MHC and antigen processing – Flashcards

Unlock all answers in this set

Unlock answers
question
what is another name for human MHC?
answer
HLA, human leukocyte antigen
question
how are MHC similar to Ig/TCR? how are they different?
answer
they are a part of the immunoglobulin superfamily of proteins, but unlike Ig/TCR, MHC are encoded by conventional, stable genes that do not rearrange or undergo any other any other somatic/developmental change.
question
what are the 2 classes of MHC?
answer
class I, (6 HLA isotypes)+II(5 HLA isotypes)
question
what are the two ways inherited diversity can occur with MHC?
answer
gene families and genetic polymorphism
question
how do gene families give MHC diversity?
answer
gene families, (represented by class I+II) consist of multiple, similar genes encoding these proteins - genes within families code for similar structures within class isotypes. class I is HLA-A through G, class II is HLA-DP, DQ, DR, DM & DO
question
how do genetic polymorphism give MHC diversity?
answer
the presence of multiple, alternative forms/alleles of a gene, (encoded proteins are called allotypes) allows for diversity. there are many more alleles of these genes than most other genes in the body = highly polymorphic
question
what does isoform mean when talkin about MHC proteins?
answer
an isoform is the combination of multiple genes and multiple alleles adding to the diversity of two classes (I and II) giving one unique MHC protein
question
what are MHC class I and II proteins called that have many different alleles and proteins encoded by them? what are these involved in?
answer
highly polymorphic MHC, which are involved in antigen presentation
question
what are MHC class I and II proteins called that have no polymorphism/only one set of genes?
answer
monomorphic MHC
question
what are MHC class I and II proteins called that have only a few alleles?
answer
oligomorphic
question
what is the physiologic role of MHC having a high polymorphism?
answer
the binding of peptide to these alleles is not specific, (like an antigen and receptor would be), so some are more selective than others and in a population the people that present peptide better than others reduce the reservoir of infection. this also makes transplanting organs really hard.
question
what are alleles?
answer
alleles are understood to be alternative DNA sequences at the same physical locus, which may or may not result in different phenotypic traits
question
what chromosome are all MHC coding genes found on? how many copies of chromosome 6 should the body have? what does is a haplotype?
answer
chromosome 6, of which you get one from each parent. the cluster of polymorphic MHC genes that you get from each parent is called a haplotype collectively
question
how are MHC haplotypes expressed? how are they passed on?
answer
MHC haplotypes expressed are codominantly, (ex: you express both HLA from mom and dad). they are passed on as one from each, (4 possible offspring combinations). these need to match for a kidney transplant which is a 1 in 4 chance for siblings, but even with this, immunosuppressants will still needed, (other MHC alleles not tested for, minor histamine complexes)
question
each haplotype contains loci containing what? which of these is expressed?
answer
1.all class I molecules,HLA-A through G
2.all class II molecules, HLA-DP, DQ, DR, DM & DO. every individual expresses 2 HLA-A molecules or isotypes (encoded for by the maternal and paternal alleles) etc. for each polymorphic gene
question
where are MHC class I expressed?
answer
on every nucleated cell in the body, (not RBCs and a few others)
question
where are MHC class II expressed? why?
answer
some activated T cells, B cells, macrophages/APC, thymic epithelial cells, (all APCs). this is to ensure that CD4 cells, (powerful immune regulators), are activated in a tight, highly controlled manner
question
what is the structure of class I MHC? is it complexed with anything?
answer
one peptide chain with 3 globular domains, alpha 1,2,3. all class I MHC isoforms are complexed with a molecule called beta2 microglobulin, (keeps molecule from tipping over)
question
what is the structure of class II MHC? is it complexed with anything?
answer
class II MHC proteins are composed of 2 peptide chains, either alpha 1 or 2 and beta 1 or 2. it is not complexed with anything.
question
how do the structures of MHC I and II compare?
answer
they both have a similar, Ig-like binding cleft with alpha helix "walls" and a beta pleated sheet "floor". however the ends of the peptide bindng cleft on class II MHC are not closed like in class I, the peptides are less uniform in size for class II.
question
where is most of the variability from MHC polymorphism, (mostly A, B, C & DR (some DP & DQ)), largely confined to?
answer
most of the variability from MHC polymorphism is largely confined to the binding cleft, so that different MHC isoforms can bind different peptides.
question
is MHC peptide binding specific?
answer
no, but it is selective, (not antigen specific like antigen receptors on B+T cells)
question
where do the non-polymorphic areas of MHC bind?
answer
the non-polymorphic areas of MHC bind to CD4, (class II), or CD8, (class I) co-receptors
question
how do T cells "see" antigen? what will a specific T cell clone recognize peptides in the context of?
answer
T cells recognize processed peptide antigen presented by products of the MHC locus. each clone of a T cell recognizes peptides only in the context of that individual's MHC isoforms -> this is called MHC restriction, and is what the T cells are tested for during positive selection in the thymus.
question
why shouldnt your T cells be able to recognize someone elses MHC?
answer
most variability from individual to individual is in peptide binding clefts of MHC molecules, so there shouldn’t be T cells in your repertoire that would recognize someone else’s MHC cell. “There is no stronger foreign antigen (in the universe) than someone else’s MHC…”
question
what is MHC restriction in a nutshell?
answer
you can only see the context of your own MHC and T cells will kill in an “MHC restricted fashion”
question
how do CTL T cells recognize class I MHCs?
answer
CTL (CD8+) T cells bind to the alpha3 domain of Class I MHC and its TCR is then able to see antigen
question
how do helper T Cells (CD4+) recognize antigen in the context of Class II MHC’s?
answer
helper T Cells (CD4+) bind to the beta2 domain of Class II MHC’s and then the TCR is able to recognize the antigen
question
what are the differences between the antigens that MHC class I+II process?
answer
class I processes endogenous antigens, (for presentation to CD8+) and class II processes exogenous antigens, (for presentation to CD4+)
question
can MHC bind self peptides?
answer
yes, they have to have a peptide for the protein to fold correctly, so if they don't have a foreign peptide, they will have a self. however, these cells should be ignored because self-reactive T cells should have been deleted.
question
what is the benefit of both MHC parental alleles, each MHC gene being expressed codominantly?
answer
this increases the number of different MHC molecules that can present antigens to T cells
question
why is it beneficial the MHC genes are polymorphic?
answer
this keeps many different genes present in the population, allowing different individuals to present and respond to different microbial peptides, keeping reservoirs of particular infections down in the population
question
why is it beneficial for MHC class II's presence to be restricted to dendritic cells, macrophages, B cells, activated T, and epithelial cells?
answer
because CD4+ helper T cells interact with dendritic cells, macrophages, B cells, activated T, and epithelial cells.
question
why is it beneficial for MHC class I to be present on ALL nucleated cells?
answer
so that CD8+, CTL cells can kill any virus-infected cell
question
what happens when a macrophage expresses antigen in the context of a class II MHC, (this antigen comes from outside the cell)?
answer
this will turn on helper CD4 cells, which when they see the antigen make cytokines, (such as interferon), which activate macrophages that will destroy the microbe
question
what happens when a B cell processes and presents an antigen via class II MHC?
answer
this calls a helper CD4+ T cell to come and interact with it. the activated T cell when makes cytokines that act on the B cell to help make Ig
question
what happens when a cytoplasmic microbe is processed and presented via class I MHC?
answer
CD8+ CTL cells will respond and kill the infected cell
question
how does class II antigen processing occur?
answer
exogenous antigen is taken up by a macrophage and placed into a phagosome, which is fused with a lysozome, (bag of proteolytic enzymes), which breaks the protein down into peptides. class II molecues are then made in the golgi for export to the cell surface and they go to the surface with the peptide bound to it.
question
how does class I antigen processing occur?
answer
endogenous antigen, (intracellular), is complexed with ubiquitin, which targets it for digestion by a proteosome. the resulting peptides are then transported to the ER by CAP proteins. Many events cause peptides to bind and interact with Class I MHC in the ER, which once bound, goes to cell surface.
question
what happens to most peptides destined for presentation on MHC class II?
answer
peptides are destined for presentation on MHC class II molecules, (to CD4+ cells), are captured and internalized into endosomes by APCs, (including dendritic cells, macrophages, and B lymphocytes)
question
how do APCs such as macrophages and dendritic cells recognize structures common to many microbes? can macrophages bind antigen or complement? how do B cells bind antigen?
answer
macrophages and dendritic cells use scavenger and related receptors, (ex: mannose, toll-like receptors), to bind and internalize particles. macrophages can also bind antigen via the Fc region or complement via C3b. B cells bind antigen via specific surface Igs.
question
after internalization of exogenous antigen, what happens to them?
answer
they are localized into endosomes or phagosomes,(more specific for particulate matter), which contain acid and proteolytic enzymes. then these fuse with lysosomes which are more dense, enzyme containing-vesicles. many different enzyme participate in the breakdowns of antigen, (cathepsins, thiol and aspartyl proteases), to linear peptides 8-25 AA long
question
where do MHC class II molecules come from upon uptake of exogenous antigen by macrophages?
answer
MHC class II molecules are exported from the ER via exocytic vesicles and targeted to late endosomes/lysosomes
question
what happens when MHC class II exocytic vesicles and endosomes/lysosomes fuse?
answer
fusion of the exocytic vesicles with these compartments brings together the MHC class II proteins with processed peptides derived from extracellular proteins. these MHC class II compartments, (MIIC), then contain proteolytic enzymes, class II MHC, invariant chain, HLA-DM
question
what is the invariant chain?
answer
a “plug” sitting in MHC Class II binding site as it comes out of the ER, keeping peptide out of the cleft while it sits in the ER
question
is there anything else other than invariant chain at the binding site of class II MHC?
answer
CLIP (Class II-Associated Invariant Chain Peptide) is under the invariant chain, it site in the peptide binding groove, further keeping unwanted binding from occuring
question
what happens to the invariant chain and CLIP in the MIIC?
answer
proteolytic enzyme acts on the invariant chain, (scaffolding), and then removes CLIP
question
what does HLA-DM do? where does this happen?
answer
HLA-DM catalyzes removal of CLIP as well as catalyzing antigenic peptide's filling of the the MHC binding groove. this happens in the ER.
question
why can't exogenous antigens go to the ER?
answer
they might interfere with class I MHC processing
question
why doesnt class II MHC bind endogenous products?
answer
its cleft is plugged up with invariant chain/CLIP
question
once antigen peptide has been placed in the binding groove of class II MHC is it ready to go to the surface?
answer
yes, if class II: Peptide complex is stable, it is delivered to cell surface, where it can interact with CD4+ cells
question
what is endogenous antigen processing used for?
answer
the processing of cytosolic proteins for presentation at the cell surface on class I MHC
question
what would endogenous antigen processing be used for?
answer
viral gene products, proteins from phagocytose microbes that have either leaked out or been transported from vesicles to the cytoplasm, or mutated/altered host genes
question
what is ubiquination?
answer
a portion of all proteins synthesized in the cells is targeted for destruction via complexation with ubiquitin and transported to a proteosome
question
what is a proteosome?
answer
a 28 subunit cylindrical protease complex that degrades proteins into peptide. this peptide is then transported to the ER by TAP protein transporters
question
what is the relationship between MHC class I in the ER and endogenous protein/antigen?
answer
newly synthesized MHC Class I and beta-2 microglobulin are transported to the ER where they form a loose association with TAP and other chaperone molecules
question
how does endogenous protein become bound to the class I MHC in the ER ?
answer
tapasin forms a bridge between the TAP transporter and allows transfer of a peptide into the MHC binding cleft.
question
what happens to the class I MHC when antigen is bound to it?
answer
when peptide is inserted, it turns MHC class I to mature antigen
question
what does the class I MHC do once bound to the antigen?
answer
class I MHC and beta2 microglobulin complex then becomes properly folded with its antigen and is exported to the cell surface
question
what is the difference between MHC classes before antigen gets to them?
answer
class I is open (binding cleft), class II is closed (filled with CLIP)
question
what is cross-presentation? how does it happen?
answer
cytolytic T cells attacking exogenous antigens. phagolysosomes are “leaky” sometimes and exogenous proteins leak into the cytosol, then get ubiquitinated. they can then be picked up be a proteosome, TAP, taken to the ER and bound to class I MHCs. this will result in CTL CD8+ generation responding to exogenouse antigen, it but doesn't you can the can kill extracellular microbes, (CTLs only kill eukaryotic cells, not bacteria b/c they don't have MHC)
question
what are class II vs class I MHC in terms of composition?
answer
class II is polymorphic alpha and beta chains, class I is a polymorphic alpha chain with a beta2 micrglobulin
question
what are class II vs class I MHC in terms of their APCs?
answer
all nucleated (eukaryotic)cells process class I, only "professional" APCs process MHC II, (dendritic cells, mononuclear cells, B cells, thymic endothelial cells)
question
what are class II vs class I MHC in terms of responsive cells?
answer
class I - CD8+
class II - CD4+
question
what are class II vs class I MHC in terms of antigen protein source?
answer
class II - exogenous protein mostly internalized from the environment, presented in endosomal/lysosomal proteins. class I - cytosolic proteins, mostly synthesized in the cell, but may enter the cytosol from "leaky phagosomes"
question
what are class II vs class I MHC in terms of enzymes responsible for peptide generation?
answer
class II - endosomal/lysosomal proteases, (cathepsins) class I - cytosolic proteosomes
question
what are class II vs class I MHC in terms of site of peptide loading to MHC?
answer
class II - specialized vesicular compartment, (MIIC) class I - ER
question
what are class II vs class I MHC in terms of molecules involved in transport of peptides?
answer
class II - invariant chain, HLA-DM class I TAP
Get an explanation on any task
Get unstuck with the help of our AI assistant in seconds
New