6 - The Major Histocompatibility Complex: Structure and Function Flashcards
What happens ~7 after you inject a mouse with a virus called LCMV?
The mouse will make LCMV-specific B cells that secrete Abs.
What happens if you inject a non-infected mouse with the serum antibodies made by a mouse infected with a LCMV virus? Will it be protected from the virus? What is the half life of the Ig?
YES. This passive immunization and the strategy used to protect us from viral infections that is commonly used.
Half life: 30 days
What is given to HIV patients for passive immunization? What about for hepatitis patients?
Gamma-globulin (IgG) injections.
HBsIgs for hepatitis patients can prevent infection after exposure.
This is called IVIg - IV immunoglobulins
What happens if you transfer the T cells of an LCMV (virus) infected mouse to a non-infected (but genetically identical [syngeneic]) mouse? Will the mouse be protected from LCMV?
YES.
T cells will divide, so the half-life involved in transferring the B cells isn’t an issue here.
What happens if you isolate and transfer LCMV-specific T cells to a non-infected mouse - but a different strain of mouse? Will the mouse be protected?
Allogeneic - genetically different mice.
NO. Although the T cells are specific for theLCMV antigen, the new mouse never sees it because the new strain of mouse has a different non-self MHC molecules presenting the antigen.
What is MHC restriction?
T cells are restricted by self-MHC, so even if an allogeneic molecule presents the same peptide, the transferred T cell will not recognize it.
Only able to recognize peptides in the context of self MHC.
What happens when tumors are transplanted from one strain of mice (A/A) into mice with the same inbred strain (syngeneic)? What about when tumor is injected into a different inbred strain of mouse (allogeneic; B/B)? What do these experiments indicate?
Syngeneic: Tumors flourished and killed these mice.
Allogeneic: Tumors of mice (A/A) were rejected.
Indicates that tissue rejection is a genetically inheritable trait and that the tumor rejection genes are codominant (A/B mice will not reject both a/a or b/b tumors).
What is the genetic locus responsible for tissue rejection?
The major histocompatibility complex.
These genes encode the MHC molecules that are responsible for MHC restriction.
What is the structure of the MHC?
Over 200 genes encoded with ~7 mil base pairs on Chromosome 6.
What three genes encode class I molecules? What are the six genes that encode class II MHC molecules? What other proteins are encoded by MHC?
Genes that encode class I: HLA-A, -B, and -C (heavy chains)
Class II: HLA-DR, -DQ, -DP (alpha and beta chains)
Others: HLA-DM, TAP
HLA stands for human leukocyte antigen.
What are the most polymorphic genes in the genome?
MHC class I and Class II genes.
MHC genes are ______, _____, and ______. This allows them to recognize almost any foreign antigen in the context of self MHC.
Polymorphic, codominant, and polygenic.
Describe how MHC molecules are polymorphic, codominant, and polygenic.
Polymorphic: many different alleles in the population
Codominant: you express one from each parents
Polygenic: three different types of genes can encode class I and 6 genes that encode class II molecules.
There’s a : chance of another sibling matching for all 10 gene products for a bone marrow transplant, assuming no recombination. Why do they only check for 10 gene products if we know there’s 12 possible? Why does the BM registry only use 8?
1:4 chance.
HLA-DP is not bothered with because it doesn’t appear to have an impact on graft rejection.
HLA-DQ not used in BM registry for the same reason.
MHC polymorphisms can be used for what?
Tracing location of people over time.
People of easter island with HLA-A29, B-12 were traced back to spain.
_____ play a major role in allograft rejection.
Class I MHC molecules.
What do the alpha chains of class I molecules associate with?
Non-covalently with non-MHC encoded polypeptide called Beta2-microgrlobulin (B2m).
Where does the peptide bind on class I molecules?
Firmly within the groove and is considered a subunit of the class I MHC complex.
What domains are common in the structure of immunoglobulins (antibodies) and other immune-related molecules. Each domain consists of a series of B sheets and are often held together by a disulfide bonds.
Immunoglobulin (Ig) domains.
Class II MHC molecules are ____ of two polypeptide chains ___ and __.
Heterodimers.
Alpha and beta - each of which is encoded by a different gene.
Which chain of MHC class II molecules is the more polymorphic?
The beta chain.
In tissue typing for class II, only the beta chains are tissue typed.
Describe the binding groove for class II molecules?
It’s an intermesh of the alpha and beta chains.
What does a T cell receptors (TCR) recognize?
A combination of both peptide and class I (or class II) helices.
Where are the polymorphic regions found in class 1 and II molecules? What is the effect of these?
Class I: in the alpha helices and beta sheet of the heavy chain.
Class II: occur in the alpha helices and beta sheet of the beta chain.
These effect what peptides can bind within the groove.
About how many molecules can bind to each class I molecule?
> 1000
Each type of class I MHC molecules (HLA-A, -B, -C) binds to a unique set of peptides (same applies to class II).
Class __ peptides are not anchored at the ends.
Class II.
A single nucleated cell expresses ____ copies of each class I molecule, thus estimated that each of the _____ distinct peptides is presented with the frequency of 100-4000 copies per cell.
10^5 (100,000) copies of each class I molecule
10000 distinct peptides
Is it possible that a virus could escape efficient presentation on a given individuals 6 MHC molecules with 100,000 copies of each type?
Yes, it would be rare but could occur.
But there’s virtually no chance of that virus escaping presentation on all 1000 allelic variants within the pop; So the individual would be susceptible to the virus but the pop would be ok.
What is ankylosing spondylosis (AS)? What tissue type is associated with it? What does this suggest?
An inflammatory, possible autoimmune disease of vertebral joints.
HLA-B27 tissue type is only in 6% of the population, but in ~93% of individuals with AS.
Suggests that having HLA-B27 predisposes individuals to developing AS.
How many genes encode the three types of class II molecules?
6
How many genes encode for class I molecules? How many distinct class I molecules do we have?
We have 6 distinct lass I molecules on the surface of all of our nucleated cells because we inherit one from each parent.
Why was the transferred graft rejected (killed) by the immune system in mouse B that got an A mouse graft?
Because the donor MHC is not what the T cells in the recipient were trained to recognize when selected in the thymus.
Alloreactivity explains this. (reaction of T cells to non-self MHC class I or II molecules)
Why did the transferred T cells from an infected mouse to a non-infected mouse not protect the mouse against the virus once it was infected?
After infection, the peptide is being displayed on the recipients class I MHC.
The injected T cell cannot recognize the recipients MHC-peptide complex.
