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Lecture 8: The Majorhistocompabitibility Complex

Terms in this set (65)

When was MHC discovered?
During the development of organ transplants
Histocompatible
Organs accepted as "self"
Histoincompatible
Organs rejected as "non-self"
Major Histocompatibility Complex (MHC)
Surface antigens part of complex
What does MHC do?
-Presents antigens to Th and Tc cells
-Essential for activation of both
Human MHC nomenclature
HLA
What chromosome are the MHC molecules on in humans?
6
What chromosome are the MHC molecules on in mice?
17
MHC Class 1 presents antigens to _____ cells
Tc
MHC Class 2 presents antigens to ______ cells
Th
What encodes MHC Class 1 in Humans?
HLA-A, -B, -B
What encodes MHC Class 1 in Mice?
H-2K, -D
What encodes MHC Class 2 in Humans?
HLA-DP, DQ, -DR
What encodes MHC Class 2 in mice?
H-21A, IE
MHC Class 3 encode ________ ________ with ________ _______
secreted products, immune functions
MHC across species are highly ___________
Polymorphic
Tight linkage (___% recombination) causes set of alleles to be inherited together
0.5
Haplotype
Set of alleles being inherited together
Structure of MHC Class 1 Molecule
__________ ____________ consists of two distinct poly peptides
Transmembrane glycoprotein
Structure of MHC Class 1 Molecule
Peptide binding region created by ________ ____ ________
Heavier alpha chain
All Class 1 gene products associate with smaller constant chain - _________ ________ ________
Beta 2 microglobulin
Association with _______ _________ essential for translocation of class 1 molecules to cell surface
Light Chain
____ - chain anchors complex at cell surface by _______ transmembrane spanning segment
Alpha, hydrophobic
How many domains do MHC Class 1 molecules possess?
5
What are the 5 domains MHC Class 1 molecules posses?
3 extra cellular domains - alpha 1, 2, 3
1 transmembrane spanning domain
1 cytosolic domain
3 Extracellular Domains in MHC Class 1 Molecules:
Alpha 1 and Alpha 2 create __________ _________ _______
Peptide Binding Cleft
What is the peptide binding cleft comprised of?
a beta sheet flanked by 2 alpha helixes
Domains of MHC Class 1 Molecules
What is the peptide length the 3 extracellular domains can accommodate?
8-10 amino acids
Domains of MHC Class 1 Molecules
______ is the point of contact for the CD8 co-receptor
alpha 3
Domains of MHC Class 1 Molecules
What is the function of the fourth domain?
Anchors MHC molecule to the surface
Domains of MHC Class 1 Molecules
How many amino acids does the 5th domain have?
30 amino acids in the cytosol
Domains of MHC Class 1 Molecules
Interaction with _____ and ______ are essential for proper folding of the MHC molecule
Alpha 3 and Beta 2 microglobulin
Daudi-tumor cells express _________- but not _______
Class 1 Alpha chain, beta 2 microglobulin
Domains of MHC Class 1 Molecules
Transfection with ______________ gene restores surface localization
Beta 2 microglobulin
Domains of MHC Class 1 Molecules
______ domain and ________ exhibit immunoglobulin fold
Alpha 3 and Beta 2 microglobulin
Structure of MHC Class 2 Molecules
Similar structure, different assembly of _____ and _____
Alpha and beta chain
Structure of MHC Class 2 Molecules
What are the domains of the two chains?
Alpha 2 and Alpha 1 and Beta 2 and Beta 1
Structure of MHC Class 2 Molecules
_____ and _______ interact to form peptide binding cleft
Alpha 1 and Beta 1
Difference between cleft structure of Class 1 and Class 2 molecules
Class 2: beta sheet and 2 alpha helices are superimposed
What anchors the MHC Class 2 molecule to the surface of the cell?
Transmembrane spanning domain
Structure of MHC Class 2 Molecules
How many amino acids are present in the cytosolic domains?
30
What revealed the difference between MHC class 1 and 2 molecules?
Crystal structure of peptide binding domain
Peptide binding domain crystalized as ________ for Class 2 molecules
Dimer
Antigen binding clefts positioned in _______ orientation
Opposite
How are the class 1 genes organized?
Into exons by domain
First exon encodes _______ , allows insertion of protein into ER co-translationally, cleaved after insertion
Leader Peptide
Introns separating exons removed by _____ _______
RNA splicing
Class 2 Molecules: introns removed by RNA splicing to generate _______
Mature mRNA
Difference between organization of MHC Class 1 and 2 genes
Transmembrane domain exon, in class 2 it encodes both transmembrane domain and part of the cytosolic domain
How many class 1 molecules does an individual express?
6
How many class 2 molecules does an individual express?
12
Ends of binding cleft for _______ sealed by alpha helices
Class 1
Ends of binding cleft for _______ left open
Class 2; allows class 2 molecules to accommodate larger peptides (13-18 aa)
What length of amino acid is the best in terms of binding?
9 amino acids in length
Length of peptides bound dictates size of _____
bulge
Peptides bound in Class 2 peptides lay _____
Flat in binding groove
Function of Class 3 genes
Heat shock proteins:
-Activated by various forms of cellular stress
-Bind aberrantly folded proteins and assist in proper folding
-May move peptides for antigen presentation
What cells exhibit high levels of MHC Class 1 expression?
Lymphocytes
Low level of MHC Class 1 expression correlates with ________
Frequency of transplant rejection (e.g. kidney vs heart)
What cell types are completely devoid of class 1 expression?
Neurons and sperm cells
MHC Class 2 antigens are restricted to what cells?
APC, thyme, and specialized epithelial cells
Heterodimer
Each subunit is encoded by a different gene, demonstrated in Class 2 Molecules
MHC expression is ________ for different cell types
Different
Class 2 expression involves which transcription factors?
CIITA and RFX
Functions of CIITA and RFX?
Both bind promoter region of Class 2 genes
Peturbations abolish class 2 expression on lymphocytes
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