Evolution of the Immune System

John Frelinger Dr. Travis Organic Evolution 30 April 2012 Evolution of the Immune System Animals are constantly bombarded by an immensely varied array of disease causing pathogens including bacteria, fungi, viruses and other parasites. The number of microbes living in the human body outnumber the actual human cells by a factor of 10, and for every single species of animal and plant on Earth, there are viruses that infect them. With the unrelenting threat of disease-causing pathogens all around us, and even within us, how can the constantly vulnerable organisms defend themselves?
Evolution has provided an answer to this problem—the immune system. The immune system is a vastly complex orchestra of cells working together to help eliminate potentially harmful pathogens from the body. Some form of host defense is found in every multicellular organism, however there are myriad variations in the immune systems of different organisms. Vertebrates have evolved an acquired immune response, in which a specific immune system is activated to clear an infection that is initially controlled by a non-specific (innate) immune response.
This highly adaptable system is important to the survival of vertebrate species. Surprisingly, however, 90% of animals (invertebrates) do not have this kind of response. Despite lacking a seemingly critical adaptation, invertebrates continue to survive and reproduce. Why does it appear necessary for vertebrates to have an acquired response in order to survive, but the more numerous invertebrate species do not? Research indicates that there is an evolutionary lineage of the immune system that stems from the split of invertebrates and vertebrates.

Innate immunity, which is found in all animals, is assumed to be at the beginning of this evolutionary tree. After the diversification of species (vertebrates branching from invertebrates), mechanisms of immunity also diverged. In this paper I will first discuss the function of the innate immune system because of its older evolutionary history, followed by the adaptive immune response that evolved later in vertebrate lineages. I will then conclude by placing the development of the innate and adaptive immune system in an evolutionary context.
Innate immunity is the first line of defense for an organism and is made up of elements that protect the organism from pathogens. Anatomical aspects such as skin act as an impermeable barrier to infectious pathogens. Chemical and biological factors, including anti-microbial peptides like defensins, are also used to inhibit bacterial growth and prevent colonization. Another immunological factor of the innate immune system are phagocytic cells (macrophages), which are cells that engulf and eliminate foreign pathogens.
These cells operate using a variety of different and generalized receptors that recognize a broad range of molecular patterns expressed by pathogens that initiate phagocytosis. One such family of receptors, known as Toll-like Receptors, recognizes common pathogen elements such as bacterial wall components or viral DNA sequences. This component is found in virtually every multicellular organism, ranging from sponges to humans (Muller and Muller 2003). Plants also express proteins that are very similar to toll-like receptors, indicating that this aspect of the innate immune system predates the divergence of plants and animals.
The innate immune system is so valuable to an organism’s survival because it is always present and in many instances can prevent pathogen entry or replication. This, in turn, prevents a harmful infection from ever occurring inside the host. Although invertebrates do not have the acquired immune response, recent research has shown that their innate response is more complex than previously thought. Insects can activate their immune systems to remain in a higher state in order to prepare for a pathogen invasion.
During bedbug mating, females are frequently injured in the process because males will stab a female to inject his sperm, infecting her with bacteria and exposing her to other potential infections. In response, females have evolved ways to enhance their immune system prior to mating in anticipation of pathogen invasion (Morrow and Arnqvist 2003). Bumblebees are capable of maintaining a heightened immune system in response to a prior pathogen invasion to aid in the prevention of future infections. Immunity such as this has been shown to pass down vertically to offspring, therefore increasing their fitness (Tyler et al. 006). Slugs have also evolved an interesting alternative response in the form of increased mutation rates of certain immune cell receptors, which allows their immune system to adapt to many foreign elements (Litman and Cooper 2007). While it is inherently different from the acquired immune response, this sensitive management of immune function was previously thought to be reserved as a characteristic of vertebrates and the adaptive immune response. As vertebrates began to diverge and evolve from invertebrates, so too did the immune system.
The new adaptive branch of the immune system originally conferred a new selective advantage for vertebrates because of its specificity and immense flexibility in recognizing new pathogens. The clonal selection theory, in which each lymphocyte clonally expresses a specific antigen receptor, can help explain how the immune system can express an extremely wide range of potential receptors capable of recognizing new pathogens. Lymphocytes are undifferentiated cells that ultimately become B-cells (Bone Marrow) or T-cells (Thymus) depending on where they migrate.
B-cells possess a uniquely structured immunoglobulin molecule (antibodies exposed on outer surface) that recognizes and binds to a specific molecular counterpart. When a foreign antigen is bound to the antibody, it stimulates the replication of that specific B-cell with the aid of Helper T-cells, which enhance B-cell maturation. This process results in the clonal expansion of cells that recognize the original antigen and subsequent production of antibodies that help in the eradication of the pathogen. An important point of this process is that the pathogens select which lymphocytes expand.
It also results in memory B-cells and T-cells that constitute a persistent immune memory for a particular antigen. This expanded pool of memory cells is activated upon a second exposure to the same pathogen, resulting in a much more rapid immune response to clear infection. Other types of T-cells are also produced during this process. For example, cytotoxic T-cells target and kill virally infected cells, while suppressor or regulatory T-cells are activated when the infectious pathogens are eliminated and signal the immune system to subside.
Cells such as these also experience selective pressures–ones that react to self-tissue (and harm the host) would be selected against, while those that recognize pathogens would survive and replicate. The clonal selection theory addresses many aspects of vertebrate immunity, however, it does not explain all of the mysteries behind the variety of antibody generation. The sheer number of antibodies that can be produced and the finding that the acquired immune response can generate antibodies to manmade molecules that are not present in nature led scientists to explore how such diversity is generated.
Research done by Susumu Tonegawa in the 1970’s indicated that B-cells have the ability to produce a huge number of antibodies due to a gene rearrangement process. B cells originally have many sets of gene segments (Variable, Diverse, and Joining) and over the course of its maturation reduce these segments to one of each type for the production of the antibody heavy chain. A similar process of gene rearrangement is involved for the production of the antibody light chain. The light chain and heavy chain proteins then assemble to form the complete antibody molecule that can specifically bind to an antigen.
Two genes that are critical for this process to work are RAG1 and RAG2. These genes are known as recombination-activating genes and distinguish the vertebrate immune system from other lineages. These genes are critical to the process because they act as the excision and joining molecules that cut and knit back together the individual VDJ segments that make up the antibody. This results in the huge potential of diverse antibodies that can be produced—hundreds of millions of possible antibody types generated from a much smaller number of gene segments that can react with virtually any antigen.
This sophisticated process may have originally been introduced by a mobile genetic element known as transposons. These transposable elements have the ability to excise themselves from one DNA sequence and incorporate themselves into another, very similar to the RAG1 and RAG2 gene functions. After the divergence of jawed and jawless vertebrates, a viral infection of the jawed lineage’s gametes may have introduced a transposon into their genome. (Thompson 1995). This may have provided the raw materials necessary to facilitate the development of adaptive immunity.
The acquired response appears to have evolved from a single lineage because all vertebrates (excluding jawless fish) retain this RAG-mediated gene rearrangement system. The specificity of this kind of response may have been selected for because of its ability to recognize a diverse number of pathogens, but also because it could conserve more energy resources compared to the generalized defense of the innate response. The adaptive immune response is structured in such a way that it can respond to an almost infinite number of pathogens, while utilizing a relatively limited number of genes.
Figure 1 illustrates a potential phylogeny based on some immune system adaptations previously discussed. Figure 1 (Reproduced from Litman and Cooper 2007). Although the vertebrate immune system is extremely adaptable to many potential threats, it is far from perfect. Epidemics such as the Bubonic Plague or the 1918 influenza killed millions of people. Similarly, when the Spanish colonized the New World, they also introduced pathogens that were devastating to the indigenous people.
One of the major limitations of the acquired immune response is that it takes a relatively long time to respond after the initial exposure in order to be effective. This time is required because the lymphocytes must clonally expand before a pathogen can be eliminated. For example, in the case of the Native Americans, when they were exposed to the new pathogens, the infections spread to a portion of the population that was large enough to leave them unable to forage for food or to tend to the sick. As a result, it nearly wiped out the entire civilization.
This limitation is significant as illustrated by these and many other historical epidemics. These difficulties have led scientists to think more fully about the effectiveness of the vertebrate immune system. If the immune system has the potential to combat virtually any conceivable threat, why then can’t it always eliminate any potentially harmful pathogen? We also look to immune hypersensitivity and autoimmunity as potential drawbacks of the immune system, indicating further imperfections of the adaptation. When the immune system mistakenly targets self-tissue, it results in serious consequences for the organism.
Concepts in evolutionary biology might help address these issues. In this context the immune system does not have to be inherently perfect by design because only some individuals of a population need to survive and reproduce for that lineage to continue. The variation introduced by the immune system generates the diversity necessary for a population to adapt to changing environmental pressures. As others have suggested, a zebra doesn’t have to outrun the lion, just the slowest member of the herd (Hedrick 2004).
The immune system is subjected to the same constraints as other characteristics in regards to natural selection. In this case even if a trait is not optimal, but helps the organism survive and reproduce, it will be selected for, regardless of any deleterious effects experienced post-reproduction. Many, but not all immunologists, believe the development of the adaptive immune system with gene rearrangement was a critical advance. It has been proposed that the development of the adaptive immune system was the “Big Bang” for the evolution of immune system (Travis 2009).
This development might have also enabled the rapid expansion of vertebrates. Moreover, the idea that the adaptive immune system can generate receptors for molecules that are not yet present, makes it extremely flexible and has been called “forward thinking” (Travis 2009). Thus, while the immune system does not anticipate every change in organisms it is ready for them by constructing a large repertoire of antigen specific receptors, which confers a big selective advantage. Others have suggested the adaptive immune system conserves resources, and thus is better than the innate system.
In contrast, as noted earlier, invertebrates lack a fully functional adaptive immune system and are very successful. Moreover, others have argued that even if the immune system was an advantage, it was only temporary and short lived (Hedrick 2004). Another relevant issue deals with the concept of parasite and host co-evolution. This constant struggle is exemplified by a quote from Lewis Carroll’s “Through the Looking Glass”, “it takes all the running you can do, to keep in the same place”. This concept, originally introduced by Leigh Van Valen, has been termed the Red Queen hypothesis.
According to this hypothesis, an improvement in fitness for one species will lead to a selective advantage for that species. However, since species are often coevolving with one another, improvement in one species implies that it gains a competitive advantage over the other species, and thus has the potential to outcompete for shared resources. This means that fitness increase in one evolutionary system will tend to lead to fitness decrease in another system. The only way that a competing species can maintain its relative fitness is to improve on its own design.
Although this theory was used to help explain the extinction of species and the evolution of sexual reproduction, it has been applied to many aspects of predator prey relationships including the development of the immune system. Because animals are constantly attacked by fast-adapting parasites, the host immune system cannot possibly gain an advantage over them. The evolution of the immune system is caused by the small advantages conferred as a result of variation in the recognition of pathogens.
As suggested by Steven Hedrick, “by selecting for more elusive parasites, the immune system is ultimately the cause of its own necessity” (Hedrick 2004). Thus paradoxically, the immune system, since it places a strong selective pressure on pathogens and parasites, ultimately has become essential for vertebrates to survive. By placing selective pressure on parasites that can evolve much more rapidly than animals (due to their higher reproductive/mutation rate), it results in parasites that are increasingly more effective at infecting hosts of that species.
In terms of the immune system, one strategy that parasites have developed is a means of altering their own antigens to become unrecognizable. In this way they escape the adaptive immune system by altering their structure. For example, trypanosomes can switch the major target antigen for antibodies, which they use as a strategy to extend the amount of time they reside in the host. This results in a more contagious host that will increase the spread of pathogens to new hosts (Stockdale et al. 2008).
Similarly, because the HIV polymerase is very error prone with no proof reading mechanism, many mutations arise in the HIV proteins during its infection. While the adaptive immune system can make neutralizing antibodies, new variants arise that can no longer be recognized by the antibodies. These new variants have a selective advantage and escape, and thus the adaptive immune system is always lagging behind. In terms of the host immune response, there is also an extremely high level of polymorphism of major histocompatibility genes, which enable the population to respond to a wider array of antigens using T-cells.
The benefit of this heterozygosity is that it allows the individual to respond to a wider variety of antigens. Moreover this diversity helps ensure that even though some individuals may perish, the particular pathogen will not be able to eliminate the entire population. Some infectious agents have even taken it a step further and evolved ways to utilize the host immune system to increase their own fitness. For example, infections that result in pus filled cysts can be used to carry parasitic progeny and spread to new hosts when they burst.
Even though this may help the host clear an infection, the pathogen can use this to increase its own fitness and infect more individuals. The Human Immunodeficiency Virus (HIV) utilizes the host immune system by initially infecting macrophages, and subsequently T-cells, which the virus uses as a reservoir for reproduction and as a means to spread to many different tissues in the body (Orenstein 2001). It also serves the virus to target immune cells for infection because crippling the host immune response akes it easier for the virus to spread throughout the body and eventually to new hosts (due to the higher viral load). In this light, it is possible that invertebrates did not evolve the adaptive immune response because they may have never needed it. By lacking the ability to develop a “memory” for a particular pathogen, those pathogens did not evolve anti-immune mechanisms to counter the host immune response. An immune memory could lead to more devious pathogens and result in a more harmful infection in the future.
This could have been a better strategy for invertebrates as it may have prevented the co-evolution of more virulent pathogens (Hedrick 2004). The immune system has a long evolutionary history in multicellular organisms. The innate immune system is a critical adaptation that helped these organisms survive the onslaught of parasites and pathogens. Vertebrates possess an adaptive immune response that allowed for the recognition of an almost infinite number of pathogenic antigens, however, it appears to have become a one-way road with the coevolution of pathogens.
Once this adaptive system appeared in the vertebrate lineage, there was no going back. Because of the immense flexibility of the adaptive immune response, it places huge selective pressures on pathogens to constantly evolve new mechanisms of infecting hosts. Thus in the context of evolution, even with the incredible versatility of the adaptive immune system, it is likely there can not be an ultimate solution to infection by parasites only a new, perhaps unstable, equilibrium. Works Cited Hedrick, S. (2004). The Acquired Immune System: A Vantage from Beneath.
Immunity 21, 607-615. Litman, G. and Cooper, M. (2007). Why Study the Evolution of Immunity? Nature Immunology 8, 547-548. Morrow, E. H. , and Arnqvist, G. (2003). Costly traumatic insemination and a female counter-adaptation in bed bugs. Proceedings of the Royal SocietyB: Biological Sciences. 270: 2377–2381 Muller, W. and Muller, I. (2003). Origin of the Metazoan Immune System: Identification of the Molecules and Their Functions in Sponge. Integrative and Comparative Biology 43, 281-292. Orenstein, J. (2001). The Macrophage in HIV Infection.
Immunobiol. 204, 598- 602. Stockdale, C. , Swiderski, M. , Barry D. , and Richard McCulloch (2008). Antigenic Variation in Trypanosoma brucei: Joining the DOTs. PLoS Biol 6. Thompson, C. B. (1995). New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3, 531–539. Travis, John. (2009). “On the Origin of the Immune System”. Sciencemag Vol. 329. Tyler, E. , Adams, S. , and Mallon, E. (2006), An Immune Response in the Bumblebee,Bombus terrestris leads to increased food consumption. BMC Physiology 6.

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