Podcast
Questions and Answers
What defines an individual as heterozygous?
What defines an individual as heterozygous?
Which type of cells express class I MHC molecules?
Which type of cells express class I MHC molecules?
What is the primary function of the Major Histocompatibility Complex (MHC)?
What is the primary function of the Major Histocompatibility Complex (MHC)?
Which class of MHC is involved in presenting antigens to CD8+ T cells?
Which class of MHC is involved in presenting antigens to CD8+ T cells?
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What is required for the expression of class I MHC molecules on the cell surface?
What is required for the expression of class I MHC molecules on the cell surface?
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What is a characteristic of MHC polymorphism?
What is a characteristic of MHC polymorphism?
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What are APCs primarily responsible for in relation to MHC class II molecules?
What are APCs primarily responsible for in relation to MHC class II molecules?
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What is the role of ubiquitin in the endogenous pathway of MHC class I?
What is the role of ubiquitin in the endogenous pathway of MHC class I?
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What region of the MHC contains the genes A, B, and C?
What region of the MHC contains the genes A, B, and C?
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How many alleles exist for the HLA-B gene in the human population?
How many alleles exist for the HLA-B gene in the human population?
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Which of these components is not a part of class II MHC molecule structure?
Which of these components is not a part of class II MHC molecule structure?
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In the endogenous pathway, which of the following represents the correct processing of antigens?
In the endogenous pathway, which of the following represents the correct processing of antigens?
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Which class of MHC genes is uniquely associated with presenting extracellular antigens?
Which class of MHC genes is uniquely associated with presenting extracellular antigens?
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What differentiates the class I MHC molecules from class II MHC molecules?
What differentiates the class I MHC molecules from class II MHC molecules?
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What is the outcome when two alleles inherited from parents are identical?
What is the outcome when two alleles inherited from parents are identical?
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Why is tissue matching between unrelated people considered unlikely?
Why is tissue matching between unrelated people considered unlikely?
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What is the role of the TAP complex in relation to MHC class I molecules?
What is the role of the TAP complex in relation to MHC class I molecules?
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Which protein blocks the peptide-binding groove of newly synthesized MHC class II molecules?
Which protein blocks the peptide-binding groove of newly synthesized MHC class II molecules?
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Which of the following statements about MHC molecules is NOT true?
Which of the following statements about MHC molecules is NOT true?
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What happens after the peptide is loaded onto the MHC class II molecule?
What happens after the peptide is loaded onto the MHC class II molecule?
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How are MHC molecules associated with disease?
How are MHC molecules associated with disease?
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Which HLA allele is correlated with Ankylosing spondylitis?
Which HLA allele is correlated with Ankylosing spondylitis?
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What is the main function of MHC class I molecules?
What is the main function of MHC class I molecules?
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What is the consequence of a mismatch in MHC molecules during transplantation?
What is the consequence of a mismatch in MHC molecules during transplantation?
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Study Notes
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).
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