Lec 43: Major Histocompatibility Complex

Question 1

Define the critical properties and function of the Major Histocompatibility Complex:

Answer 1

• 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

Question 2

List the names/designations for each of the human MHC class I genes:

Answer 2

• HLA-A
• HLA-B
• HLA-C

Question 3

What is the tissue distribution of the MHC?

Answer 3

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

Question 4

List the names/designations for each of the human MHC class II genes:

Answer 4

• HLA-DR
• HLA-DP
• HLA-DQ

Question 5

Explain the nomenclature for designating MHC alleles:

Answer 5

• 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

Question 6

Explain co-dominant expression and its significance, as it relates to MHC genes:

Answer 6

All are equally expressed and present on the surface, 3 come from each parent. Increases likelihood the population will survive.

Question 7

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:

Answer 7

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

Question 8

Name and describe the MHC regions bound by CD4 and CD8:

Answer 8

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

Question 9

Compare and contrast the types of peptides bound by class I and class II MHC:

Answer 9

• 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

Question 10

Why is the MHC so highly polymorphic?

Answer 10

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

Question 11

Explain the general clinical relevance of MHC polymorphism, and list examples of the medical relevance of MHC polymorphism:

Answer 11

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

Question 12

Describe the location of polymorphisms in the MHC protein, and explain why the polymorphisms are found in these regions:

Answer 12

• 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

Question 13

Explain in detail which regions of the TCR contact the peptide + MHC complex, and how specificity of TCR recognition is genetically determined:

Answer 13

• 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

Question 14

Describe the endogenous pathway of antigen processing and presentation, and explain the function, as it relates to the loading of MHC molecules:

Answer 14

Endogenous pathway:

• Cytosolic (“endogenous”) peptides associate with MHC class I
• Cytosolic (“endogenous”) proteins: e.g., host cell structural proteins, viral pathogen proteins
  
  1. Virus enters: production of proteins in the cytosol
  2. Misfolded proteins and ubiquitin activated marked for proteolytic degradation of proteins
  3. Transport of peptides from cystol to ER (TAP complex completes this step)
  4. Assembly of peptide-class I complexes in ER (finishes folding)
     
     • Surface expression of peptide-class I complexes (available for recognition by CD8+

Question 15

Describe the exogenous pathway of antigen processing and presentation, and explain the function, as it relates to the loading of MHC molecules:

Answer 15

Exogenous pathway:

• Extracellular (“exogenous”) peptides associate with MHC class II
• Extracellular (“exogenous”) proteins: e.g., host serum proteins, bacterial pathogen proteins
  
  1. Uptake of extracellular proteins into vesicular compartments of APC (APC are constantly phagocytizing)
  2. Processing of internalized proteins in endosomal/lysomal vesicles
  3. Biosynthesis and transport of class II MHC molecules to endosomes
  4. 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)

Question 16

Compare and contrast the sources of MHC class I and MHC class II peptides, and describe how these sources relate to the endogenous and exogenous processing pathways:

Answer 16

MHC class II = exogenous pathway (Extracellular)

• Extracellular (“exogenous”) proteins: e.g., host serum proteins, bacterial pathogen proteins

MHC class I = Endogenous pathway (cystolic)

• Cytosolic (“endogenous”) proteins: e.g., host cell structural proteins, viral pathogen proteins

Question 17

Why don’t antigens mix with class I and II MHC?

Answer 17

The invariant peptide blocks in class II while in the ER

Question 18

Define and describe the functions of TAP:

Answer 18

TAP: Transporter associated with antigen processing (TAP), a protein that spans the membrane of the rough endoplasmic reticulum, transports the peptides into the lumen of the rough endoplasmic reticulum (ER).

Question 19

Define and describe the functions of proteasomes

Answer 19

Proteasomes: break the protein up into peptides that include some around nine amino acids long (suitable for fitting within the peptide binding cleft of MHC class I molecules)

Question 20

Define and describe the functions of the invariant chain:

Answer 20

Invariant Chain: MHC class II protein in the rough ER has its peptide-binding cleft blocked by Ii (the invariant chain; a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway. The invariant chain also facilitates MHC class II’s export from the ER in a vesicle. This fuses with a late endosome containing the endocytosed, degraded proteins.

Question 21

Define and explain in detail the concept of MHC restriction.

Answer 21

A given TCR will only recognize a specific MHC molecule in complex with a unique (or a few similar) peptide(s). Normally, as T cells are stimulated only in the presence of self-MHC molecules, antigen is recognized only as peptides bound to self-MHC molecules. Peptide-binding “pockets” are what restrict as individual MHC alleles bind to unique or chemically similar amino acid side chains (“anchor residues”). The more pockets the more specific and thus it is limited for binding.

Question 22

What is the evolutionary reason for having both class I and class II molecules?

Answer 22

The two types of MHC and their associated antigen processing pathways are critically important for effective responses to the two general types of pathogens:

• Intracellular pathogens: viruses, etc: MHC class I:
  
  • All cells are vulnerable to such infections, and all cells must thus have a way of presenting such pathogen peptides to T cells, for recognition and elimination
• Extracellular pathogens: bacteria, fungi etc: MHC class II
  
  • These pathogens can be readily accessed by phagocytosis and other engulfment mechanisms. The evolution of specialized antigen sampling cells is a very efficient way to monitor the entire extracellular space of an organism.