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39 Cards in this Set
- Front
- Back
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Through what process does HLA polymorphism come about?
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natural selection
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What do MHC's do?
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bind to degraded polypeptides and present them to alert the immune system
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How do Antibodies and TCRs differ in what they recognize?
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Ab - extracellular, conformational (discontinuous) or linear (continuous)
epitopes TCR - linear epitopes ON the surface of PRESENTING cells FROM the interior of antigens |
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MHC I structure
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membrane spanning heavy chain with three domains (a1, a2, a3)
bound (noncovalently) to a soluble light chain, B2microglobulin |
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MHC II structure
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two transmembrane glycoproteins, alpha and beta
- each has two domains (1,2) - a1 and B2 form binding cleft |
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What else is on the genome for MHC's other than the alpha and beta genes? (4)
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L - leader sequence
TM - transmembrane domain CYT - cytosolic tail 3'UT - 3' untranslated sequence |
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What chromosome is the MHC region located on?
The light chain B2M? |
- chr 6
- chr 15 |
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What does Polygenic mean?
What does Polymorphic mean? |
-having more than one gene
- having more than one ALLELE (version) of a gene - The HLA is BOTH - both contribute to HLA diversity |
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Where are polymorphisms on MHC focused?
- what structures are affected by variation? |
regions that encode the peptide binding domains (a1, a2, B1)
- residues lining the peptide-binding groove |
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How are HLA alleles expressed?
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- co-dominantly --> most people are heterozygous at each HLA locus and express all alleles from both chromosomes
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When can more than 6 different HLA class II molecules be expressed on the same human cell?
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When DP and DQ subregions have more than one A and B gene and DR have more than one DRB gene
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What is the likelihood of a child sharing all the HLA molecules with a sibling or parent?
What is the only time when HLA genes are the same? |
Not likely, HLA has high polymorphism
- child gets one haplotype from mom, other from dad - identical twins |
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How do MHC I and II differ in their binding sites and the peptides they bind?
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MHC I - binds short, uniform size peptides (10 residues)
- closed groove MHC II - binds larger peptides (15 residues) - open groove to enable larger peptide to extend beyond groove |
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What allows MHC's to bind specific peptides?
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Contours on the floor of the binding groove containing contact residues
- shape and charge of pockets allows limited diversity of binding |
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What do we know about peptides bound to the same HLA?
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have structurally related "anchor" proteins
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From where do peptides derive?
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self (endogenous) or non-self(pathogen)
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What is the strength of peptide binding once associated with HLA?
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- tightly bound
* all surface expressed MHC on all types of cells are bound to peptides |
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What do CD8 T cells do?
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- recognize MHC I + foreign peptide
- kill these viral or tumor affected cells |
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What do CD4 T cells do?
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- recognize MHC II + foreign peptide
- make cytokines that regulate B cell/and or macrophage mediated immune response |
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What are the CD4 and CD8 molecules?
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co-receptors on the surface of T cells that bind selectively to invariant portions of MHC's
- serve to tighten the binding between TCRs and MHC's |
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What forms the basis of MHC restriction of T cell function?
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Tcells expressing CD4 are restricted to interacting w/ presenting cells expressing MHC II
Tcells w/ CD8 can only bind with MHC I expressing cells |
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What is MHC restriction of an Antigen?
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TCR's are antigen specific and recognize a complex of an antigenic peptide and a self-derived HLA
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What happens when a Tcell is faced with a different peptide or a non-self HLA?
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No recognition, no activation
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How are secretory and endocytic vesicles functionally different?
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Secretory - moves contents OUT of cells
Endocytic - moves contents INTO cells |
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How are the paths of MHC I and II antigens different?
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MHC I - antigen enters cytosol, degraded there by proteasome complex, translocated to ER by TAP to associated with MHC I --> folded, peptide bound MHC I leaves ER in secretory vesicles and arrive at the surface
* great majority of peptides loaded onto MHC I's are normal self-proteins MHC II - antigen remains in vesicles, enter MHC II pathway |
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What does calnexin (CNX) do?
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chaperone protein that associates w/ MHC I heavy chain before it forms the peptide-binding complex
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What is the peptide binding complex composed of?
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calreticulin (CRT)
ERp57 tapasin TaP1, 2 |
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What is retrograde transfer?
Where does this pathway occur? |
movement of extracellular antigens from phagosome to cytosol
- occurs only in APC - usually cross-priming, cross-presentation, or indirect presentation |
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What is the purpose of retrograde transfer?
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Allows APC (dendritic cells) to sense infections/tumors ongoing in other cell types and then activate T cells that destroy diseased cells
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What adverse outcome can retrograde transfer contribute to?
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graft rejection
- host APC uptakes, processes, and presents foreign Ag from transplanted donor cells |
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What is the only type of cell that can efficiently activate naive T cells due to its ability to cross-present and upregulate co-stimulatory molecules?
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Dendritic cells
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Process of MHC II processing and presentation?
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Ag taken up into endocytic vesicles is degraded by resident proteases in acidic compartments
- MHC II is folded in ER and associates w/ invariant chain - MHC II targeted to endocytic vesicles where invariant chain is cleaved to leave CLIP, which blocks the peptide binding groove - processed Ag encounter MHCII/CLIP complex, where DM replaces CLIP w/ antigenic peptides - mature MHC II transit to surface, present Ag to CD4 Tcells (majority self peptides) |
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What prevents healthy class I positive cells from being killed by NK cells?
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NK inhibitory receptors interact w/ MHC I's on healthy cells and attentuate killing
viruses downregulated MHC I, no longer engage inhibitory receptors on NK cells, get killed |
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What does CD1 do?
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non-peptidic self and foreign Ag presentation
- non-processed, lipid/glycolipid Ag - grooves: narrow and hydrophobic for lipid ligands - resembled MHC I, chr 1 |
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Where are lipids loaded into CD1 groove?
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endocytic compartments, similar to MHC II
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What do superantigens do and give an example:
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- bind directly to MHC II and TCR's without being processed
- "bridge" Vb domains of TCR with outer face of MHC II - binds specifically to one TCR V protein, but can stimulate a large fraction of T cells (20%) SE and TSST-1 |
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What results from stimulation caused by a superantigen?
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massive production of toxic cytokines
does NOT lead to productive immune response |
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What is association of HLA polymorphisms with disease indicative of?
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ability of host's HLA alleles to bind specific self or pathogen derived antigen
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What is linkage disequilibrium?
What effect does this have? |
HLA genes are inherited with a frequency different from that expected on the basis of their physical distance from each other
- makes it difficult to interpret observed associations of HLA with diseases, even though they DO occur |
