Upload
lexi2706
View
220
Download
0
Embed Size (px)
Citation preview
8/13/2019 13 14 Immunology Leitenberg MHC&AgPresentation 01-15-13
1/3
13_14 Immunology
Dr. Leitenberg
January 15, 2014
3:45-4:30pm
Notetaker #19
Slide 31: If most peptides bout to MHC molecules are self peptides, why dont we all have
autoimmune disease because of CD4+ and CD8+ T cells reacting to self? In the example on
the left, peptide y might be a self peptide and peptide x might be a microbe. Peptide y is not
recognized. We have regulatory mechanisms that act at multiple levels here to prevent the
development of self MHC complexes.
Slide 32: In people we refer to the MHC as the HLA. These different MHC class 1 and class 2
molecules will have differences in their ability to present different peptides. Depending on
which MHC molecules u inherit from mom and dad will influence which t cells develop?
Slide 33: This shows the exon structure of the MHC gene complex. Dont need to memorize
this. It is found on chromosome 6. In MHC class 1 the peptide binding group is all
determined by the alpha chain. 3 proteins, the A, B and C. Each of these will encode an
alpha chain and depending on which proteins you inherit from mom and dad will
determine which peptides get into the peptide binding groove. Class 2 is more complicated
because the groove is made of the alpha and beta chain. The HLA-DR molecule which is a
heterodimer of both the alpha and beta chain has one gene for the alpha chain and 2 genes
for the beta chain. DQ has one alpha and one beta, and DP has one alpha and one beta.
Slide 34: The MHC genes that exist in our population are variable. There is lots of variance.
Even though the MHC molecules you inherit from mom and dad there is a lot of diversity inthe population of people in the world. That gene diversity--one way of describing it is that
they are polymorphic. Antibodies and TCRs are diverse through Somatic Recombination
mechanisms which we will talk more about later. Unlike antibodies and TCRs, MHC
molecules are fixed in the genome, youve got what you are born with. MHC molecules are
fixed in the genome. So MHC diversity is mediated through genetic polymorphisms, which
are multiple alleles of MHC.
Slide 35: This bar graph is showing diversity, some things are more diverse than others. To
get across the idea, there are roughly 303 different HLA A alleles, fewer C alleles, a lot of B
alleles. Likely that my HLA A allele is different than my neighbors. About 20% of us all have
HLA A 2. Diversity for MHC Class 2 is similar. The one that is most diverse is the beta chaingene encoding for the HLA DR molecule. People pay attention to this in transplantation.
This is why we cant receive organs at random. If you have a different HLA allele the kidney
will be rejected. Need to match HLA genes as much as possible when transplanting organs.
When people do the matching, tend to pay attention to some of them more than others.
Example, HLA DQ is not that diverse so dont need to pay as much attention to is as
opposed to DR beta. There is a graded response and we will go into this in more detail in
transplant lecture.
8/13/2019 13 14 Immunology Leitenberg MHC&AgPresentation 01-15-13
2/3
Slide 36: Might have differences in amino acids that make up this peptide binding groove
and whether or not the peptide stability associates with the groove and it will also affect
whether or not the T cell receptor will recognize the peptide and MHC molecule or not.
Slide 37: This is how these MHC polymorphisms affect T cell immune response. Have a Tcell recognizing MHC peptide complex. HLA A 0201 and this is what normally happens
and the T cell gets activated. If you had the same T cell receptor it will not recognize this
different MHC peptide complex. Even though it is same peptide, it is a different complex so
wont have T cell activation. Far right image, same MHC molecule, different peptide, and
again no activation. The T cell receptor needs to recognize both the peptide and MHC
molecule.
Slide 38: What happens in transplantation is complicated but we will come back to it. The
ability of T cells to recognize non-self HLA molecules or non-self MHC molecules.
Allorecognition is recognition by T cells of non-self MHC molecules (different MHC alleles).
Sometimes, and partly it is because of things that happen in T cell development, some ofthese T cells will cross react with a non self MHC molecule. They are very specific but they
have ability to cross react with things they have never seen before, like a kidney cell. If all
of a sudden see your kidney, might have T cells that cross react with your MHC cells and
eventually kill your kidney because perceive it as being dangerous. Sometimes when you
get a foreign MHC molecule that you have never seen before they will cross react and
recognize non-self MHC complex. The T cell receptor in both cases is either recognizing
some non-self thing.
Slide 39: Because of transplantation and some other reasons, it is sometimes appropriate to
clinically assess which MHC haplotypes a patient has. This is an example of how these
different MHC genes are inherited. Get a set from M and D. These genes represent MHCclass 1 because they are HLA A, B, or C. Get both of these sets of HLA genes. You express
ALL of these genes co-dominantly. Express both moms and dads together on the same cell
at the same time. Means these genes are inherited codominantly.
Slide 40: For MHC class 1 that is a simple concept because get one gene from mom and one
from dad so if they arent related to eachother you will have 2 alleles for MHC A, B, and C.
Class 2 is more complicated because you can have multiple chains. Dont worry about this
too much, just know inheriting one set from both mom and dad. Definition of haplotype is
the word we use to describe the set of MHC genes somebody hasbasically what is encoded
on chromosome 6 so all of these MHC genes define your haplotype.
Slide 41: Answer is C. 2. Get one from mom and one from dad. But if we measured the
amount in this room, we would have more than that since the HLA gene is polymorphic in
the pop.
Slide 42: This is a paternity testing thing. Paternity testing looks at the different MHC
haplotypes. This is why when parents give a transplant to their kids it is not likely to be
8/13/2019 13 14 Immunology Leitenberg MHC&AgPresentation 01-15-13
3/3
complete match because mom and dad likely arent related. More likely to have a better
match with a sibling.
Slide 43: The answer C. if an allele is only listed once, it means homozygous for that allele.
Mom has A 25 so she cold have given that, dad has an A1 and A25. Mom has B 17, dad B 7.
Slide 44: Why have we evolved to have all this MHC diversity? The more diversity in our
MHC haplotype allows us to present more peptides and activate more T cells which is good
if we are exposed to a new pathogen. The potential survival advantage is greater with a
larger haplotype. If you have multiple haplotypes you can present more haplotypes to the
immune system and generate a more diverse response.
Slide 45: People have studied DNA from diff populations. Here you can see selection of
certain MHC haplotypes of various diseases. In the far left picture, see the population has a
diverse array of haplotypes but then they encountered a series of diseases and there was a
strong advantage for only the heterozygotes to survive so have a heterozygote survival
advantage. Then the people married and have increase in haplotypes again. Anotherepidemic and everybody without the blue haplotype died but because there are some blue
haplotypes there is survival of the species.
Slide 46: One of the things you may have learned about previously is that MHC halotypes
are associated with certain autoimmune disease. It is really just an associated it isnt that
the MHC gene is the cause of the disease. MHC is not the CAUSE of the disease, but there
sometimes is a strong association with having a particular MHC allele and the incidence of
the disease. IF you have the human MHC HLAB27 class 1 allele, you have an 87 fold greater
change of developing Akylosing Spondylitis compared to the population that does not have
the HLA B27 allele. It doesnt mean that just because you have HLA B27 you will get this
disease because it is rare. But if you do express HLA B27 you are more likely to get it . It is arelative risk.
Slide 47: Dont memorize this. Important point is that these relative risks can be a positive
association with various disease but also they can be associated with a negative risk.
Slide 48: The answer is D. Not E because they bind multiple peptides.
Slide 49: This is just a summary slide, didnt read it. The End.