Untitled Quiz

Major Histocompatibility Complex (MHC)

• MHC is a collection of genes found in all mammals
• In humans, MHC is located on the short arm of chromosome 6
• MHC protein products are called HLA (human leukocyte antigens)
• HLA was first discovered on leukocytes

Teaching Objectives

• Definition of MHC
• MHC Classes
• MHC genes
• MHC polymorphism
• Structure of MHC class I and II
• Function of MHC
• Differences between MHC class I and II
• MHC association with disease
• Antigen processing and presentation. How the antigen is processed and presented to T cells by APCs.

MHC Genes

• The layout (design) consists of three major regions (classes): class I, II and III
• Class I region contains 3 independent genes (loci): A, B, C
• Class II region contains 3 sets of genes (loci): DP, DQ, and DR.
• Each set in class II encompasses 2 genes
• Class III region contains multiple genes, located between regions I and II

MHC Polymorphism

• Each MHC gene has a number of alternative forms (alleles)
• High MHC variation in the human population exists
• There are at least 350 alleles for HLA-A, 620 alleles for HLA-B, 400 alleles for DR, and 90 alleles for DQ
• Any two individuals (except identical twins) will express differing MHC molecules.
• This is known as genetic polymorphism or population diversity
• MHC polymorphism makes tissue matching between unrelated people very unlikely

MHC Polymorphism Details

• An allele is one of two or more versions of a gene
• An individual inherits two alleles for each gene, one from each parent
• If two alleles are the same, the individual is homozygous for that gene
• If the alleles are different, the individual is heterozygous

MHC Antigens (MHC molecules)

• Products of class I and class II genes are expressed as membrane proteins called MHC molecules.
• A diploid cell expresses up to 6 different class I and class II molecules from both paternal and maternal MHC gene products
• The immune system recognizes its own MHC molecules as "self" and will not react against them.

Class I MHC molecules

• Class I molecules (A, B, C) are expressed on all nucleated cells
• They consist of 2 separate, non-identical, non-covalently linked polypeptide chains
• A long alpha chain (α1, α2, α3), trans-membrane segment, and a short cytoplasmic segment
• The groove between α1 and α2 is the peptide binding site; amino acid sequence varies by allele
• A small beta chain (β2 microglobulin); amino acid sequence is constant in all class I molecules.
• β2 microglobulin is required for expression and stabilization on the cell surface

Class II MHC molecules (DP, DQ, DR)

• Class II molecules are expressed on professional antigen-presenting cells (APCs)
• They consist of 2 separate, non-identical, non-covalently associated alpha (α) and beta (β) chains
• Both chains are encoded by different genes within the MHC locus; polymorphic
• Each chain has extracellular segments (α1, α2, β1, β2), a trans-membrane segment, and a cytoplasmic segment

Antigen Processing and Presentation

• Endogenous Pathway of MHC I: Processes intracellular antigens (ex: viruses, mutated proteins from tumors)
• Exogenous Pathway of MHC II: Processes extracellular antigens; APCs (eg: dendritic cells, macrophages, B cells) load partially degraded peptides into the groove of MHC class II molecules

Endogenous Pathway of MHC I

• Intracellular proteins are targeted by ubiquitin and degraded in proteasomes
• Proteins are transported via the TAP complex (transporter of antigen processing) to bind to freshly synthesized MHC class I molecules
• Peptide-MHC class I complexes are transported to the cell membrane for presentation to CD8+ T lymphocytes (cytotoxic T lymphocytes)

Exogenous Pathway of MHC II

• MHC class II molecules are synthesized in the APC along with an invariant chain (Ii)
• Ii binds to the peptide-binding groove of newly synthesized MHC II
• The CLIP fragment of Ii blocks the peptide binding site
• The vesicle containing Ii and ingested peptides fuses with MHC II to exchange CLIP with peptides
• The peptide-MHC II complex is transported to the cell surface to interact with CD4+ T-helper lymphocytes

MHC Functions

• MHC molecules act as antigen-presenting molecules to recognize antigens
• Class I molecules present processed antigens to CD8+ T cells
• Class II molecules present processed antigens to CD4+ T lymphocytes
• MHC molecules are associated with self/non-self discrimination
• MHC molecules are responsible for rejection of incompatible transplants

MHC Association with Disease

• A number of human diseases occur at higher frequencies in individuals with certain HLA alleles; often inflammatory or autoimmune in nature
• Examples given include: Ankylosing spondylitis (HLA-B27), Insulin dependent diabetes mellitus (HLA-DR3), Multiple sclerosis (HLA-DR2/DR3), Systemic lupus erythematosus (HLA-DR3), Rheumatoid arthritis (HLA-DR4).