Lec 43: Major Histocompatibility Complex Flashcards
Define the critical properties and function of the Major Histocompatibility Complex:
- In T-cell cellular immunity it presents peptide antigens to T-cells stimulating
- Development of T-cells and it is how it sees foreign and self antigen
- This is the only way that the T-cell sees the antigen and contacts the peptide
List the names/designations for each of the human MHC class I genes:
- HLA-A
- HLA-B
- HLA-C
What is the tissue distribution of the MHC?
Class I MHC: all nucleated cells
- every cell of every organ/tissue; NOT red blood cells
Class II MHC: restricted to “professional” antigen-presenting cells (APCs)
- Dendritic cells (most important APC)
- B cells
- Macrophages
List the names/designations for each of the human MHC class II genes:
- HLA-DR
- HLA-DP
- HLA-DQ
Explain the nomenclature for designating MHC alleles:
- Class I MHC: Gene + number (e.g., A2, B27, etc.)
- Allele is a natural variant of gene, closer the number the smaller the difference
- Class II MHC: Gene + number (e.g., DR4)
* Each individual has 6 class I and class II
Explain co-dominant expression and its significance, as it relates to MHC genes:
All are equally expressed and present on the surface, 3 come from each parent. Increases likelihood the population will survive.
Compare and contrast the structures and functions of class I and class II MHC, and the tissue distribution of MHC class I and class II proteins:
MHC class I
- Heavy chain (encoded in the matrix compatibility complex a,b,c chains)
- partner protein beta 2 microglobulin (light chain) comes from a different chromosome
- function is to bind peptides for presentation to the T cell receptor
MHC class II:
- alpha and beta chains of approximate equal weight
For I and II there are two supporting domains with a beta sheet and two alpha helice domains creating a peptide binding cleft: holds the peptide for presentation
Name and describe the MHC regions bound by CD4 and CD8:
CD8 and CD4 bind to non-polymorphic regions of the MHC-I and MHC-II molecules (respectively)
- CD4: close to the base of the beta 2 molecule
- CD8: closer to the base of the alpha 3 molecule
Compare and contrast the types of peptides bound by class I and class II MHC:
- MHC class I: can only present an 8-11 peptide chain length (ends are blocked in the groove)
- MHC class II: ends are open, and the peptide can hang out over the edge/end
Why is the MHC so highly polymorphic?
Evolutionary selective pressure to protect the species via “herd immunity.”
- An individual may be highly susceptible to infection by a specific pathogen, due to inability of that individual’s MHC to efficiently present peptides from the specific pathogen
- However, within the community or “herd” as a whole, individuals will have many different MHC alleles, of which many will bind the pathogen peptides conferring resistance to pathogen infection
Explain the general clinical relevance of MHC polymorphism, and list examples of the medical relevance of MHC polymorphism:
Transplantation: Rejection of tissue transplants!
- Basis for the need to “cross-match” donor and recipient
- With good cross-matching and immuno-suppressive drug treatment, long-term allograft survival is routinely achieved for many tissues.
Associations with autoimmune diseases:
- HLA typing is the most useful test in definitive diagnosis of many autoimmune diseases
- Misdiagnosis of autoimmune disease can often be avoided by obtaining and properly interpreting HLA typing data
Disease association with specific alleles:
- example: B27
- Ankylosing spondylitis: relative risk 90x more likely than the avg population to have dx
- Reactive arthritis: relative risk 18x
- Reiter’s syndrome: relative risk 37x
Syndromes related to infectious diseases
Describe the location of polymorphisms in the MHC protein, and explain why the polymorphisms are found in these regions:
- Determined by the size and shape of “pockets” in the floor of the MHC molecule
- Pockets specify subsets of peptides, which contain specific anchor residues that fit into the pockets
- Many MHC polymorphisms affect the size and shape of these pockets – basis for differential peptide binding by distinct MHC alleles
- Polymorphisms thus influence
- MHC recognition by the TCR
- MHC binding to peptides
- Polymorphisms thus influence
Explain in detail which regions of the TCR contact the peptide + MHC complex, and how specificity of TCR recognition is genetically determined:
- Peptide residues which are not buried in the MHC groove serve as binding sites for the TCR
- Peptide and MHC molecule are both important for contact with the TCR
Describe the endogenous pathway of antigen processing and presentation, and explain the function, as it relates to the loading of MHC molecules:
Endogenous pathway:
- Cytosolic (“endogenous”) peptides associate with MHC class I
- Cytosolic (“endogenous”) proteins: e.g., host cell structural proteins, viral pathogen proteins
- Virus enters: production of proteins in the cytosol
- Misfolded proteins and ubiquitin activated marked for proteolytic degradation of proteins
- Transport of peptides from cystol to ER (TAP complex completes this step)
- Assembly of peptide-class I complexes in ER (finishes folding)
- Surface expression of peptide-class I complexes (available for recognition by CD8+
Describe the exogenous pathway of antigen processing and presentation, and explain the function, as it relates to the loading of MHC molecules:
Exogenous pathway:
- Extracellular (“exogenous”) peptides associate with MHC class II
- Extracellular (“exogenous”) proteins: e.g., host serum proteins, bacterial pathogen proteins
- Uptake of extracellular proteins into vesicular compartments of APC (APC are constantly phagocytizing)
- Processing of internalized proteins in endosomal/lysomal vesicles
- Biosynthesis and transport of class II MHC molecules to endosomes
- Association of processed peptides with class II MHC molecules in vesicles (CLIP helps the class II MHC stay together)
- invariant chain displaced by CLIP
- CLIP displaced
- peptides from outside the cell are loaded (extracellular)