Kristen Westergaard Rough Draft

Kristen Westergaard
Immunology Paper
4/2/08
The immune system plays an important role in the survival of organisms. This system has helped organisms to fight off invading microbes and pathogens for years. There are two kinds of responses that are involved in the immune response, the innate immune response and the acquired immune response. Both help to determine the difference between self molecules and non-self molecules [7]. This is important because organisms don’tavoid contractions want to attack their own cells, but need-parrell these words, ie organisms don't want…..but do want to be able to defend themselves against foreign molecules. They also assist in ridding hosts of pathogens, but only one system is thought to be associated with invertebrates.

While invertebrates aren't are not believed to possess the acquired immune system, it is practical to study the innate immune system of the invertebrates because it allows us to gain a better understanding of vertebrate immune responses. Invertebrates provide an opportunity to study the innate immune system alone, without the acquired immune system interfering and changing the response to pathogens. The innate immune system has been conserved throughout evolution and is present in both invertebrate and vertebrate organisms. While most pathways are conserved, there may be a difference in the particular participating proteins in each species. These proteins or recognition receptors may undergo positive selection to be present in certain organisms rather than others, depending on exposure [19].

The innate immune system is a general, broad-range response to any organism that is recognized as foreign within the bodyhow?. Resulting infections of the same pathogen elicits the same general response to conquer it and the same response is given for different pathogens, as well. kind of a long awkward sentence As part of this response, both invertebrates and vertebrates possess cells that can engulf pathogens and can use super oxides to degenerate pathogens [26].

The innate immune response consists of many mechanisms. Invertebrates use melanization to trap microbes and release phenoloxidase to destroy them. The phenoloxidase is an enzyme that produces radical oxygen species that causes damage to the proteins and DNA of the microbes [5]. The melanin capsules have also contained some antimicrobial peptides [35]. Melanin spots can be found on the invertebrate organisms that utilize melanization to defeat pathogens
The innate immune response can also involve the complement cascade. This system uses a group of proteins produced by multiple cells and found throughout the body. The complement cascade was originally thought to have developed in deuterostomes, or organisms that develop an anus first (like echinoderms or chordates), but further research has indicated that this mechanism may have existed in protostomeswhich are the oposite of deuterostomes?, as well [25]. This method of defense has been incorporated into organisms for an extremely long time and has been conserved** would "and is very conserved" work better here?**. This new evidence shows that it was found in different lineages of organisms, which means that the innate immune system must have originated much earlier, before the two groups diverged in evolution.

The complement cascade can begin when a complement protein, C1 for example, binds to a pathogen and it initiates a cascade of other complement proteins that binding and cleaving *other complement proteins** until the membrane-attack complex forms maybe explain what the MAC is. There are multiple pathways for the complement cascade. The classical pathway begins when the C1 protein binds to the pathogen and creates a conformational change that cleaves the C2 protein into C2a and C2b. Then C1 is able to cleave C4 into C4a and C4b, which creates the C2bC4b complex (C3 convertase). The alternative pathway is stimulated by the random cleavage of C3 protein and the lectin pathway is initiated when the mannose-binding lectin binds to mannose on a microbe. The lectin pathway helps to recognize fungal pathogen, and all three pathways create a more diverse response to potential pathogens [6]. Some lectins are dependent on the presence of other molecules, such as the C-type lectins that assist in the engulfment of bacteria when calcium is present [31]. I would explain the lectin path and the alternative path until 3 three is cleaved.

The pathways all converge when the C3 convertase is used to cleave C5 and led to the production of the membrane-attack complex. maybe i'm jsut retarded, but i though that c3 convertase cleaved c3 and then c3b and c3 convertase interact to make c5 convertase to cleave c5, double check this Defects in these complement proteins may cause problems in the organisms’ ability to defend themselves against pathogens. However, there are some pathways in the complement cascade that also bypass C2 and C4 proteins, which allows organisms to defend themselves even if they possess defects in these proteins [1].

A humoral response is also used for defense against pathogens. This response includes the production of antimicrobial peptides (AMPs), cytokines, and activation of clotting pathways. Antimicrobial peptides are produced by cells that are exposed to microbes frequently, such as alveolar cells all alveolar cells? and the Paneth cells found in the intestines. They are also produced by myeloid lineage white blood cells, like neutrophils, basophils, eosinophils, and mast cells. The cells each possess granules with these proteins inside and upon exposure to a pathogen, they are utilized. Neutrophils engulf the pathogen and then use the AMPs and other enzymes in the granules to defeat the pathogen. Eosinophils and basophils attack larger microbes and upon recognition of a pathogen, will release the AMPs into the atmosphere is atmosphere really the word you want to use? to attack. This process can cause some damage to the pathogen as well.how? Antimicrobial peptides are used to insert holes into bacteria and induce death, and these properties have even been found in the histones of some invertebrates [17]. There are other forms of peptides that defeat pathogens, such as the lipopeptides that have been discovered to attack fungal pathogens. These peptides form oligomers that create channels in the membrane, instead of individually creating holes in the membrane of the pathogen [23].

Cytokines are proteins that are created and secreted in response to recognition of a foreign microbe or molecule. Receptors, such as the Toll receptors in Drosophila, in the membrane of the hosts’ cells are required to initiate the production of cytokines [27]. The Toll receptors of Drosophila are able to recognize microbes quicker more quickly may sound better here because they can interact as dimers, individual receptors, or bind the foreign molecule and then form a dimer [37]. can you explain what a dimer is? These foreign molecules are recognized by these receptors and a cascade of chemical reactions that activates a transcription factor called NF-KB. This transcription factor enters the nucleus to produce act as a transcriptional acivator for cyotkine genes the cytokines. Toll-like receptors, imd receptors, and other receptors recognize conserved molecules of microbes, but recently JNK receptors were determined to be involved in producing cytokines as well and the over production of cytokines by this stimulation can assist organisms that are mutated in other pathways [33]. GATA is another transcription factor that has been found to produce cytokines and antimicrobial peptides, but within parts of the body that are not typically associated with **microbial defense [32]. This means that other parts of the body are able to fight off pathogens as well as those which are dominantly exposed. It is important as animals evolved into larger, more complex organisms that could be exposed to many more pathogens to have defense mechanisms in different parts of the body.

Lipopolysaccharide has been known to be detected by lipopolysaccharide-binding protein and interacting with CD14 of the cell membrane. However,but just recently they who is they? maybe include the researcher's names determined the presence of a peptidoglycan recognizing protein that can respond to gram positive bacteria and elicit a similar response of cytokines [8, 9]. These molecules create the inflammatory response by interacting with the endothelial cells that line the blood vessels and "this" might be better than "and" increasing es their permeability and inserting s more receptors in their luminal membranes.this sentence is a little long, i would break it into two Some cytokines are also able to decrease the inflammatory response, which is important for regulation, as excessive inflammation can be detrimental to the host organism [20, 39].

A mechanism that also involves is also created by cytokines of the humoral response would be the clotting response. This reaction decreases the blood flow to the area of infection. This can be helpful to reduce the blood loss, if there is an external exposure, but it also prevents blood from circulating and spreading the microbe throughout the body. Without this, infection of the blood could lead to sepsis and death. Clotting helps to trap the microbe and create a confined area for the cells of the immune system to defeat the pathogen [15]. Conserved portions of pathogens, such as LPS, activate proteins in the blood that initiate a cascade of reactions that converts coagulogen to coagulin [40]. Coagulin acts like fibrin to form a clot and trap blood cells and platelets within the polymers. The clot that forms can then trap the pathogen as well as the immune cells needed to kill the pathogen.

Finally, the immune cells are involved in a cellular response to foreign molecules and microbes. This response may be phagocytosis or encapsulation. These cellular responses are conserved throughout both the invertebrates and the vertebrates [4, 26]. There are specific cells that are able to rearrange its cytoskeleton, allowing it to phagocytote a microbe, creating vacules in which the microbe is encapsolated — and create vacuoles that contain the microbe within the cell—. The cells may interact with molecules of the complement cascade, or they may interact directly with the pathogen. The cell’s ability to bind to a molecule on the pathogen, such as a lectin, is temperature dependent, which can influence the body’s ability to rid itself of the pathogen [16]. Not only is temperature important, but there are specific genes that can influence the ability to encapsulate pathogens. When these genes are expressed, the pathogen is more easily encapsulated [24]. do know what these specific genes are??

Invertebrates are not only able to attack bacterial and fungal pathogens, but they also have mechanisms that help defeat viruses. It has been discovered that the Toll pathway can also be utilized to create an antiviral response as well as produce the cytokines in response to bacteria [36]. Also, RNAi techniques have been discovered to help detect viruses with double-stranded RNA as their genetic material [34]. RNAi is when a complementary RNA strand is created by the hosts, which can then bind to the viral RNA and prevent it from being reverse-transcribed into DNA to be inserted into the host's genome. This technique is also used for an organism’s own RNA to prevent unwanted translation of RNA into proteins. Both of these techniques have developed to allow invertebrates to be more efficient in their response to different types of pathogens.

It has become evident through many experiments that the different systems of the innate immune system interact together to balance each other out and to create a more efficient response. While genetic diversity in receptors or secreted peptides can increase the response rate, synergistic interactions of different pathways within the innate immune system help to diversify the response and attack more pathogens [22]. Antimicrobial peptides have been found within the melanotic capsules of melanization [35]. Also, pathways can converge or interact with each other to stimulate the production of cytokines. Even though a specific receptor was not activated, the subsequent steps may overlap, or the molecules may be able to activate other pathways to induce a greater response. An example would be the imd pathway and the Toll pathway that can be stimulated individually, but can also act together to produce more cytokines and antimicrobial peptides [30]. This produces an immune response based upon many different stimuli.

Not only is it important for the pathways of the innate immune response to interact and produce a more efficient response, but it is also important that such responses are regulated so they don’t-contractions are generally not accepted create damage to the host. It was mentioned earlier that some of the cytokines increase the immune response, and others decrease the response. It has been shown that the presence of some defensive molecules can actually contribute to the damage within a host [2, 20]. Antimicrobial peptides, at a high enough concentration, can attack our cells as well as pathogens, even though they are constructed to be more specific for pathogens. To help regulate the immune response, pathways will induce transcription of peptides, cytokines, or more receptors, but some products may also repress the pathway. Down-regulation, or removal of NF-KB from the cytoplasm, is a response to activation of the pathway, so that it doesn’t overproduce cytokines and create damage [10]. The Caspar gene is a gene that was discovered to produce molecules that inhibit the imd pathway [11]. There are other mechanisms that are used to reduce the immune response. Once the pathogen is eliminated, the stimulus will be removed and the response will turn itself off. Also, negative feedback, or when production of a product can turn off its own production, can be used to produce enough antimicrobial peptides to be effective [21].

Fortunately, or unfortunately, the body will always respond to a foreign molecule and try to rid the body of it. A study showed that even when bumblebees had been put through a physically challenging situation of near-starvation, the introduction of bacteria still elicited an immune response [14]. The production of cytokines and antimicrobial peptides consumes a lot of energy, and caused a shorter survival rate for those bees, because they did not have the energy reserves that other bees might have possessed.*this sentence has two different tenses, I don't know if you wanted to do that, but check it out.** Producing the molecules to fight off infections may be very taxing for an organism. With so many pathways to choose from, it is often found that one pathway will dominate over another, in order to conserve energy and still attack the pathogen [5].

The innate immune system has been shown to be quite complex as it involves several mechanisms and these mechanisms interact to create an efficient response. I would break this into two sentences However, there is another detailed portion to the immune system, which is the acquired immune response. This kind of response allows organisms to create more efficient responses to particular pathogens. Previous exposure to a foreign organism develops a specific and faster response upon a second encounter. The acquired immune response is typically found in animals that have a longer lifespan and may encounter the same pathogens twice. It is thought to only be present in vertebrates and not associated with invertebrates, but more recent findings suggest that a form of specific immune response may exist in some invertebrates.

It has been shown that previous exposure to a pathogen can elicit a more efficient response. If the pathogen is more closely related to that which the organism was previously exposed, the invertebrates are able to defeat the pathogen quicker [12]. An organism that doesn’t possess closely related structures has higher pathogenicity within the invertebrates, because the organism has not discovered its features. Some researchers have determined that the specific response of invertebrates is due to a large production of antimicrobial peptides that remain active long enough for another encounter with a pathogen [29]. Another way that vertebrates, particularly mammals, achieve an acquired immune response is through maternal transfer. Some antibodies can be passed from the mother to the child through the umbilical cord. Such a transfer is typically not associated with invertebrates because they do not grow and develop within the mother, and they do not receive milk from their mother like mammals. However, some research has indicated that previous exposure to a pathogen by a mother can help offspring to have a quicker defense to the same pathogen [13]. It is unclear whether or not this adapted response is based on higher concentration of AMPs, cellular response, or other mechanisms [13].

The ability of invertebrate organisms to have an acquired immune response goes against the discoveries of previous scientists and researchers. There are some who still believe the results that lead to the indication of a specific immune response were based on poorly planned experiments, that don’t take into account environmental factors that could impact the results [28]. There are discrepancies in the specific immune responses that have been observed and their methods of production. Some specific responses have been based on the ability of immune cells to engulf the pathogens after previous exposure to the same pathogen, not the overproduction of AMPs [18]. High doses and long-term exposure to pathogens can also induce a more specific response [22]. This could be due to up-regulation of receptors and molecules that are needed to fight off the pathogen.

Also, multiple pathways could be activated to respond more effectively as time passed. Bumblebees have been found to have a better response to specific strains of bacteria, rather than a general response [38]. This is another example of how the immune system must balance which pathways are activated to be most efficient and save energy. In the case of the bumblebees, the specific response to pathogens is more effective than the general response. There is potentially a homologous pathway that exists within invertebrates that activates an acquired immune response, too. The EBF pathway in vertebrates is needed for B cell development, which are involved in the acquired immune response [3]. In invertebrates, the genes in the pathway induce the attraction of lamellocytes, which engulf pathogens, and not B cells, but it functions similarly to the EBF pathway, which could suggest the origins of forming an acquired immune system [3].

An immune response is important for the survival of organisms. Without such a response, invertebrates and vertebrates alike could be infected with pathogens easily and damage could be done to the hosts’ bodies. This would be detrimental for both the pathogen and the host, as the pathogen would kill of off all the possible hosts for them to live in. Immune responses have continued to evolve and develop as organisms changed, grew, and lived longer. so when you save "have continued" you are implying that it is still occurring but then you say"changed, grew, and lived longer" which implies it is not still happening? The innate immune response provides a general response to all pathogens and can be found within invertebrates as well as vertebrates. This type of response has many mechanisms to assist the organism. The acquired immune response has ** would was work better?** originally been thought to be found only in vertebrates, but more research indicates that specific immune responses may be found in invertebrates, too. This suggests that an acquired immune system may have developed from these earlier specific responses. However, more research needs to be done to confirm the results and determine the mechanisms of such an acquired immune response within invertebrates. It is important to study these responses to determine how many different organisms’ and our own, human, immune systems respond to pathogens. We could develop new drugs or methods of treating infections by these studies. There are some disagreements within the experiments and the mechanisms of these specific responses, but this is a new and exciting path of research for immunology.

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