Membrane associated glycoprotein molecules whose function is to bind peptide antigens and present them to T-cells.
What does MHC stand for?
Major Histocompatibility Complex
How was MHC discovered?
Many genes influence tissue transplantation success, but one genetic locus was shown to have a greater effect than others.
What is Human Leukocytic Antigen?
MHC in humans, specifically. MHC was discovered in mice. HLA is only in humans.
What is the function of MHC I?
Binding and transport of peptide antigens generated in the cytosol to the cell surface for recognition by CD8 / Cytotoxic T-cells. Also involved in IgG uptake in the gut, iron metabolism, and NK cell function regulation.
What is the function of MHC II?
Binds and transports antigens generated in endocytic vesicles to the cell surface for recognition by CD4 / Helper T-cells.
What is the structure of MHC I as far as protein chains?
Divided into a heavy chain composed of three alpha subunits and a light chain composed of one beta (beta-2 microglobulin) subunit. The chains are coded on different genes.
What subunits of MHC I form the peptide-binding cleft?
Alpha 1 and alpha 2.
What gene codes for the MHC I heavy chain?
What gene codes for the MHC I light chain?
What is the protein structure of MHC II?
Has two transmembrane chains: alpha and beta, each with two subunits.
Which subunits combine to for the peptide-binding cleft of MHC II?
Alpha 1 and Beta 1.
Where is MHC II coded for?
On chromosome 6.
What portion of MHC I complex binds CD8?
Alpha 3 subunit
What part of MHC II binds CD4?
Beta 2 subunit
Do T-cells express MHC II?
Only when activated.
Where is MHC I expressed?
On all nucleated cells. Not RBC's.
Where is MHC II expressed?
On antigen presenting cells. Specifically: B-cells, macrophages, and certain epithelial cells.
Is the beta chain of MHC I mono or polymorphic?
Monomorphic for all isotypes. (Is the same for all versions of MHC I)
Is polymorphism good or bad for MHC molecules?
The more polymorphic the MHC, the better for the host's immune system. Means there is higher variability for potential foreign portein structures.
What are the more versatile versions of MHC I?
Isotypes: HLA-A, B, and C.
What are the most versatile versions of MHC II?
Isotypes: HLA-DP, DQ, and DR
What is polymorphism?
The presence of multiple alternative forms of a gene within a population.
What is polygeny?
The existence of multiple similar genes encoding MHC I heavy chains, MHC II alpha chains, and MHC II beta chains.
Why are MHC molecules so diverse?
They arise from the combination of multiple genes and multiple alleles. These genes are all codominant.
What is codominance?
Two alleles expressing together something different than either would express individually.
What do T-cells specifically recognize since MHC is constantly expressed on cell surfaces in the absence of infection?
The MHC-foreign peptide complex.
What do MHC molecules express in the absence of infection?
They express only self peptides on the cell membrane.
Which MHC molecule usually binds larger peptides?
What protein on T-cell surfaces recognizes MHC complexes?
TCR (T-cell receptor)
What is MHC-restriction?
A particular TCR is specific to a particular MHC-foreign peptide complex. Presenting a different peptide by the same MHC allotype will fail to induce T-cell response.
What example was used to demonstrate polymorphism is better for MHC molecules?
Progression of HIV compared to HLA chain polymorphism. The more polymorphic the structures, the longer on average patients remained AIDS free.
What is an autologous MHC molecule?
A self-peptide presenting MHC.
What is an allogenic MHC molecule?
A non-self peptide presenting MHC.
About what percentage of T-cells are alloreactive?
1-10% of circulatory T-cells.
When is alloreactivity a problem?
In transplantation. Irradiation and immunosuppressive drugs are used to prevent a response.
What is alloantibody?
Antibody raised in one member of a species against the allotypic protein of another member of the same species. (In pregnancy, can develop against HLA molecules of the fetus derived from the father.)
What is mixed lymphocyte reaction (MLR)?
An in vitro experimental reaction where t-cells from an individual is cultured with leukocytes of another individual to assess prognosis for organ transplantation.
What is a common immunosuppressant used in organ transplantation?
What is peptide dominant binding?
Peptide fits so strongly with TCR that the mismatch of MHC to TCR is overridden.
What is MHC dominant binding?
MHC - TCR binding is so strong, the peptide mismatch is overridden.
What are superantigens?
Distinct class of antigens that stimulate T-cell response after being presented on the MHC complex intact (without processing).
What are the examples of Superantigens?
Staphylococcal enterotoxin (SE) and Toxic shock syndrome toxin (TSST)
Why are superantigens dangerous?
They induce a polyclonal T-cell response which results in the production of heavy amount of cytokines. Specifically, IL-1 which is a pro-inflammatory that makes blood vessel more permeable and in high concentration leads to shocking.
Where are MHC I presented peptides generated?
In the cytosol after proteasome degradation.
How do MHC I molecules get into the ER?
Through a TAP complex.
What is clanexin?
Hold heavy chain of MHC I anchored in ER until Beta 2 binds.
What is tapsin?
Allows the chaperone protein bound pre-MHC complex to bind TAP so a peptide can be loaded.
What happens if your patient is deficient of TAP protein?
MHC I is bare because peptides can't load the complex, thus poor CD8 T-cell response and chronic viral infection.
How does the foreign peptide load once it passes through TAP?
By proximity, and once it loads the chaperone protein and tapasin leave so the MHC I molecule can be exported from the ER.
What types of peptides does MHC II bind?
Ones derived from extracellular source / those that have been endocytosed.
How are MHC II peptides processed before MHC II introduction?
In endocytotic vesicles that fuse with lysosomes containing hydrolases and proteases.
How are peptides loaded onto the MHC II molecule?
MHC II is released from ER with CLIP protein. The vesicle fuses with endocytotic vesicle and foreign protein replaces CLIP protein.
What is CLIP protein?
The placeholder protein that binds the binding portion of MHC II until the foreign peptide is introduced. Prevents binding of MHC II to ER peptides.
What facilitates release of CLIP protein?
HLA-DM which is structurally similar to MHC II but cannot bind peptide.
What type of infection do CD4 / MHC II complexes indicate?
What type of infection do CD8 / MHC I complexes indicate?
What is the TH1 response?
Cytokines activating macrophages.
What is TH2 response?
Cytokines activating B-cells to produce antibodies.
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