now known as mouse Toll-like receptor 4 (TLR-4). It turns out that the mouse has ten Toll-like receptor genes, each seemingly involved in a variety of host defense functions.

The first mouse Toll gene isolated turned out to be defective in two mouse strains that cannot respond to bacterial lipopolysaccharide (LPS), one of the pathogen-associated molecular patterns, or PAMPs, recognized by innate immune system pattern recognition receptors. These mice lack TLR-4 function; in one strain the defect is due to a point mutation in the so-called TIR domain (Toll/IL-1 receptor domain, since it is found in both Toll and IL-1 receptors), while in the other strain it is due to a null mutation that abolishes expression of the gene altogether. These mice are exceptionally susceptible to infection with gram-negative bacteria, which carry LPS on their surface, and cannot mount an adaptive immune response against them. This was, in a sense, the first proof that the loss of innate immunity had a discernible effect on the adaptive immune response, and served as a proof in principle that the adaptive immune response depended on an effective innate immune response, at least in some cases. The question remaining is: How general is this basic principle?

Fruit flies illustrate the virtues of a nonclonal system of host defense

The common fruit fly, Drosophila melanogaster, is a wonderful model for studying aspects of host defense that are obscured by the adaptive immune response in vertebrates. The study of insect immunology, which was pioneered by research groups in Sweden and France, clearly demonstrated the relative efficacy of a nonclonal system of host defense. One of the most obvious advantages was the absence of autoimmune diseases, which were therefore clearly shown to depend on adaptive immunity.

One of the most surprising results to emerge from an analysis of fly immunity to infection with various microorganisms was that there was a primitive form of specific recognition. For instance, flies bearing different Toll mutations were susceptible to infection with different types of pathogens, leading to the belief that the innate immune system had developed its own specificity sensors. This is still being investigated, but it looks as though a general specificity system based on variations in Toll and other pattern-recognition receptors exists in the fruit fly, and thus, may exist in humans as well. How extensive these variations are, and whether they are important in animals such as mice and humans, are as yet unknown.

Many genes that operate in fruit fly immunity also operate in humans and plants and appear to be universal components of host defense

Many of the genes involved in immunity to disease in flies have homologues that also operate in humans, for example, Toll genes in the fly, Drosophila and TLR genes in man. Homologues of these genes have also been found in mice, sharks, nematodes, and plants. Furthermore, they are involved in host defense in all of the species in which they have been studied. Their identification in plants is most impressive, where the genes were identified by positional cloning of disease-resistance genes, a very demanding technique.

In fruit flies, there is a very strict order of Toll pathway gene products starting with Toll and going on to dMyD88, Pelle, Cactus, and Dif/Relish, all of which are cytoplasmic proteins involved in the transmission of the signal from Toll, a cell-surface receptor, to the nucleus to induce the activation of specific sets of genes. The same order is found in the homologues of the Toll pathway found in the innate immune system in vertebrates(Fig. 1). The plant genes do not seem to be arranged in the same order. However, if one examines the plant genome carefully, there are signs of all these signaling elements. There are clear-cut examples of some genes that are separate in the fly and fused in plants, and vice versa. This consistency of function, structure, order, and purpose over such a wide evolutionary range is a most impressive example of the evolution of a biological function, save for essential processes such as DNA and RNA replication and cell division. It makes one feel certain that the Toll receptors are performing the same defensive function throughout evolution. In mammals, as we learned in Chapter 2, their role is to induce co-stimulatory molecules on the surfaces of myeloid cells that have taken up pathogens, and thus pave the way for the induction of the adaptive immune response, which we will discuss in the next section.

Figure 1. A comparison of the Drosophila and mammalian Toll signaling pathways.

Figure 1

A comparison of the Drosophila and mammalian Toll signaling pathways. The components of the mammalian Toll-like receptor signaling pathway that culminates in the activation of NFκB have direct parallels in the components of the signaling pathway (more...)

Summary

The innate immune system exists to provide early defense against pathogen attack, and to alert the adaptive immune system to the fact that pathogen invasion has begun. This dual function appears to operate through a very ancient signaling pathway, the Toll pathway, that long predates the adaptive immune system, and is present in the fruit fly, vertebrates, and, most probably, also in plants. Another component of innate immunity, the phagocytic cells such as macrophages that scavenge incoming pathogens, could have their origins in unicellular amoeba-like eukaryotes.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2001, Garland Science.
Bookshelf ID: NBK27138