Lecture #2-2 Flashcards
What occurs in Bare Lymphocyte Syndrome?
Due to a defect in MHC expression, APCs cannot activate T cells. This leaves a patient with SCID.
Name Major Class I genes:
HLA-A, HLA-B, HLA-C
Name Major Class II genes:
HLA-DP, HLA-DQ, HLA-DR
How many regions are a part of the HLA complex?
3 (though only 2 contribute to antigen processing/presentation)
What subunits make up a Class 1 MHC receptor?
alpha 1, 2, and 3 domains of heavy chainbeta 2 - microglobulin
What subunits make up a Class II MHC receptor?
One alpha chain (a-1/2) and one beta chain (b-1/2)
What does an MHC Class 1 receptor bind?
The T cell receptor of an CD8+ T cell
What is polymorphism?
Presence of multiple alternative forms of a gene.
Define haplotype.
In ref to a linked set of polymorphic genes – the set of alleles on a single chromosome.
Name two ways that human MHC Class I and II isotypes differ.
In function and extent of polymorphism.
What are the MHC Class loci?Most polymorphic MHC Class I locus?
A-GB (872)
Most polymorphic MHC Class II locus?
D RB1 (466)
Which MHC Class II loci help peptide loading?
DM and DO
Which MHC Class II loci present antigen to CD4+ T Cells.
DP, DQ, DR
Purpose of polymorphism?
Allows human population to handle a variety of pathogens.
How many combinations of haplotypes can be found in offspring? How many does each individual have?
Four. Two.
Which MHC class isotypes I are very polymorphic? What part of these receptors is not polymorphic?
HLA-A, HLA-B, and HLA-Cbeta-microglobulin is monomorphic.
What MHC Class II receptors present to CD4 T Cells.
HLA-DP, HLA-DQ, HLA-DR
Describe the binding affinity of HLA-DR
The alpha subunit is oligiomorphic and the beta subunit is highly polymorphic.
What are anchor residues important for?
Binding to MHC (other residues are not important)
Why is it good that MHC only binds the anchor residues?
Allows for degenerate binding – binding in which each MHC molecule handles many different peptides.
Give an example of a peptide HLA-A will bind?
HIV reverse transcriptase
Give an example of a peptide HLA-B will bind?
Influenza A Nucleoprotein
Give an example of a peptide HLA-DRB1 will bind?
IgK light chain
Give an example of a peptide HLA-DQ will bind?
Transferrin Receptor
What Class II HLA can people have more than type of?
Everyone has a DR-alpha and DR-beta. Some also have DR beta 3/4/5.
HLA-DR alpha chain is ____morphic.
Mono
The two most polymorphic MHC components are…
HLA-DRB1 and HLA-B
An average person expresses ____ MHC Class I Isoforms.
3-6
An average person expresses ____ MHC Class II Isoforms.
3-8
Which cell types express MHC I?
Almost all of them.
Who are professional APCs?
B cells, macrophages, and dendritic cells
Which cells express MHC Type I and II?
B cells, Macrophages, DCs, and thymic epithelial cells
What type of antigens does MHC I respond to? MHC II?
Intracellular. Extracellular.
Describe the MHC I processing/presentation pathway.
- Cytoplasmic proteins are ubiquitinated and fragmented by the proteasome. 2. MHC I proteins are synthesized and assembled in ER and associated w/ TAP via calnexin3. MHC I binds peptides, vesicles fuse with mem, and MHCI pep complexes are presented to CD8 T cells
How do viral proteins get into the ER?
TAP proteins
Effect of no TAP expression?
Bare Lymphocyte Syndrome
Describe the assembly of MHC I complex in the ER.
- Class I heavy chain is stablized by Calnexin till B-2 gets there2. Calnexin is released, complex with Calretulin, tapasin, TAP, and ERp57 is formed. 3. Peptide enters through TAP, binds to heavy chain4. MHC I dissociates from peptide-loading complex, export
HSV protein inhibits TAP function. Why?
To prevent viral protein fragments from activating the adaptive immune response.
How do MHC II antigens get processed?
- P-APCs internalize antigens into endosome and degrade into fragments. 2. MHC II proteins are synthesized with the CLIP region of the invariant chain protecting the binding site. 3. Exocytotic vesicles with MHC II fuse with the endosomes with peptides. 4. The CLIP is removed by HLA-DM protein5. MHC II proteins binds peptides and vesicles fuse with plasma membrane.
HLA-A - Amino acid sequence of bound peptides.
L _ V _V
HLA-B - Amino acid sequence of bound peptides.
_ R _ _ _ _ _ _ R
HLA-DRB1 - Amino acid sequence of bound peptides.
_ _ _ _ Y _ _ W _ _ _ _ L _ _ _ _
HLA-DQA1/DQB1 - Amino acid sequence of bound peptides.
_ _ _ L _ _ _ _ _ _ _ _
Where do MHC molecules bind peptides?
In fused vesicles (not ER)
Why might mycobacteria prevent phagosome and lysosome fusion.
Live on in the phagosome, stops MHCII presentation and immune response.
CD8 binds what domain?
alpha-3 of MHC I
CD4 binds what domain?
beta-2 domain of MHC II
T cell recognition requires what two things to be correct.
Correct peptide and right MHC
List the four given methods to do HLA typing.
- Microcytotoxicity assay for HLA antigens2. Restriction Fragment Length Polymorphism3. PCR4. Flow Cytometry/ELISA
Name a crude method to test for HLA compatability between people.
Mixed Lymphocyte Reaction.
Disease associated with HLA-DR3/2
Systemic Lupus Erythematosus
Disease associated with HLA-DR4
Rheumatoid Arthritis
Disease associated with HLA-B7 and HLA-DR2
Multiple Sclerosis
Disease associated with HLA-B8, HLA-DR3/4
Type I Diabetes
Disease associated with HLA B27
Ankylosing Spondylitis
AA sidechains on MHC are important for…
Making interactions with antigen. Hydrogen bonds and ionic interactions hold it in place.
Difference between structure of Peptide bound to MHC I and II.
MHCI binds peptide by ends (8-15 pp long)MHCII binds and has peptide beyond the groove.
Influence of IFN-gamma on MHC?
Induces increased expression of MHC II in APCs
