Origins of the Immune System
Origins of the Immune System
Abstract and Keywords
This chapter is concerned with a surprising chimerical hypothesis for the origin of the immune system. It argues for the idea that even the vertebrate immune system may be an organ of symbiosis. It shows that there may be systematic differences in the ways invertebrates and vertebrates tend to interact with the microbial world. This chapter suggests that invertebrates and gnathostome vertebrates differ in the ways they sense and interact with the ubiquitous microbial world in which they are embedded. The immune systems of these two groups are distinguishable.
Evolution in crowded environments leads to surprising developments. Here McFall-Ngai argues for the striking idea that even the vertebrate immune system may be an organ of symbiosis.
Over the eons, animals, plants, and all other multicellular eukaryotes diversifi ed within the context of a bacteria-rich environment. (See plate XII.) Evolutionary selection pressure was exerted by prokaryotic and other microbes on larger organisms, especially animals. These organisms had to sense and respond to biotic cues and stimuli in marine settings steeped with life. In animals, a complicated reaction to the biotic world involves the activation of a multifaceted immune system. The vertebrate immune system evolved in the presence of bacteria that were sensed, responded to, and integrated into it. As most animals are digestive tubes—from mouths through stomachs and intestines to anuses, covered by integument such as skin—the animal immune system probably evolved, in my view, from the exigency of distinguishing healthy necessary bacterial inhabitants of these tubes and coverings relative to opportunistic, potentially dangerous hungry exploiters. Although animals possess both types of coevolved partners—those in symbiotrophic symbioses and those that are potential threats in necrotrophic associations—the vertebrate immune system mainly evolved from bacterial interactions that nurture or tend to destroy physiological homeostasis (often syntrophies) of co-evolved animal-microbial partnerships. Our concepts of animal biology change rapidly when we recognize that the animal kingdom comprises far more than single types of eukaryotic cells. More accurately, it comprises the interconnected, coevolving sets of communities with one principal eukaryotic cell type and often more than several hundred distinct kinds of bacteria. The findings that the integumentary (skin) and the digestive systems of the average human body harbor a (p.200) coevolved consortium of 1011 skin bacteria and 1014 digestive bacteria demand that biologists reconsider their most basic concepts of the physiology of these systems.
Perhaps the most obvious and dramatic changes will be seen in our view of the form and function of the immune system, as a principal response to the biotic environment. The growing appreciation of the true nature of animals renders obsolete the traditional idea of the immune system as a “non-self” recognition system. Most notably, humans require the partnerships of many different kinds of bacteria (phylotypes) for normal growth, development, and homeostasis. Our understanding of the immune system must be expanded to include these new findings. Let us step back and reconsider the function of the immune system in light of related basic biological principles.
What similarities and differences exist in the ways animals respond to physical, chemical, and biological environmental stimuli? The primary purview of the animal nervous system is to modulate activity in response to abiotic, or physical changes. Three major types of neurons carry out this task: sensory neurons, interneurons, and motor neurons. Sensory neurons act as transducers of the environmental information (e.g., changes in light, changes in temperature, mechanical stimuli) and convert it into a usable form. The interneurons integrate the input so that an eventual appropriate response is made. The response or output is the job of the motor neurons, which mediate the activity of the effectors (e.g., muscles, chromatophores, bioluminescent organs). Of course, much of the information carried by these abiotic forces provides the animal with knowledge about the state of the biotic world, such as the presence of predators or prey, competitors, and food.
Animals use light to respond to the biotic world (e.g., predators, prey, mates, young, fruits, seeds). In the big picture, perhaps light is secondary for all five kingdoms, but it is crucial to invertebrate and vertebrate animals as a response to other living creatures and their products released into the environment. The same might be said for temperature among communal vertebrates. The immune system seems to respond to antigens, to biotic products of metabolism, and to prokaryotes.
The immune systems of animals also have sensors, integrators, and effectors that respond to interactions with citizens of the microbial world. The emphasis of study has been on microbial pathogenesis (necrotrophy). The most widely held belief is that the immune system views microbes as germs sensed by certain animal cells. The information would be integrated in such a way that the entire animal responds to rid (p.201) its body of the encroaching dangerous microbe. This viewpoint changes with our increasing awareness of the importance of our normal microbiota in health. The normal microbiota of an animal is an integral, coevolved portion of the whole. The microbial component is an essential part of the developmental response. For example, as the mammalian gut encounters bacterial, chemical, and other antigens ingested with food, the effector system that responds to the foreign biotic world involves a tripartite dialog among its epithelial cells, its immune cells, and the normal microbiota of the gut. The response is not confined to those portions of the immune system that carry out surveillance of the gut.
Comparing Animal Immune Systems
As new ideas of microbial interactions with animal immune systems take shape, comparative biology sheds light both on aspects common to most animals and on how animals differ in immune function—that is, on how the diversity of the system evolves. The most obvious difference in immune systems across the animal kingdom is the restriction of the combinatorial (adaptive) immune system to the gnathostome vertebrates. The combinatorial immune system correlates with the presence of some specialized genes (abbreviated RAG) at the agnathan-gnathostome transition (the transition from the jawless lampreys and hagfish agnathans to the vertebrates with jaws). Macromolecular sequence analyses of both DNA and proteins suggest that this evolutionary process involved lateral gene transfer from bacteria. With the integration and natural selection into the animal genome of the RAG genes, the vertebrate immune system became capable of V(D)J (variable-disjoined) recombination—that is, rearrangement of the immunoglobin proteins to generate infinite diversity of the antibody repertoire. Immunologists assume that the combinatorial immune system is an “advance” in evolution of the immune system that renders gnathostome vertebrates “stronger”—that is, capable of more sophisticated non-self recognition. If we integrate concepts of the interaction of coevolved microbiota, does this anthropocentric viewpoint continue to be valid? Two issues that bear on this question are the position of the non-gnathostome-vertebrate animals within the animal kingdom and their patterns of the interaction with microbiota.
More than 96 percent of the diversity of the animal kingdom at both the phylum level and the species level lies with the invertebrates. However, perhaps because many biologists deal principally with a few invertebrate “models,” such as Drosophila melanogaster (fruit fly) and (p.202) Caenorhabditis elegans (nematode worm), the major theory as to how the invertebrates survive to reproduce without the combinatorial immune system is that they are “r” selected. A typically “r” -selected animal is small and short-lived and has many young, whereas “K” -selected animals tend to be large and long-lived and to have few young. Knowledge of invertebrate diversity reveals that this assumption is naive. Invertebrates have representatives with every known life-history strategy.
How do invertebrates as abundant as the gnathostome vertebrates rely entirely on the innate immune system to interface with the microbial world? Perhaps there is a difference—reflected in the form and function of the immune system—in the ways that invertebrates and gnathostome vertebrates have evolved to interact with microbes. Let me briefly analyze the trends in animal-microbe relationships in the two groups.
An obvious difference between invertebrates and vertebrates lies in the propensity to form intracellular associations with microbes. To my knowledge, no reports confirm the presence of intracellular bacteria as components of the normal microbiota of vertebrates, although several pathogens adopt this lifestyle (e.g., Treponema pallidum, Listeria mono-cytogenes, Toxoplasma gondii, Mycobacterium tuberculosis). By contrast, intracellular bacteria occur as components of the coevolved microbiota in members of the major invertebrate phyla. Approximately 11 percent of all insect species have intracellular bacteria associated with the fat body (their liver analog) that provide essential nutrients to the animal.
Invertebrates, but not vertebrates, have a propensity to form binary associations with bacteria, i.e., associations in which a monoculture of specific bacterial symbionts occurs in a restricted portion of the body (often a symbioorgan), either intracellularly or extracellularly. The vast majority of the intracellular relationships mentioned above occur as binary associations. Extracellular heterotrophic binary associations have been reported in eight of the ten major invertebrate phyla. (Both autotrophic and heterotrophic intracellular and extracellular associations have been studied in coelenterates (e.g., Hydra vividis) and Porifera, green sponges.) Extracellular binary associations are rare in the vertebrates, by contrast. Independently evolved symbioses of different kinds of luminous bacteria with only distantly related teleost fishes are notable exceptions.
Invertebrates appear to have a proclivity to form intracellular or extracellular binary associations with bacteria, whereas the gnathostome vertebrates (e.g., fish, amphibians, reptiles, and mammals—backboned (p.203) animals with jaws and teeth) have complex coevolved consortia that live along the apical surfaces of the mucosal epithelia and are associated with at least eight of their ten major organ systems. The microbiota appears to persist even under extreme conditions such as starvation. Although no entirely representative survey of nearly forty invertebrate phyla is available, consortia have been reported in arthropods, in mollusks, in echinoderms, in coelenterates, and in sponges. In the insects, where gut consortia have been studied extensively under experimental conditions, it appears that most elements of the consortia are “tourists”—i.e., that the microbes take advantage of nutrient-rich environments, such as the gut. When the insects are starved, much of the community is lost, and the community’s composition is drastically altered by a change in diet (Broderick et al. 2004). Some invertebrate species appear to lack coevolved microbiota (Boyle and Mitchell 1978; Garland et al. 1982). Exceptions to these trends include xylophagous roaches and termites, which harbor complex coevolved microbial communities in their hypertrophied hindguts. However, the extracellular community of microbes is kept at a distance from the animal tissue by the chitinous layer that lines the digestive system. The community, including both bacteria and amitochondriate protists, is shed with each molt of the insect. Consortia in vertebrates, such as those in the mouth, occur in intimate association with the epithelium and with immune cells. They are not periodically shed.
There may be systematic differences in the ways invertebrates and vertebrates tend to interact with the microbial world. Binary intracellular or extracellular relationships are common in the invertebrates, whereas stable, complex coevolved consortia are rare; the opposite may be true of vertebrates. Far more investigation is needed.
Are these differences between invertebrate and vertebrate animals reflected in the nature of their immune systems? What is the relationship between the normal microbiota of animals and their immune systems? How do animals maintain their alliances? Invertebrates rely on an innate immune system that recognizes common molecular features of microbial cells: membrane lipopolysaccharides and cell-wall peptidoglycan, molecules unique to bacterial surfaces. Once such molecules are detected, the innate immune system clears the bacteria from the invertebrate’s body. Invertebrates may circumvent activities of the innate immune system by forming alliances that promote specific associations by intracellular incorporation of one or a few types inside the body’s protected sites, such as the interior light organ of squids, beyond detection of the immune (p.204) system. Special, limited associations with only a few bacteria have evolved, for example in weevils with the Sitophilus primary endosymbi-ont (SOPE) and in wasps with Wolbachia.
How, then, do vertebrates maintain complex coevolved consortia? Such maintenance may be controlled by the adaptive immune system or by the interplay of the innate and adaptive immune systems. I suggest that selection pressure on the evolution of the adaptive immune system functioned to mediate animal-microbial interactions to maintain them in healthy balance. Although we can never reconstruct the history precisely, certain features of extant vertebrates should be detectable if I am correct. If an adaptive immune system is a shared, derived character of vertebrates, then complex coevolved microbial consortia should also be a shared, derived character. Evidence of a tripartite dialog among the microbiota, the immune system, and the animal is accumulating. In the past ten years, molecular techniques have made it possible to identify and estimate the number of resident microbes and to detect their metabolic activity. We now know that coevolved microbial consortia that associate with mammals (and perhaps with other vertebrates) may have thousands of members. Vertebrates’ immune systems devote more than half of their cells to interactions with epithelia mucosa that support these consortia. Maintaining the critical interface between the innate immune system and the combinatorial immune system requires incessant interaction with normal microbiota. The microbial gastrointestinal consortia are not “commensal” for the vertebrate; that is, they do not merely “eat at the same table” as the animal that harbors them, with little effect on that animal’s health and reproduction. There is strong and extensive evidence that growth and metabolism of specific microbial associates are essential for the development of animal tissues in which they reside. Microbes, far from being “enemy germs,” are critical for the development of healthy immune systems in vertebrates.
Surveys of the animal kingdom may support or refute my idea that vertebrates, from their origin, coevolved with specific microbial consortia less frequently than invertebrates. The ratio of required “residents” relative to facultative, transient tourists should be estimable in any given consortium. To what extent is the composition of the consortium a direct response to the chemistry of the animal body alone, relative to the biochemistry of the tissue under the influence of the coevolved microbial alliance? I predict that the innate immune system in general will be distinguishable in vertebrates relative to invertebrates—i.e., that invertebrates are less likely to develop immunological “tolerance” that welcomes (p.205) specific “others” into their bodies and does not indiscriminately kill all foreigners.
I suggest that invertebrates and gnathostome vertebrates differ in the ways they sense and interact with the ubiquitous microbial world in which they are embedded. The immune systems of these two groups are distinguishable: Invertebrates limit their interactions with microbes to only a few species; i.e., their approach is “restrictive”: to rid themselves of all that dare enter. By contrast, an individual vertebrate associates with several microbial communities, each composed of hundreds of distinct individually recognized microbial groups (phylotypes). The vertebrate approach is “permissive.” If my idea is valid, the primary selection pressure on invertebrate immune systems results in recognition of non-self, whereas the primary selection pressure on vertebrate immune systems involves subtle control of the complex set of microbial communities required by vertebrate animals for survival.