MHC and antigen processing

what is another name for human MHC?
HLA, human leukocyte antigen
how are MHC similar to Ig/TCR? how are they different?
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.
what are the 2 classes of MHC?
class I, (6 HLA isotypes)+II(5 HLA isotypes)
what are the two ways inherited diversity can occur with MHC?
gene families and genetic polymorphism
how do gene families give MHC diversity?
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
how do genetic polymorphism give MHC diversity?
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
what does isoform mean when talkin about MHC proteins?
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
what are MHC class I and II proteins called that have many different alleles and proteins encoded by them? what are these involved in?
highly polymorphic MHC, which are involved in antigen presentation
what are MHC class I and II proteins called that have no polymorphism/only one set of genes?
monomorphic MHC
what are MHC class I and II proteins called that have only a few alleles?
oligomorphic
what is the physiologic role of MHC having a high polymorphism?
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.
what are alleles?
alleles are understood to be alternative DNA sequences at the same physical locus, which may or may not result in different phenotypic traits
what chromosome are all MHC coding genes found on? how many copies of chromosome 6 should the body have? what does is a haplotype?
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
how are MHC haplotypes expressed? how are they passed on?
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)
each haplotype contains loci containing what? which of these is expressed?
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
where are MHC class I expressed?
on every nucleated cell in the body, (not RBCs and a few others)
where are MHC class II expressed? why?
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
what is the structure of class I MHC? is it complexed with anything?
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)
what is the structure of class II MHC? is it complexed with anything?
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.
how do the structures of MHC I and II compare?
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.
where is most of the variability from MHC polymorphism, (mostly A, B, C & DR (some DP & DQ)), largely confined to?
most of the variability from MHC polymorphism is largely confined to the binding cleft, so that different MHC isoforms can bind different peptides.
is MHC peptide binding specific?
no, but it is selective, (not antigen specific like antigen receptors on B+T cells)
where do the non-polymorphic areas of MHC bind?
the non-polymorphic areas of MHC bind to CD4, (class II), or CD8, (class I) co-receptors
how do T cells “see” antigen? what will a specific T cell clone recognize peptides in the context of?
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.
why shouldnt your T cells be able to recognize someone elses MHC?
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…”
what is MHC restriction in a nutshell?
you can only see the context of your own MHC and T cells will kill in an “MHC restricted fashion”
how do CTL T cells recognize class I MHCs?
CTL (CD8+) T cells bind to the alpha3 domain of Class I MHC and its TCR is then able to see antigen
how do helper T Cells (CD4+) recognize antigen in the context of Class II MHC’s?
helper T Cells (CD4+) bind to the beta2 domain of Class II MHC’s and then the TCR is able to recognize the antigen
what are the differences between the antigens that MHC class I+II process?
class I processes endogenous antigens, (for presentation to CD8+) and class II processes exogenous antigens, (for presentation to CD4+)
can MHC bind self peptides?
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.
what is the benefit of both MHC parental alleles, each MHC gene being expressed codominantly?
this increases the number of different MHC molecules that can present antigens to T cells
why is it beneficial the MHC genes are polymorphic?
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
why is it beneficial for MHC class II’s presence to be restricted to dendritic cells, macrophages, B cells, activated T, and epithelial cells?
because CD4+ helper T cells interact with dendritic cells, macrophages, B cells, activated T, and epithelial cells.
why is it beneficial for MHC class I to be present on ALL nucleated cells?
so that CD8+, CTL cells can kill any virus-infected cell
what happens when a macrophage expresses antigen in the context of a class II MHC, (this antigen comes from outside the cell)?
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
what happens when a B cell processes and presents an antigen via class II MHC?
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
what happens when a cytoplasmic microbe is processed and presented via class I MHC?
CD8+ CTL cells will respond and kill the infected cell
how does class II antigen processing occur?
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.
how does class I antigen processing occur?
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.
what happens to most peptides destined for presentation on MHC class II?
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)
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?
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.
after internalization of exogenous antigen, what happens to them?
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
where do MHC class II molecules come from upon uptake of exogenous antigen by macrophages?
MHC class II molecules are exported from the ER via exocytic vesicles and targeted to late endosomes/lysosomes
what happens when MHC class II exocytic vesicles and endosomes/lysosomes fuse?
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
what is the invariant chain?
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
is there anything else other than invariant chain at the binding site of class II MHC?
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
what happens to the invariant chain and CLIP in the MIIC?
proteolytic enzyme acts on the invariant chain, (scaffolding), and then removes CLIP
what does HLA-DM do? where does this happen?
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.
why can’t exogenous antigens go to the ER?
they might interfere with class I MHC processing
why doesnt class II MHC bind endogenous products?
its cleft is plugged up with invariant chain/CLIP
once antigen peptide has been placed in the binding groove of class II MHC is it ready to go to the surface?
yes, if class II: Peptide complex is stable, it is delivered to cell surface, where it can interact with CD4+ cells
what is endogenous antigen processing used for?
the processing of cytosolic proteins for presentation at the cell surface on class I MHC
what would endogenous antigen processing be used for?
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
what is ubiquination?
a portion of all proteins synthesized in the cells is targeted for destruction via complexation with ubiquitin and transported to a proteosome
what is a proteosome?
a 28 subunit cylindrical protease complex that degrades proteins into peptide. this peptide is then transported to the ER by TAP protein transporters
what is the relationship between MHC class I in the ER and endogenous protein/antigen?
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
how does endogenous protein become bound to the class I MHC in the ER ?
tapasin forms a bridge between the TAP transporter and allows transfer of a peptide into the MHC binding cleft.
what happens to the class I MHC when antigen is bound to it?
when peptide is inserted, it turns MHC class I to mature antigen
what does the class I MHC do once bound to the antigen?
class I MHC and beta2 microglobulin complex then becomes properly folded with its antigen and is exported to the cell surface
what is the difference between MHC classes before antigen gets to them?
class I is open (binding cleft), class II is closed (filled with CLIP)
what is cross-presentation? how does it happen?
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)
what are class II vs class I MHC in terms of composition?
class II is polymorphic alpha and beta chains, class I is a polymorphic alpha chain with a beta2 micrglobulin
what are class II vs class I MHC in terms of their APCs?
all nucleated (eukaryotic)cells process class I, only “professional” APCs process MHC II, (dendritic cells, mononuclear cells, B cells, thymic endothelial cells)
what are class II vs class I MHC in terms of responsive cells?
class I – CD8+
class II – CD4+
what are class II vs class I MHC in terms of antigen protein source?
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”
what are class II vs class I MHC in terms of enzymes responsible for peptide generation?
class II – endosomal/lysosomal proteases, (cathepsins) class I – cytosolic proteosomes
what are class II vs class I MHC in terms of site of peptide loading to MHC?
class II – specialized vesicular compartment, (MIIC) class I – ER
what are class II vs class I MHC in terms of molecules involved in transport of peptides?
class II – invariant chain, HLA-DM class I TAP
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