So I tried looking it up quickly and it seems like there's an association with DRB1*15:01 for multiple sclerosis and not B*15:01. So Class I HLA molecules are categorized as A,B,C. Class II are DR, DQ, and DP. So for this study they looked at B*15:01 which is a different loci compared to DRB1. The naming for all of these can get confusing, and considering you can have millions of different combinations it can all get confusing.
Here's a review article that may interest you. It has other loci and alleles as well. It can be a bit much when looking at all of this information, and with many alleles it may boil down to correlations.
the rollout started on 14 December 2020. While watching every single day, how many more got injected, I was TERRIFIED, that so many believed all the lies.
In the epitope story, the two substitutions by non-charged residues alanine and glutamine can't change the electrostatic interaction..
From how the study is reported, they mention that the people included were unvaccinated aside from one person who appeared to be vaccinated for one section examining cross-reactivity. The timing of vaccine rollout across nations doesn't inherently mean that the people included in a study were vaccinated. Some of these people could be lying, but without any additional data we sort of have to go off of the author's remarks that the people were unvaccinated.
Glutamine may be uncharged, but it's still a polar molecule due to the amide group, so it can still engage in hydrogen bonding, dipole interactions, form salt bridges, etc. Alanine on the other hand only has hydrophobic interactions, so there is a difference in electrostatic interactions between the two. There's also the size difference that should be taken into account as well, so I wouldn't dismiss these differences as just them being uncharged. The inference here with the melting temperatures just suggests that these residues overall aren't big contributors to binding.
Thank you for the response and the thoughts. After spending years with fitting protein molecules and dealing with atomic bonds, working for groups which produced hundreds of protein structures per year, all what I can say is, a solid salt bridge is build between charged residues, mainly those will be submitted to PDB data bank. I do not recall ever fitting Q as a part of a salt bridge...
Yes glutamine is polar but it transfers very weak signals, frequently driven by equally polar water, all partial dipoles, transient ones. That small epitope peptide, if fitted 180deg opposite in that cleft, would make actually the Lys(epitope)-Glu76)HLA a strong bond.. Not sure what resolution of all these HLA-epitope compleses are. Also,
any study based on positive PCR tests and covid19 infections, which have nothing in common in particular while running it for >35 cycles, is questionable to me...
I've been a bit of a stickler for these types of images because I thought they would distract from the actual processes. But honestly if you're trying to relate information to people who may not have a background in these topics why not use these images? It becomes more memorable and will make it easier for people when they do look at the actual structures, so I can't fault them! There's plenty more in the paper that are great if you are curious!
Jul 20, 2023·edited Jul 20, 2023Liked by Modern Discontent
Superb write-up. I would be fascinated to see rates of adverse reactions to the injections amongst those who carry the allele cited by the authors versus those who do not (would need a very large sample size). My hypothesis would be that adverse reactions might be lower with this class of individuals than with those who would develop symptomatic infections and that there might be a link here to auto-immune disease post injection. The confounders are obviously many, with terrible quality control on the injections themselves, haphazard injection (hope they didn't find a vein), and large differentials in the injection schedule, age, body mass, etc...
There's a lot to consider when looking at HLA alleles within the context of adverse reactions and autoimmunity. One thing to consider is the fact that some peptides may not go recognized by certain allele carriers. For instance, B*46:01 doesn't appear to recognize certain peptides from SARS-COV2, and so if someone is infected or vaccinated with spike and it goes unrecognized, then not much may be done in the way of clearing these things out. But there's also the fact that prior immunity would come into play as well. So it could be that those who have prior cross-reactive immunity memory may have greater buffering.
For autoimmunity the role of HLA is complex. It boils down to what peptide gets presented. I believe in celiac disease one of the issues is that a peptide from gluten (some articles mentioned gliadin so I'd have to look deeper) gets recognized by one HLA allele in particular, and so it unfortunately makes gluten immunogenic and causes the downstream immune response. So sometimes otherwise inert proteins can be recognized as being immunogenic.
In this case with a virus-derived antigen the issue would be if the recognized peptide happens to be a peptide found in one of our cells or tissues, so these HLA molecules present this peptide, the immune system responds, and later goes scattering around and looks at our own tissues and goes "hey, there's that thing I'm supposed to target"! In this case, it certainly becomes an issue in figuring out if there are some alleles that happen to be presenting spike antigens that are also self-antigens so to speak. But unfortunately, a lot of this research seems to be in the early phases right now.
It's a shame we can't see Shi Zhengli's lab notes! Does the spike protein contain peptides found in human cells; and, if so, is it by accident of nature, as an accident of the lady's work or as a deliberate insert?
I'll deviate from others and say that any overlap is likely to be convergence rather than intentional insertion (well, maybe aside from the furin cleavage site). A thing to remember is that genes and proteins serve a function. The arrangement of amino acids are there for a reason. They either aid in the folding of a protein, a protein's binding to other proteins, the list can go on.
When we look at arrangements of things from a statistical perspective we may say that something may not be due to chance because probability states that this arrangement has a 1 in a million or 1 in a billion chance of occurring. But if this is pivotal to a protein's function, then you can't use statistics to argue why something is arranged the way it is. For a simpler comparison, let's say that a protein has 3 sequential glycine residues. You may look at the amino acid makeup and say that's a 20*20*20 chance of occurring, or around 1 in 8000 (nucleotide sequence will get you in the millions). So you can look at that and say well those odds are pretty slim.
But what do glycines do? Glycines are the most flexible amino acid given it lacks an R group. If you happen to find glycine-rich regions in a protein maybe it's because that portion requires a good deal of flexibility. In this case, what appears like a statistical anomaly may be explained by functionality. In that regard, many proteins may end up converging on similar amino acid sequences because it happens that these sequences work the best for the protein.
Now, it could be that someone saw something good and tried making it "better" through modifications, but there's always a balance to changing things.
Given that many bacteria and viruses, and heck even random foods can produce autoimmune responses we have to consider a convergence due to functionality as a possibility. I mean, it's not like wheat is getting amino acids changed to give everyone celiac disease.
The close nature of SARS-COV2 and seasonal coronaviruses in the case of this one epitope above suggests that it's likely due to them being coronaviruses, and this mutation just doesn't seem to confer much one way or the other in the virus' functionality.
A lot of words to pretty much say that we shouldn't discredit nature's ability to go with things that just happen to work.
Good article. It made me wonder if taking a flu shot every year may have made us more susceptible to COVID? This is because there is evidence the COVID vaccines made our systems more susceptible to COVID or at least to side effects.
Isn't this the same allelle implicated in increased risk of multiple sclerosis?
So I tried looking it up quickly and it seems like there's an association with DRB1*15:01 for multiple sclerosis and not B*15:01. So Class I HLA molecules are categorized as A,B,C. Class II are DR, DQ, and DP. So for this study they looked at B*15:01 which is a different loci compared to DRB1. The naming for all of these can get confusing, and considering you can have millions of different combinations it can all get confusing.
🙏 thank you for the clarification
Here's a review article that may interest you. It has other loci and alleles as well. It can be a bit much when looking at all of this information, and with many alleles it may boil down to correlations.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687745/
That:
"Note that this study took place in early 2020 up until April 2021- prior to any vaccine rollout."
is not right, here little bit more about the timing:
https://www.bbc.com/news/world-us-canada-55305720
the rollout started on 14 December 2020. While watching every single day, how many more got injected, I was TERRIFIED, that so many believed all the lies.
In the epitope story, the two substitutions by non-charged residues alanine and glutamine can't change the electrostatic interaction..
From how the study is reported, they mention that the people included were unvaccinated aside from one person who appeared to be vaccinated for one section examining cross-reactivity. The timing of vaccine rollout across nations doesn't inherently mean that the people included in a study were vaccinated. Some of these people could be lying, but without any additional data we sort of have to go off of the author's remarks that the people were unvaccinated.
Glutamine may be uncharged, but it's still a polar molecule due to the amide group, so it can still engage in hydrogen bonding, dipole interactions, form salt bridges, etc. Alanine on the other hand only has hydrophobic interactions, so there is a difference in electrostatic interactions between the two. There's also the size difference that should be taken into account as well, so I wouldn't dismiss these differences as just them being uncharged. The inference here with the melting temperatures just suggests that these residues overall aren't big contributors to binding.
Thank you for the response and the thoughts. After spending years with fitting protein molecules and dealing with atomic bonds, working for groups which produced hundreds of protein structures per year, all what I can say is, a solid salt bridge is build between charged residues, mainly those will be submitted to PDB data bank. I do not recall ever fitting Q as a part of a salt bridge...
Yes glutamine is polar but it transfers very weak signals, frequently driven by equally polar water, all partial dipoles, transient ones. That small epitope peptide, if fitted 180deg opposite in that cleft, would make actually the Lys(epitope)-Glu76)HLA a strong bond.. Not sure what resolution of all these HLA-epitope compleses are. Also,
any study based on positive PCR tests and covid19 infections, which have nothing in common in particular while running it for >35 cycles, is questionable to me...
😂 the graphic from that paper is great!
I've been a bit of a stickler for these types of images because I thought they would distract from the actual processes. But honestly if you're trying to relate information to people who may not have a background in these topics why not use these images? It becomes more memorable and will make it easier for people when they do look at the actual structures, so I can't fault them! There's plenty more in the paper that are great if you are curious!
Superb write-up. I would be fascinated to see rates of adverse reactions to the injections amongst those who carry the allele cited by the authors versus those who do not (would need a very large sample size). My hypothesis would be that adverse reactions might be lower with this class of individuals than with those who would develop symptomatic infections and that there might be a link here to auto-immune disease post injection. The confounders are obviously many, with terrible quality control on the injections themselves, haphazard injection (hope they didn't find a vein), and large differentials in the injection schedule, age, body mass, etc...
There's a lot to consider when looking at HLA alleles within the context of adverse reactions and autoimmunity. One thing to consider is the fact that some peptides may not go recognized by certain allele carriers. For instance, B*46:01 doesn't appear to recognize certain peptides from SARS-COV2, and so if someone is infected or vaccinated with spike and it goes unrecognized, then not much may be done in the way of clearing these things out. But there's also the fact that prior immunity would come into play as well. So it could be that those who have prior cross-reactive immunity memory may have greater buffering.
For autoimmunity the role of HLA is complex. It boils down to what peptide gets presented. I believe in celiac disease one of the issues is that a peptide from gluten (some articles mentioned gliadin so I'd have to look deeper) gets recognized by one HLA allele in particular, and so it unfortunately makes gluten immunogenic and causes the downstream immune response. So sometimes otherwise inert proteins can be recognized as being immunogenic.
In this case with a virus-derived antigen the issue would be if the recognized peptide happens to be a peptide found in one of our cells or tissues, so these HLA molecules present this peptide, the immune system responds, and later goes scattering around and looks at our own tissues and goes "hey, there's that thing I'm supposed to target"! In this case, it certainly becomes an issue in figuring out if there are some alleles that happen to be presenting spike antigens that are also self-antigens so to speak. But unfortunately, a lot of this research seems to be in the early phases right now.
It's a shame we can't see Shi Zhengli's lab notes! Does the spike protein contain peptides found in human cells; and, if so, is it by accident of nature, as an accident of the lady's work or as a deliberate insert?
I'll deviate from others and say that any overlap is likely to be convergence rather than intentional insertion (well, maybe aside from the furin cleavage site). A thing to remember is that genes and proteins serve a function. The arrangement of amino acids are there for a reason. They either aid in the folding of a protein, a protein's binding to other proteins, the list can go on.
When we look at arrangements of things from a statistical perspective we may say that something may not be due to chance because probability states that this arrangement has a 1 in a million or 1 in a billion chance of occurring. But if this is pivotal to a protein's function, then you can't use statistics to argue why something is arranged the way it is. For a simpler comparison, let's say that a protein has 3 sequential glycine residues. You may look at the amino acid makeup and say that's a 20*20*20 chance of occurring, or around 1 in 8000 (nucleotide sequence will get you in the millions). So you can look at that and say well those odds are pretty slim.
But what do glycines do? Glycines are the most flexible amino acid given it lacks an R group. If you happen to find glycine-rich regions in a protein maybe it's because that portion requires a good deal of flexibility. In this case, what appears like a statistical anomaly may be explained by functionality. In that regard, many proteins may end up converging on similar amino acid sequences because it happens that these sequences work the best for the protein.
Now, it could be that someone saw something good and tried making it "better" through modifications, but there's always a balance to changing things.
Given that many bacteria and viruses, and heck even random foods can produce autoimmune responses we have to consider a convergence due to functionality as a possibility. I mean, it's not like wheat is getting amino acids changed to give everyone celiac disease.
The close nature of SARS-COV2 and seasonal coronaviruses in the case of this one epitope above suggests that it's likely due to them being coronaviruses, and this mutation just doesn't seem to confer much one way or the other in the virus' functionality.
A lot of words to pretty much say that we shouldn't discredit nature's ability to go with things that just happen to work.
Point well-taken. :)
Good article. It made me wonder if taking a flu shot every year may have made us more susceptible to COVID? This is because there is evidence the COVID vaccines made our systems more susceptible to COVID or at least to side effects.