Somatic hypermutation is an amazing process which increases the diversity of the antibody response and can also lead to an increase in antibody affinity over time. As we noted in lecture, the human body has the potential to make 10 billion different antibodies from just a few gene regions and somatic hypermutation helps increase this diversity.
Somatic hypermutation is a process which essentially involves specific but semi-random mutation events which are focused only on a small region of the antibody genes. The small region just happens to be the binding site of antibodies for foreign antigens.
Mutations at large in the genome are often deleterious, yet somatic hypermutation and a process of selection leads to positive benefit for the host. Thus, from a design perspective we cannot say that all mutations or natural selection processes are neutral or bad or deleterious.
But from a design perspective, why use a mutation process to increase antibody diversity and affinity?
What are some of the advantages involved in using a mutation system to increase immune function in this way?
Due Nov 24
Why use “random” mutation in a designed system? For one, it is an efficient use of space, as it isn’t necessary to code for absolutely all possibilities of antigens and innumerable variety in specificity of binding. Rather, those with the highest affinity (produced by mutation) are selected and produced as needed, all based off of a few, conserved genes in the genome common to all cells. Though mutation is often associated with randomness, somatic hypermutation is actually rather specific. It is specific as to the location that the mutation takes place, occurring in the specific region of the antibody which binds to the antigen. So, it is specific in location, though it is random in mutation. If had a whole repertoire of genes coding for all possible antibodies, or at least a great number of possibilities, there would be needed a cell signaling pathway, relating the specificity of the antigen to the genome, and there stimulating the proper transcription factors so that the proper gene is transcribed to give rise to the specific antibody needed. This would be long, tedious, and the antibodies themselves are designed to bind to antigens; with another pathway, would need another set of receptors to bind antigens, which would need to be coded for, same problem at its core. Rather, the antibodies (already designed/function to bind antigens) are selected by their affinity to the antigen; thus, mutations are helpful, or positive, leading to an increase in affinity as well as diversity of the antibodies. -T.A.
ReplyDeleteThe mutation system can produce highly specific antibodies, and thus with high affinity, all from a common or set origin. The little giving rise to the many. Again, mutation after production means a set amount (a type) can be output regularly (set, coded for, the same) and yet the end result (after mutation) is even greater than was produced. As mutations are random, they are not set or coded for; this means they can go many more ways than one or a few predetermined ways, giving rise to great diversity. Antibodies can already bind to antigens (they are not useless, they fulfill their function), but the mutation allows for increased affinity and specificity, which means upon concurrent exposure to the antigen, the response of the immune system and production of antibodies is much more rapid and effective. The selective location that the mutations take place at (the binding region of the antibody) ensures that the antibody is not disabled or rendered ineffective by mutation (a deleterious mutation) as might occur if the mutation took place in the Fc region (wouldn’t bind to Fc receptors, not recognized, wouldn’t activate system, etc.). -T.A.
ReplyDeleteSomatic Hypermutation seems to be very purposed as Tirza mentioned. In Somatic Hypermutation, there are cells called AID (Activation-induced deaminase) cells that introduce point mutations into the variable regions of the antibodies. It would seem that this could be a much faster way of producing a large amount of very diverse cells which could then be separated out to find one that has an increased affinity for the antigen. This also would allow for the body to be able to increase affinity for a particular antigen no matter what the antigen sequence was, giving our bodies an unlimited and intelligent way to up regulate its binding to antigen. It also allows for the antibody to bind to the antigen even if it changes just a little bit. This is interesting because like Dr. Francis mentioned, this mutation is good and is needed to survive. Most mutations seem to be bad and yet we find this one working in B-cells to provide a sort of “natural selection” to increase the affinity for antigens.
ReplyDeleteMutation is often thought of as random and bad in the effects it can have on the body. Somatic hypermutation (SMH), though, is very advantageous and actually not random at all. Researchers Dr. Matthew Scharff and Dr. Michael Neuberger found that SMH is actually regulated by Activation-induced deaminase (AID), like Sean discussed. When the B-cell is stimulated by antigen, AID gets activated and targets DNA in the hyper variable regions. It works by deaminating (taking off amines) cytosine and converting it into uracil. This process calls upon different repair enzymes to fix the DNA that its changed, and in doing so, different groups are put on changing the structure slightly. These produce thousands of differing receptors with different affinities. The ones with the best affinity start to change into plasma cells and memory B cells. What is advantageous about this process is that it creates high affinity quickly without having to have known the antigen structure beforehand. In this way, thousands of genes are not needed to code for each antigen receptor in the body. SMH allows for an efficient quick way to find high affinity receptors.
ReplyDeleteThe difference in this process than other mutations known is that it is directed. It is not a random process. Dr. Matthew Scharff and Dr. Michael Neuberger even found that the antibodies produced in this way compared to ones produced by a random mutation process are better recognized by the body. The process is actually really complex and shows design. I think using this process to create greater affinity and diversity shows the best efficiency. As I stated earlier, not that much DNA is needed to create such diversity. There are so many different antigens we could be introduced to that would require way more DNA for us to have if we didn’t use this process. It does open up for possible error and seems a little over-designed, but I think that is due to a fallen world and that we do not know other possible functions for this design.
ReplyDeleteSomatic hypermutation has a very complex mechanism but it is believed to have a DNA repair process that has the specific focus in the V region coding sequence. From a design position the complexity of have a back up mechanisms for DNA is significant. TA made a good point on the specificity that comes with the increased affinity in the antibodies. To expand on that the high affinity receptors from the B cells are the only ones that survive where most are gone from apoptosis. There is a specific system that keeps only the highest affinity antigen receptors. The antibodies are very abundant and have continually higher affinity this is in the immune response and this makes a stronger protection against the pathogen. Each part of the mutation process has a purpose. The fact that B cells are able to make antibodies bind to antigen with high affinity all helps with the antigen stimulation and all this improves the antibodies. One advantage of the mutation system is it simply offers more protection due to the higher affinity of the antibodies.
ReplyDeleteI found it fascinating that somatic hypermutation occurs at least a million times faster (10^6) than spontaneous mutations of the genome. Thus, if this process had error in it, it could cause huge problems. The substitution of individual nucleotide pairs are usually concentrated at the antigen binding site. Sometimes it affects that amino acid sequence of the polypeptide but other times, it changes the third codon and parts of the untranslated regions (places that do not make much of a difference in sequence). It is also interesting to note that there are mismatch-repair systems (MMR) that are involved in replacing base pairs that do not match up correctly like a G-U match. So this process was definitely not by accident since there is even a process that fixes the “messed up” parts of the somatic hypermutation.
ReplyDeleteThe great thing is speed of somatic hypermutation and how one process could be responsible for countering so many different kinds of antigens, however I felt that the weak point is having all your eggs in one basket could be quite dangerous if the system was to collapse, its nice to know that MMR could self-correct any errors done by somatic hypermutation, it really does seem like the system has been well-thought of when placed together. Why, because there is a back up plan if the system was to default, it would not make sense, for mutations to have repair systems by random chance, rather there seems to be a complex strategy involved against antigens. I don't think that random chance would have so much intelligence to create a back up plan when things go sour.
DeleteWhy use a mutation process to increase antibody diversity and affinity? From a creationist point of view, it could be stated that God has a purpose for everything; every organism and every system plays a role in life. Though mutation often has a bad connotation, it appears that somatic hypermutation is actually beneficial to the immune system. I think Dr. Francis was spot on when he said, "Thus, from a design perspective we cannot say that ALL mutations or natural selection processes are neutral or bad or deleterious." Somatic hypermutation may have a design feature that allows more diversity in antibodies to counter the ever mutating pathogens, bacteria and viruses that plague our world today. The design here might be for our protection and defense against foreign organisms. This would make sense since the activation of the immune system requires a specific and high affinity antibody to a specific antigen.
ReplyDelete- JLo
Mutations are beneficial in creating antibodies in multiple ways. Antibodies are needed to be greatly diverse with a wide variety to attack antigens from any source that is foreign to the body. Some foreign agents that the body has never experienced before must be recognized and destroyed. This is done by diversity in antibodies. This diversity is best created by random yet purposeful mutations which can counter the diversity of infectious agents the body may experience. As mentioned in the blog, 10 million antibodies are able to be produced through only a few genes. Mutations help in another way by keeping the genome small. If the cell would create all these antibodies strictly from genes, there would be way too much DNA in the nucleus and the efficiency of the cell would be incredibly hurt. Instead this method of using mutations allows the cell to use a minimal amount of space and processing to create incredible diversity in antibodies.
ReplyDeleteThus overall, two great functions of using mutations from a design perspective is that it allows for greater diversity in antibody production by having random sequences in the variable region. Also, having mutations create diversity in antibodies allows for the cell to be more efficient instead of having genes for each and every antibody.
The use of a mutation process is beneficial, because it allows the antibody to adapt to the antigen it targets. By focusing on changing its gene according to the antigen that infects the body, it allows for a more effective process than have millions of antibodies for every antigen. This allows for a more quicker adaptive immune system response based on the antigens that infect the body. Also there will be more antibodies produced in the body targeting a specific antigen which will lead to a higher affinity for the antigen, then having a few antibodies produced for every possible antigen which will have a much lower affinity to antigens. We can see that from a design perspective that it would having a hundreds of millions of random genes in antibodies each targeting a specific antigen would not be a great plan of attack, instead there is a plan involved where a specific antibody is developed by somatic hypermutation against a specific antigen.
ReplyDeleteSomatic hypermutation allows for a greater variety of antibodies that can be used to target specific antigens that infect the body, this allow for a more effective attack against antigens. Also the process of SHM is non-random process in the coding of the DNA sequences, this allow for a quicker and targeted response against the antigen. Also this leads to the antibodies developing "memory" which improves the response after each infection with the same antigen, which would be a much better solution than having random sequences generated for each antigen without reacting on prior infections by the antibody.
ReplyDeleteSteven clearly explained important advantages of using a mutation system to increase immune function. Another advantage of using a mutation system is the discovery and investigation of cancer drivers. "International research consortia are collecting thousands of genome-wide molecular profiles of dozens of cancer types. Discovery of cancer drivers will provide insight into the biology of tumor development, and reveal diagnostic or predictive markers and new avenues of therapy development. Targeted drug development for such mutations may lead to effective multi-cancer therapies." The study of how these mutations work may introduce a breakthrough in medicine, possibly a cure for cancer.
Delete- JLo
http://www.nature.com/msb/journal/v9/n1/full/msb201268.html
As has been mentioned, the process of somatic hypermutation is the most efficient way to produce high affinity antibodies for foreign antigens in the body. One reason for this is that there is an astronomical amount of bacteria in the world. The number of viruses is astronomically higher due to their constant mutation. In order to code for high affinity antibodies, one would need an impossible amount of DNA! With somatic hypermutation, the immune system only has to account for that which it comes into contact with.
ReplyDeleteIt is interesting to note that while SHM is necessary, it still poses risks. In malignant B cells it can occur at non-Ig genes. Thankfully, the targeting mechanism largely prevents this, promoting Ig-loci over non-Ig loci. http://www.myelomabeacon.com/resources/mtgs/ash2013/abs/sci-13/
ReplyDeleteSHM can also lead to a loss in B cell tolerance, which means B cells begin to attack self cells. The process has been implicated in autoimmune diseases, including systemic lupus erythematosus. This SHM occurred outside germinal centers, where naive lymphocytes normally come into contact with foreign agents.
http://www.sciencemag.org/content/297/5589/2066.short
Since mutation usually leads to a random result, it is the best process to happen for producing a multi affinity amount of antibodies. It’s just amazing to see how a random process, known to be usually bad and a cause for cancers and abnormalities in the human body, can be also used to be helpful for one’s body.
ReplyDeleteMutation leads diversity, since it’s a random process that can lead to many results, and that’s why it’s perfect for increasing antibody diversity and affinity.
I think that one of the advantages of being a random process is that the human body doesn’t really need to have a focus in the process. Being random, it lacks the necessity of a specific mechanism (even if it has its own mechanisms, but not necessarily a specific one).
The commentary Hannah gave comparing bacterias and viruses amount of variations was totally important. Because of mutations, these organisms have a great variety even if they lack structures other cells have (keeping on mind that they have their own complexity).
ReplyDeleteAs those organisms, our cells have a limited genetic material, which would not be able to produce the amount of variety in their own. That when mutation comes to the history, making it possible for the individual to produce a great variation of antibodies.
It's just amazing how science shows the perfection of God's design in His creation.
As we studied bNABS over time mutations in the antibody can create an antibody that can bind to many different receptors. So unlike evolution suggest that new genes and variety are being added, here it seems like genes and variety is already there just needs to be accessed. Just like we learned that there can be 10billion different antibodies created just by small amount of genes, there can be a lot of different responses to many different antigens. Because of somatic mutation it looks like a person’s body can make a large number of antibodies and occupy small space to make all those antibodies. Also from design perspective somatic mutation shows that a human body is created with very ample amount of defense system to live in the fallen world.
ReplyDeletePriyank Puranik