The Evolution and Mechanism of Immunological Memory and its Impact on Immunology Research. Recently, the Center for Disease and Control reported that it has discovered a super bug, a bacteria, that has the capability of resisting almost any antibiotic known to human. In addition to resisting antibiotics, these superbugs are deadly. Not only do the bugs cause death to half of the patients with serious infectious diseases, but they also spread their genes that make the bugs resistant to other bacteria cells (USA TODAY, 2013). This class of superbugs is known as carbapenem-resistant enterobacteriaceae (CRE).
Currently, CRE are found mainly in hospitals and nursing homes. However, if these bacteria escape into the environment, the results can be devastating. For instance, the bacteria may cause small diseases, such as the common cold, to become untreatable because the CRE alters the small disease genetics in a way where it is resistant to vaccination and other medicines (USA TODAY, 2013). Although this type of bacteria is new and deadly, it is not the first time that the world has encountered something similar to CRE. For instance, Staphylococcus aureus is one of the well-known examples of bacteria that are resistant to antibiotics.
One reason doctors use antibiotics is because bacteria are often resistant to the immune system of a body. The resistance of bacteria to the immune system is due to natural selection and genetic mutation. Because bacteria reproduce at a rapid rate, some bacteria that contain the adaptive, resistant traits survive and reproduce offspring that contains the resistant genes. They produce immune-resistant genes through genetic mutation. The alteration made by the genetic mutation can create a trait that is resistant to the immune system.
As a result, the genetically mutated bacteria will be able to reproduce without interference from the host’s defense system. As a powerful tool that the body uses to protect itself from pathogens and bacteria, the immune system consist of several parts, and the immunological memory is one of the most important. Understanding the evolution and the mechanism of both the immune system and immunological memory, new research areas can be developed and new vaccines can be created that target the immune systems of pathogens or that alter the immune system to make it more efficient in combating pathogens.
Evolution of the innate immune system and the innate memory Organisms of the same species’ innate memory are almost the same. This memory comes from millions of years of evolution (Sompayrac, 2008). The immunological innate memory is based on pattern recognition receptors. Pattern recognition receptors are the main components that allow the innate immune system to recognize the pathogens and activate antigens (Kurtz, 2004). These receptors have gone through millions of years of evolution. One of the main receptors is the Toll-like receptors (TLRs) (Sompayrac, 2008).
Instead of studying the body’s defense to pathogens, current research investigate the evolution of the innate immune system through observing the examples of specific receptors in simple organisms. Wu and Huan (2011) are studying the Toll/interleukin-1 receptor (TIR) and the leucine-rich repeat (LRR), which are the two domains that make up the TLR. TIR and LRR are connected by a transmembrane helical starch that is 20 amino acids long. TIR plays an important role in activating the innate immune system by detecting lipopolysaccharide from gram-negative bacteria.
The interaction between the receptors of both the innate immune system and bacteria is handled by LRR. Figure 1: Illustration of evolutionary tree of invertebrates. Amphimedon came before Cnidarians. (Wu and Huan 2011) To understand the evolution of TLR, scientists have to discover when the TIR and LRP first appeared. One research conducted by Dr. Wu and coworkers (2011) attempted to create a phylogenetic tree of the TLR. After comparing the protein of different organisms, they discovered that sponges, such as Amphimedon queenslandica, contained a single TIR domain that was distinctly related to the TLR of vertebrates (Wu and Huan, 2011).
The finding prompted them to conduct further analyses of TIR proteins in organisms that appeared later than Amphimedon queenslandica. As shown in Figure 1, cnidarians appeared after Amphimedon queenslandic. Cnidarians had TIR proteins that were similar to that of vertebrates. Cnidarians are one of the simplest organisms, and their TIR proteins allow them to have the characteristics of allorecongnition, the ability to distinguish its own tissue from another (Wu and Huan, 2011). LRR was not found in cnidarians.
The finding of TIRs that were similar to vertebrates in cnidarians only answered part of the question. Wu and Huan were not able to find the first appearance of LRR. They found the combination of LRR and TIR to make TLR after analyzing the TLR proteins of three basal deuterostome invertebrates and five protostome mammals. The conclusion is that the combination of TIR and LRR occurred after the divergence of bilateria and nonbilateria. After the separation, the receptors became more complex because they started to have the capability of allorecongnition and a killing mechanism (Wu and Huan, 2011).
After further comparison of the TLR of vertebrates, they determined that another combination occurred between the TIR and LRR during the evolution of primates (Wu and Huan, 2011). They believe that this second combination gave rise to our present TLR, which has the capability of signaling the innate and alerting the adaptive immune system. The innate immune system is the oldest defense system. Because of this, the earliest form of the innate immune system of simple organisms, such as cnidarians, are closely related to vertebrates, such as people.
As organisms moved from water to land, they encountered more types of pathogens. Pressure from pathogens caused many organisms to develop an innate memory that is more expansive. However, as organisms became more complex, the innate memory did not adequately protect the organism. The inadequacy of the innate immune system leads to the formation of the adaptive immune system. Evolution of the adaptive immune system and the adaptive memory The adaptive memory is different from the innate memory because the receptors in the adaptive memory begin life with a blank memory.
There are two major types of lymphocyte receptors that play an important role in the adaptive memory: B cell and T cell. It is hypothesized that B cell receptors (BCRs) and T cell receptors (TCRs) have a common ancestor (Flanjnik et al. 2010). The characteristics of these genes are discovered in gnathostomes, but not in agnatha. These characteristics include being able to have large amount of cells for differentiation. This finding caused scientists to create a theory called the ‘big bang theory’ of adaptive immune system (AIS) emergence.
The finding also prompted scientists to examine the changes of these receptors’ characteristics from gnathostomes to mammals. These finding lead scientists to determine the origin and evolution of the adaptive immune system. Figure 2: A summary of the immunoglobulin’s structures and functions found in gnathostomes to mammals. The first receptor that researchers focused on was the B cell receptors. Immunoglobulin M (IgM) is a B cell receptor that has the same function in all organisms starting from the gnathostomes (Flajnik and Hasahara, 2009). Some of these functions include having its transmembrane form defining the B cells.
In humans, IgM is responsible for increasing the complement activation during the interaction of antigens and lymphocytes. This characteristic caused the IgM to be very efficient at causing lysis in microorganisms. IgM also causes clumping of pathogens. The clumping of pathogens was discovered in bony fish, while the increasing of the complement activation was found in cartilaginous fish. This showed that although the function of IgM did not change, it was altered as organisms became more complex. Immunoglobulin D (IgD) is another B cell receptor.
IgD is different from IgM because although both humans and bony fish have IgD, IgD in humans is attached to the surface of basophils, while in bony fish, the IgD is attached to granulocytes’ surface (Flajnik and Hasahara, 2009). Although the function of IgD is still unknown, the finding of IgD at two different locations indicates that there are possible changes in its functionality. The only vertebrates that do not have IgD are birds. These findings support the idea that like IgM, IgD is an old antibody class that has changed its function from gnathostomes to mammals. Amphibians have a B cell receptor known as IgY.
Mammals have IgG, IgE, and IgA B cell receptors. Mammals obtained IgG and IgE through the alternative splicing of IgY. IgG has the same function as IgY. IgE’s function is different from IgG because it is responsible for releasing various pharmacological mediators, while IgG’s function is to activate complement when reacting with an antigen. IgA is found in reptiles. The discovery of IgE, IgG, and IgA in mammals reinforces the idea that as organisms became more complex the type of immunoglobulin receptors increased, thus making the adaptive immune system more complex. Like BCRs, some TCRs had a similar situation. ? T cell receptors from jawed fish to mammals have the same function. ? T cell receptors in both sharks and marsupials are structurally the same. Both sharks and marsupials have three domain receptor chain with two amino-terminal V domains and a membrane-proximal C domain. However, the formation of the V domains and C domains are different for sharks and marsupials. The V domain for sharks is made from VDJ rearrangement, while the V domain for marsupials is generated by one set of V, D and J segments of a pre-rearranged VDJ gene. The function of these receptors has not been reported.
The difference in the formation of the V domain indicates that due to pressure from the environment, part of the adaptive immune system underwent evolution to meet the needs of marsupials. Examining the change of the receptors from the gnathostomes to mammals has shown that the adaptive immune system underwent change as organisms became more complex. However, this does not illustrate how the adaptive immune system formed. The recombination-activating gene (RAG) transposon and the whole-genome duplication are the two events that brought about the adaptive immune system (Flajnik and Hasahara, 2009).
RAG encodes enzymes that impact the rearrangement of T cell receptors and immunoglobulin. There are two main types of RAG in vertebrate immune system: RAG-1 and RAG-2. These two types of RAGs play a major role in the formation of immunoglobulin superfamily (IgSF). During the 1970s, two Japanese researchers discovered that recombination signal sequences (RSSs) were flanked by V,D, and J rearranging segments. These segments within the RSSs had repeats that were reminiscent of a transposon. From this, they reasoned that a transposon invaded IgSF (Flajnik and Hasahara, 2009).
The invasion resulted in IgSF not being able to function unless through recombinase. Flajnik and Hasahara believed that IgSF genes were invaded by the RAG transposons. Researchers could not obtain all RAG genes from agnatha, but they were able to obtain it from gnathostomes. This indicates that the RAG transposon plays a role in triggering IgSF (Flajnik and Hasahara, 2009). The invasion of the genome by the transposon was vital for the adaptive immunity system because it gave rise to BCR and TCR, which are part of the IgSF and both play a major role in the adaptive immune system.
The occurrence of whole genome duplication also plays a role in the formation of the vertebrate adaptive immune system. Susumu Ohrno was the first researcher to propose the idea that the vertebrate genome underwent two rounds of whole gene duplication (WGD), which occurred after the emergence of the jawed vertebrates. WGD is an event that creates an organism with additional copies of the entire genome. At first, this idea was met with great skepticism but scientists now accept the idea because many ohnologues are essential components of the jawed ertebrate adaptive immune system. Ohnologues are paralogues that are close to the origin of vertebrates through whole-genome duplication (Flajnik and Hasahara, 2009). Understanding what influences the evolution of the adaptive memory is also important in understanding the evolution of the adaptive memory. There are many speculations on why the adaptive immune system is developed. Some reasoned that because the innate immune system was inefficient and difficult to regulate, it lead to the development of the adaptive immune system.
Pressure from pathogens and the ability to have few offspring also caused natural selection to favor the formation of an adaptive immune system (Flajnik and Hasahara, 2009). For instance, organisms such as seahorses live in an environment that has few pathogens that will threaten its livelihood. In addition, seahorses produce large amount of offspring. Because there are not many pathogens that a seahorse encounters, the innate immune system is adequate in dealing with the few pathogens. Organisms such as sharks are predators, and many produce few offspring during their lifetime.
This pressurizes sharks to have an adaptive immune system because the offspring will have the ability to combat pathogens of all types. Sharks adaptive immune system is not as complex as vertebrates that dwell on land because water does not contain as many pathogens as compared to land. Mazmamian of California Institute of Technology recently conducted a research that indicated that microbiota had a larger influence on the evolution of the adaptive immune system than pathogens’ influence (Lee et al. , 2012). Microbiota have a symbiotic relationship with the body.
An example of this occurs with bacteria located in the gut. A function of these bacteria is that they help food move quickly through the body. Researchers have discovered that the microbiota, which includes bacteria and viruses, have many different antigens. This provides the adaptive immune system and the microbiota with a challenge because the immune system must either react toward or ignore the foreign antigen (Lee et al. , 2012). In order to prevent overreaction from both parties, both the adaptive immune system and the microbiota develop tolerance through the expansion of regulatory T cell (Lee et al. , 2012).
Scientists speculated that this symbiotic relationship between vertebrates and microbiota could have influenced the adaptive memory because symbiotic microbiota could have pressured vertebrates to develop the current adaptive immune system that have developed tolerance to bacteria that is good for the body (Lee et al. , 2012). Current research applications Edward Jenner was the first to start experimenting with vaccines. Afterwards, research on vaccines became more complex. Vaccine researches now include the study of the pathogens and virus’ immune system. Mycobacterium tuberculosis and human immunodeficiency virus.
One of the most studied pathogens is the Mycobacterium tuberculosis. Currently, there are two standard strategies to combat Mycobacterium tuberculosis. The first strategy involves identifying the protein that is produced by the bacterium that is essential to its virulence (Flynn, 2004). Once the protein is identified, the immune system can neutralize the protein. This will result in the bacteria not being infectious to the body. This strategy cannot be applied to Mycobacterium tuberculosis because although there is ongoing research, scientists have not been able to identify the protein that causes its virulence (Flynn, 2004).
Mycobacterium tuberculosis’ main virulence is its ability to survive within macrophages. The second strategy is to use an attenuated form of the pathogen, which will cause an effective immune response, but will not cause disease. The second strategy involves the adaptive memory immune system because the vaccine is causing the adaptive memory to remember the pathogens that is similar to Mycobacterium tuberculosis. Currently, the second strategy is implemented through the vaccine Bacillus Calmette-Guerin (BCG) (Flynn, 2004). BCG is used by 4 million people around the world (Flynn, 2004).
Although BCG is the most commonly used vaccine to treat tuberculosis, it is still not effective because the vaccine can only prevent tuberculosis only in children, but not in adults. Researchers are now investigating the immune response to M. tuberculosis in order to create more effective vaccines. Current research involves injecting patients with the cytokine interleukin 12 (IL-12) (Flynn, 2004). Il-12 plays an important role in controlling M. tuberculosis infection. Studies have shown that when mice are injected with the Il-12 DNA, the amount of bacterial numbers of M. tuberculosis is greatly reduced.
Tumor necrosis factors ? (TNF-? ) and interferon-gamma (IFN-? ) are important cytokines that play an important role in combating M. tuberculosis. IFN-? is a central cytokine in control of M. tuberculosis because it activates the macrophages to attack M. tuberculosis (Flynn, 2004). Organisms with defective IFN-? are more susceptible to infections. TNF-? is important because in synergy with INF-? , it leads to the formation of nitrogen oxide synthase 2 (NOS2) (Flynn, 2004). Although NOS2’s role is not clearly known, it is shown that when organisms were under the infection of M. uberculosis, NOS2 expression was low (Flynn, 2004). This indicates that a high expression of TNF-? , IFN-? , and NOS2 can cause the body to fend off tuberculosis. It is known that overexpression of TNF-? can also cause harm to the body by increasing the chance of getting tuberculosis (Flynn, 2004). As a result, researchers are now conducting vaccine research on how to create the right amount of expression of the three cytokines that allow the immune system to effectively combat M. tuberculosis. The human immunodeficiency virus (HIV) is another area targeted for vaccine research.
Currently, there are three vaccines approaches in creating a vaccine that targets the HIV-1 protease (McMichael et al. , 2009). HIV protease is an important aspect of the HIV life cycle. All of these methods have failed. Scientists are now proposing to use less empirical approach and to focus more on understanding the immune response to HIV-1 infections when producing new vaccines (McMichael et al. , 2009). During an HIV infection, natural killer cells (NK) become activated. NK cells have the ability to control HIV replication through cytolysis of the infected cells.
NK cells also have the capacity to influence T cell responses (McMichael et al. , 2009). HIV-1 has responded by reducing its receptors, making it harder for the NK cells to detect the infected cells. Current research is focused on priming the antiviral activity of the NK cells through vaccination. Researchers are cautious when activating the innate immune system because the innate immune response can be harmful because the activation of the innate immune system produces pro-inflammatory cytokines and chemokines, which can promote the HIV-1 replication (McMichael et al. , 2009).
As a result, the vaccine-induced activation of the innate immune system must be thoroughly tested and used with caution. Conclusion There are many laboratories around the world conducting research on creating an effective vaccine to target the different diseases that people combat every day. Although this strategy is new, implementing a research strategy that focuses more on the immune system when creating vaccines will allow the vaccine to be more effective. In addition, implementing this strategy requires deep understanding of the mechanism and evolution of both the innate and adaptive immune systems.
Both the innate and adaptive immune system evolve from being able to perform simple tasks in primitive organisms to perform complex tasks in complex organisms, such as humans. Therefore, in order to create a vaccine, it is vital to start from simple organisms. Once that is accomplished, one can build on top of the newly developed vaccine that targets more complex organisms and combat the superbug carbapenem-resistant enterobacteriaceae. Literature Cited 1. Flajnik and Hasahara, Martin F. , and Masanori Kasahara. “Origin and Evolution of the Adaptive Immune System: Genetic Events and Selective Pressures. Nature Reviews Genetics 11. 1 (2009): 47-59. Print. 2. Flynn, JoAnne L. “Immunology of Tuberculosis and Implications in Vaccine Development. ” Tuberculosis 84. 1-2 (2004): 93-101. Print 3. Kurtz, Joachim. “Memory in the Innate and Adaptive Immune Systems. ” Microbes and Infection 6. 15 (2004): 1410-417. Print 4. Lee, Yun Kyung, and Sarkis K. Mazmanian. “Has the Microbiota Played a Critical Role in the Evolution of the Adaptive Immune System? ” Science 330 (2012): 1768-773. Print. Kurtz, Joachim. 5. McMichael, Andrew J. , Persephone Borrow, Georgia D.
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