Major Histocompatibility Complex Flashcards
What is the major histocompatibility complex (MHC)? What is its importance?
MHC is a set of closely linked genetic loci (genes of the MHC) that have been found to be overwhelmingly important in determining the fate of
engrafted tissue
There are two main types of MHC gene products (designated Class I and Class II molecules). What is their physiological function? How do they accomplish this?
their physiological function is to present peptides to T lymphocytes. They accomplish
this by sampling intracellular pools of peptides and presenting these peptides, at the cell surface, to T lymphocytes.
Humans (and other mammals) have a tightly linked gene cluster of cell surface
glycoproteins that regulate immune cell interactions and evoke intense allograft rejection.
In humans, the human leukocyte antigens (HLA) consist of three types of genetic loci.
Describe each class, where they are present and what they present to.
Class I Loci
- HLA-A
- HLA-B
- HLA-C
These molecules are present on virtually all nucleated cells and present antigen to CD8+
T lymphocytes.
Class II Loci
- HLA-D Subset loci: (DR, DQ, DP)
These molecules are found on dendritic cells, B-lymphocytes, and macrophages and
present antigen to CD4+ lymphocytes.
Class III Loci
- These are genes that happen to reside in the MHC region but do not present antigen to T lymphocytes.
Describe Class I Loci molecules (A, B, C of humans)
What does each loci code for?
What does the resulting cell surface have (3 components)?
- Each of the loci codes for a polypeptide chain of about 44,000 daltons.
- On cell membranes these chains are associated non-covalently with a lighter chain, beta2
microglobulin (12,000 daltons), which is specified by a gene on another chromosome. - The resulting cell surface molecule has one alpha chain, the Class I polypeptide, and one
light chain beta2 microglobulin (see Figure 2).
(see Figure 2 p 5… have beta pleated sheets, alpha helices,
Describe the alpha chain of the class I MHC molecule.
How much of the alpha chain is constituted by carbohydrates?
Describe the C-terminal fragment of the alpha chain
The molecule consists of a MW 44,000 polymorphic transmembrane glycoprotein termed the a chain, which bears the antigenic determinant in non-covalent association with a
MW 12,000 non-polymorphic protein termed ß2 microglobulin. The a chain has three extracellular domains termed a1, a2, and a3.
beta2 microglobulin is the same in all of these molecules, but alpha chains, specified by different alleles, differ in amino acid sequence.
Carbohydrates constitute approximately 10% of the weight of the a chain.
The C-terminal fragment of the alpha chain traverses the cell membrane.
What parts of the alpha chain and beta2 chain resembel immunoglobulin chains?
Parts of the alpha chain and beta2 –microglobulin resemble immunoglobulin chains, in particular the
amino acid sequence of CH domain of immunoglobulin chains.
Describe Class II Loci molecules.
Each loci codes for what?
D of humans.
Each of the loci codes for a polypeptide chain of about 60,000 daltons with two
polypeptide chains per molecule:
- (34,000) - a chain
- (29,000) - beta chain
p 7
MHC class I and II molecules bind peptides of about what length?
MHC class I molecules bind short peptides of about 9 amino acids in length (variability is 8-10 amino acids).
MHC class II molecules bind longer peptides of 13-17 amino acids in length.
Describe the anchor residues that may bind a particular MHC Class I molecule.
The anchor residues (circled) that bind a particular MHC class I molecule in Figure 5 do not need to be identical but are always related. For example, valine (V), leucine (L), and Isoleucine (I) are all hydrophobic amino acids. Peptides also bind class I MHC molecules through their amino and carboxy termini.
p 8
Describe the anchor residues that bind a particular MHC Class II molecule.
The anchor residues (circled) that bind a particular MHC class II molecule in Figure 6 do not need to be identical but are always related. In this case, the first anchor residue (circled and on the left of the figure) is hydrophobic, the next anchor residue is negatively charged, the next exhibits a tendency to be a basic amino acid, and for the last anchor residue a hydrophobic amino acid (on the right of the figure).
Describe MHC genes encoding MHC molecules on the surface of nucleated cells.
Describe the genes that encode MHC class I a chains and MHC class II a and beta chains.
Where are the proteins that these genes encode for located?
MHC class I a chains and MHC class II a chain and beta chains are encoded by separate genes of the MHC locus. (beta2 microglobulin is not encoded within the MHC region of chromosome 6.)
These genes encode for proteins that associate in the endoplasmic reticulum and shuttle to the cell surface where they are membrane glycoproteins.
How are class I and class II genes of chromosome 6 expressed?
Describe how these genes are inherited.
Each individual expresses in a co-dominant fashion the class I and class II genes of both chromosomes 6.
Thus each individual expresses 3 maternal and 3 paternal class I molecular types, as well as 3 maternal and 3 paternal class II molecular types (on cells that express both class I and class II).
Each individual has two“half sets” (haplotypes) of genes. One haplotype is inherited from
each parent. Both of these haplotypes are expressed equally
With one exception, the number of different alleles (the variant genes that can occupy the locus) for class I and class II MHC genes is very large. What is the exception?
With the exception of the DR a locus the number of different alleles (the variant genes that can occupy the locus) for class I and class II MHC genes is very large.
Figure 9 p 11
The high degree of polymorphism in nucleotide sequence results in a high degree of polymorphism in amino acid sequence. The polymorphisms are located at specific sites within the MHC molecules. See Figure 10. What do differences in aa sequence allow for?
The differences in amino acid sequence allow for peptide
binding and for T lymphocyte recognition.
What does a specific T cell response to an antigen depend on?
a specific T cell response to antigen (Ag) on cell surfaces depends not on recognition of the Ag alone but on recognition of an antigenic peptide in the groove of an MHC molecule on
the cell surface.
