Major Histocompatibility Complex (MHC)

Based on the notes provided, here are the answers to your learning objectives:

1. Steps for Antigen Presentation Pathways

Endogenous Pathway (MHC I):

  1. Ubiquitin Tagging: Ubiquitin binds to the target protein, directing it to the proteasome.
  2. Degradation: The proteasome degrades proteins into short peptides (8-15 amino acids).
  3. Transport: The Transporter Associated with Antigen Processing (TAP) moves peptides into the interstitial endoplasmic reticulum (ER) space.
  4. Binding: The peptide is trimmed to approximately 9 amino acids and binds to a vacant MHC I molecule within the ER.
  5. Surface Display: The MHC I-peptide complex is transported to the Golgi and then to the cell surface via exocytic vesicles for recognition by CD8+ T cells.

Exogenous Pathway (MHC II):

  1. Internalization: Extracellular antigens are taken up into vesicular compartments via phagocytosis or endocytosis.
  2. Degradation: Lysosomal enzymes degrade the antigens into short peptides.
  3. MHC II Synthesis: MHC II \alpha and \beta chains are synthesized and assembled in the rough ER.
  4. Invariant Chain: An invariant chain occupies the peptide groove to prevent premature binding during transport through the trans-Golgi.
  5. CLIP Formation: The invariant chain is partially digested, leaving a fragment called CLIP in the groove.
  6. Peptide Exchange: CLIP is replaced by the antigenic peptide (facilitated by HLA-DM), and the complex is transported to the cell surface for presentation to CD4+ T cells.

2. Comparison of Antigens

  • Endogenous Pathway: Predominantly presents antigens derived from proteins synthesized inside the cell. This includes normal cellular proteins and viral proteins if the cell is infected.
  • Exogenous Pathway: Predominantly presents antigens derived from extracellular proteins that have been internalized by professional antigen-presenting cells (APCs).

3. MHC Restriction and Heterozygote Advantage

  • MHC Restriction: This principle states that T cells can only recognize and respond to an antigen fragment when it is bound to a specific MHC molecule. If a foreign molecule cannot bind to an individual's MHC molecules, no adaptive immune response will be triggered.
  • Heterozygote Advantage: This refers to the benefit of having multiple different MHC alleles (variants). Because each MHC molecule can bind a different set of peptides, a heterozygote individual can present a wider variety of antigenic fragments, leading to a more robust and flexible immune response against diverse pathogens.

4. MHC-Associated Disease Resistance and Susceptibility

  • BoLA-Aw7: Associated with resistance to bovine leukemia (bovine leukosis virus).
  • BoLA-A*16: Correlated with resistance to mastitis in cattle.
  • BoLA DR locus: Linked to susceptibility to Dermatophilus.
  • ELA-A9: Linked to susceptibility to equine recurrent uveitis.
  • ELA-A3, ELA-A15, and ELA-Dw13: Associated with susceptibility to sarcoid tumors derived from bovine papilloma virus.