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 in the 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 chain gene 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.

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 T cell 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 of these 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 MHC class 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 each other 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 has basically 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

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. Another epidemic 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 a relative 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.