MHC Flashcards
[13-minute video]: Major Histocompatibility Complex (MHC) - Human Leukocytic Antigen (HLA) - Immune System [Medicosis Perfectionalis]
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[6-minute video]: Antigen Processing and Presentation by Major Histocompatibility Complexes [Professor Dave Explains]
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What is MHC?
The Major Histocompatibility Complex is a collection of genes located within a specific region of DNA. In humans, those genes are found on chromosome 6. MHC proteins enable the immune system to recognize and respond to peptide fragments derived from pathogens and display them on the cell surface for recognition by T cells.
In humans, MHC is referred to as the Human Leukocyte Antigen (HLA) complex.
Further notes:
In mice, MHC are located on chromosome 17 and are known as H-2 complex.
What are the three families of glycoproteins coded by the MHC?
The MHC codes for three families of glycoproteins known as Class I, Class II, and Class III MHC molecules.
Where are Class I and Class II MHC molecules primarily expressed, and what is their function?
Class I and Class II MHC molecules are primarily expressed as membrane glycoproteins on the cell surface. Class I molecules are found on almost all nucleated cells and present peptide fragments to cytotoxic T cells (CD8+ T cells). Class II molecules are mainly expressed on antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells, and present peptide fragments to helper T cells (CD4+ T cells).
How do Class III MHC molecules differ from Class I and Class II MHC molecules in terms of expression and function?
Unlike Class I and Class II MHC molecules, the products of Class III genes are usually soluble molecules. They are not involved in antigen presentation but play other roles in the immune response.
What are the three main genes that code for MHC Class I in humans?
HLA-A, HLA-B, and HLA-C
[Diagram]: The HLA region
What are the three main genes that code for MHC Class II in humans?
HLA-DP, HLA-DQ, and HLA-DR
[Diagram]: The HLA region
Discuss the structure and regions of MHC Class I molecules.
⚔ Class I MHC molecules are composed of two different polypeptide chains: a heavy (alpha) chain and a light (beta-2 microglobulin) chain.
⚔ The alpha chain is a transmembrane glycoprotein that consists of three extracellular domains (α1, α2, and α3), a transmembrane segment, and a cytoplasmic tail.
⚔ The α1 and α2 domains form the peptide-binding groove, which is the site where peptide antigens are presented. The groove is highly polymorphic, allowing for the binding of a diverse range of peptides.
⚔ The α3 domain is structurally similar to immunoglobulin constant regions and interacts with the CD8 co-receptor on cytotoxic T cells.
⚔ The cytoplasmic tail is involved in intracellular signalling and interactions with other cellular components.
⚔ The β2 microglobulin is a non-covalently associated light chain that stabilizes the structure of the alpha chain. It is not encoded within the MHC region but is essential for the proper folding and surface expression of the Class I MHC molecule.
[Diagram 1] [Diagram 2]
Further notes:
⚔ The peptide-binding groove is formed by the α1 and α2 domains and can accomodate peptides typically 8-10 amino acids in length. The groove has pockets that interact with specific amino acid residues of the peptide ensuring a stable binding.
⚔ It is composed of an α-helix on two opposite walls and a floor made up of eight β-pleated sheets.
Discuss the structure and regions of MHC Class II molecules.
⚔ HLA-DP, DQ and DR molecules are made up of one heavy chain (α) and one light chain (β) each. The two chains are non-covalently associated with each other.
⚔ The α chain has two domains: α1 and α2.
⚔ The β chain has two domains β1 and β2.
⚔ The α1 and β1 domains are highly polymorphic.
⚔ The α2 and β2 domains are not polymorphic.
⚔ The entire structure has four regions: the peptide binding region, the immunoglobulin-like region, the transmembrane region and the cytoplasmic region.
⚔ The peptide binding region is a groove formed by the α1 and β1 domains of the alpha and beta chains. The groove is the site of polymorphism.
⚔ The immunoglobulin-like region is a region that includes the conserved α2 and β2 domains. The β2 domain is particularly important as it is the site to which the CD4 co-receptor on T cells binds.
⚔ The transmembrane region consists of a stretch of hydrophobic amino acids that span the cell membrane, anchoring the MHC molecule to the cell surface.
⚔ The cytoplasmic region is important for intracellular signalling and the stability of the MHC molecule on the cell surface.
State the respective functions of Class I HLA and Class II HLA molecules.
⚔ Class I HLA molecules present peptide epitopes to cytotoxic T cells (CD8+ T cells). These peptides are typically derived from intracellular proteins, such as those produced by viruses or abnormal proteins from cancer cells.
⚔ Class II HLA molecules present peptide epitopes to helper T cells (CD4+ T cells). These peptides are typically derived from extracellular proteins, such as those from bacteria or other pathogens that have been engulfed and processed by APCs.
How do MHC molecules initially accommodate a wide variety of peptide sequences?
MHC molecules adopt a flexible, “floppy” conformation when they are not bound to a peptide. This flexibility allows them to accommodate a wide variety of peptide sequences.
What happens to MHC molecules when a peptide binds to them?
⚔ When a peptide binds to the MHC molecule, the molecule undergoes a conformational change, folding around the peptide to increase the stability of the MHC-peptide complex.
⚔ MHC molecules use a small number of anchor residues to tether the peptide within the binding groove.
