WK 4- MHC COMPLEX, ANTIGEN PROCESSING AND PRESENTATION Flashcards
What is MHC also called
HLA
What is the MHC
MHC is a cluster of genes which form a molecule on the surface of cells- aids in presenting peptides from pathogens. MHC determines if transplanted tissue is compatible between donor and host.
Where is MHC1 found
MHC1 is found on all nucleated cells, including plasma cells
Where is MHC2 found
Found on subsets of haematopoietic cells- APC (dendritic, macrophage and NK cells)
What genes encode for MHC1
Alpha chain is encoded by HLA-A, HLA-B, HLA-C
What genes encode for MHC2
Alpha and beta chains are encoded by HLA-DR, HLA-DP, HLA-DQ
What MHC complex presents peptides from intracellular pathogens
MHC1 expresses peptides from pathogens that reside within the cell-> MHC1 presents the peptides to CD8 cytotoxic cells
What MHC complex presents peptides from exogenous peptides
MHC2 expresses peptides from pathogens that were exogenous and then engulfed and broken down-> presents them to CD4T cells
What is MHC restriction
MHC restriction is the requirement that APC cells express MHC molecules that the T cell recognizes and matches, in order for T cell to respond to the antigen presented by that APC. (T cells will only recognize antigens presented by their own specific MHC molecules- allows for T cell specificity)
What does polygeny mean
MHC molecules display polygeny as they have multiple genes encoding for the same structure/function
What does polymorphic mean
Refers to a minor difference between genes-> caused by inheriting multiple alleles for each gene because you inherit combinations from each parent, and both are expressed
What is a haplotype
A set of genetic determinants located on a single chromosome and inherited as a block- the HLA genes from each parent are inherited as a haplotype
True or false, HLA genes are expressed co-dominantly
True- each inherited gene is expressed-> polygeny and polymorphism contribute to diversity
What is an altered cell
Altered cells are those which are infected with a virus or cancer-> MHC1 allows for these cells to be identified and killed by cytotoxic CD8T cells
What is antigen processing
Generation of peptides from intact antigens-> must occur in order for MHC to present signals to T cells (T cells only recognise peptides)
What is antigen presentation
Display of peptide on cell surface by MHC molecules
What is a super antigen
Super antigens are produced by bacteria and viruses and don’t require processing into peptides and aren’t presented by MHC-> they bind directly to the portion between the MHC and TCR and activates the T cell directly, causing toxic shock
Why is toxic shock so severe
Super antigens activate around 20% of the T cell population at once, causes an over exaggerated immune response leading to an overproduction of cytokines into the body-> causes life threatening tissue damage and systemic effects
Why don’t super antigens create memory cells
No memory cells can be created because super antigens don’t need to be processed by MHC so therefore don’t initiate the adaptive immune response
What is immunological tolerance
Defined as the state of specific immunological unresponsiveness of the lymphoid tissue to an antigen (tolerogen) that would normally cause an immune response
What is self-tolerance
Inability to mount an immune response to self-antigens or endogenous antigens (important in preventing auto-immune)
What causes self-tolerance
Self-tolerance is due to the deletion of self-reactive T cells and B cells-> these cells are tested in the primary lymphoid tissue for self-reactivity
What is central tolerance
Is clonal deletion that deletes self-reactive lymphocyte clones
What is peripheral tolerance
Mechanisms acting on lymphocytes after they have left primary lymphoid organs-> if the self-reactive lymphocytes escaped the BM/Thymus they are captured and destroyed by anergy, suppressor cells and clonal deletion
What is acquired tolerance
Tolerance arising as a result of administration of an exogenous antigen-> this is how immunisations work
What is the structure of MHC1- what forms the peptide binding cleft
Consists of 2 polypeptide chains and an alpha heavy change encoded by HLA-A/B/C, and a non-covalently bound B2 microglobulin
Alpha 1 and Alpha 2 pair together to form the peptide binding cleft
What is the structure of MHC2- what forms the peptide binding cleft
Consists of two non-covalently bound polypeptide chains, each has 2 domains (alpha 1/2, beta 1/2)- beta 1 and alpha 1 form the peptide binding cleft
What is the process of presentation by MHC1 molecules
- Virus adheres to membrane and enters cell
- Once inside the cell it will enter the nucleus and begin to replicate→ will then move to cytosol where it is synthesized (translation and transcription) into proteins
- The proteins then encounter proteasomes in the cytosol→ proteasome cleaves the protein into small peptides
- The peptides are transported to the ER via the TAP1/2 (transporters associated with antigen processing)
- MHC is in its inactive form in the ER and has several molecules capping it→ MHC1 is originally bound to calnexin→ when released from calnexin it binds to a complex of proteins (calreticulin, ERp57) and TAP via tapasin→ the proteasome (that degrades the viral protein) also degrades the cytostolic proteins and DRIPs (defective ribosomal products) and causes the TAP to deliver the peptides to the ER→ the peptide will then bind to the MHC1 molecule and be released from TAP and into the cell membrane
- At the cell membrane the MHC1:peptide complex is presented and will trigger CD8 cells that will release cytotoxic granules and cause the virus infected cell to undergo apoptosis
What is the process of presentation by MHC2 molecules
Process of presentation:
- Virus/protein is taken up form extracellular space into by an endosome or phagosome via phagocytosis
- In early endosomes the pH is neutral and the proteases are inactive→ acidification of vesicles will activate the proteases that degrade the antigen into peptides
- Initially, the MHC2 has an invariant chain→ this invariant chain is cleaved in an acidified endosome leaving a short peptide ‘CLIP’ still bound to the MHC (removal of capping molecules only occurs when there is a peptide containing vesicle fusing with an MHC molecule)
- When HLA-DM binds to the MHC2 molecule is will release CLIP and allow binding
- . Vesicles full of peptides produced from the virus will fuse with vesicles containing MHC class 2 molecules in the ER and the peptides will bind to the peptide binding site
- The MHC2 molecule will then travel to the cell surface and trigger CD4 cells→ the functions CD4 depend on the subtype produced
What is the invariant chain
Present in MHC2 presentation- blocks the binding site to prevent binding of peptides or misfolded proteins in the ER
What is required to bind to the MHC2 in order for CLIP to be released
HLA-DM
What is a the difference in antigen processing between MHC2 and MHC1
MHC1 uses a proteosome in order to digest the pathogens proteins to peptides
MHC2 uses the acidic granules in a lysosome to break down proteins from a peptide
