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Define and compare exogenous Ags and endogenous Ags.
- 1. Exogenous Ags - Ags that originated outside of the body
- 2. Endogenous - Ags that were generated inside the body due to abnormal metabolism or infection
How are exogenous and endogenous Ags processed and presented?
- Endogenous Ags
- 1. Degraded in the cytosol of any cell
- 2. Peptide fragments bind to MHC I molecules
- 3. Presented to CD8 T cells
- 4. Results in cell death
- Ags in a Mf (Intravesicular Ag)
- 1. Degraded in endocytic vessicle in Mfs
- 2. Peptide fragments bind to MHC II molecules
- 3. Presented to CD4 T cells
- 4. Results in Mf activation to kill intravesicular bacteria/parasites
- Exogenous Ags
- 1. Degraded in endocytic vessicles in B cells
- 2. Peptide fragments presented to MHC II molecules
- 3. Presented to CD4 T cells
- 4. Results in activation of B cells to secrete Abs to eliminate extracellular bacteria/toxins
What is the location and function of TAP (Transporters associated with Ag processing)?
- 1. Location - spans the ER membrane
- 2. Function - Actively transports (ATP) peptides that bind MHC I molecules from the cytosol to the ER
What is the basic function of the proteasome and how is it regulated?
- 1. Degrades proteins into peptides
- 2. Peptides that are presented by MHC I molecules are generated by the proteasome
- 3. Proteosome exists in all cells as inactive constituitive proteasome
- 4. Stimulated by interferons, the constituitive proteasome becomes the active immunoproteasome
Describe in detail the pathway for peptide loading onto MHC I molecules
- 1. Partly folded MHC I alpha chians bind to calnexin until beta2-microglobulin binds
- 2. This complex is released from calnexin and binds to chaperons, which bind to TAP via tapasin
- 3. Peptide fragments created by the proteosome in the cytosol are transported into the ER by TAP
- 4. A peptide fragment binds to MHC I which completes its folding and is transported to the cell membrane
How do viruses evade Ag processing and presentation pathways of the host cell
- 1. See Fig. 6.7
- 2. Viral evasins block Ag presentation by preventing peptide movement through TAP
- 3. Some adenoviruses can compete with tapasin and inhibit peptide loading onto nascent MHC I
- 4. Herpes virus ligase can target MHC I for degradation by the proteasome
Describe in detail the pathway for peptide loading onto MHC II molecules.
- 1. Invariant chain binds in the grove of MHC II
- 2. Invariant chain is cleaved in an acidified endosome, leaving a short peptide fragment (CLIP) still bound in the MHC II groove
- 3. Ag is taken up from extracellular space into endosome
- 4. Acidification of endosome activates proteases to degrade Ag into peptide fragments
- 5. HLA-DM binds to MHC II, releasing CLIP and allowing Ag peptide fragments to bind
- 6. MHC II:Ag complex moves to cell surface
Why is cross-presentation necessary to the antiviral immune response?
- 1. The process by which extracellular proteins taken up by DCs can give rise to peptides presented by MHC I molecules
- 2. Allows Ag from extracellular sources to be presented on MHC class I molecules and activate CD8 T cells
What are the possible molecular pathway of cross-presentation?
- 1. Translocation of ingested proteins from phagolysosome into the cytosol -> degradation by proteasome -> enter ER through TAP -> loaded onto MHC I molecule
- 2. Transport of Ag directly from phagolysosome into a vesicular campartment -> peptides bind to MHC I molecules
Containing several separate loci encoding MHC molecules of identical functions
- 1. MHC genes with more than one allele at a gene locus
- 2. Allelic variation
- 1. MHC product of both alleles at a locus are expressed equally in the cell
- 2. Both gene products can present Ags to T cells
MHC genes with only one allele
Define MHC haplotype
The particular combination of MHC alleles found on a single chromosome
What is are the mechanisms that drive gene evolution in the MHC?
- 1. Ancestral MHC gene undergoes gene duplication and divergence resulting in multiple genes
- 2. Multiple genes undergo gene conversion between misaligned chromosomes during meiosis
- 3. DNA sequences from one chromosome is substituted on the other
What is MHC restriction?
- 1. The fact that an Ag can only be recognized by a given T cell if it is bound to a particular self MHC molecule
- 2. A consequence of events that occur during T cell development
What is alloreactivity?
The recognition by T cells of MHC molecules other than self
How do you test for alloreactivity
- 1. Mixed lymphocyte rxn
- 2. lymphocytes from donor and recipient are cultured together
- 3. If the 2 people are histoincompatible, the recipient's T cells recognize the allogeneic MHC molecules on the cells of the donor as 'foreign' and proliferate
What are superAgs and how do they function?
- 1. Bind simultaneously MHC II molecules and V-beta domains of TCRs
- 2. Cause massive production of cytokines by CD4 T cells
- 3. Results in toxic shock syndrome
Why is it important to have extensive MHC polymorphism in a population?
MHC polymorphism extends the range of Ag to which the immune system can respond
What is the function of MIC-A and MIC-B?
- 1. Expressed in the GI tract
- 2. Stressed-induced activation of NK and CD8 cells
What is the function of HLA-E?
NK cell inhibition
What is the function of HLA-G?
Modulates maternal/fetal interaction
What is the basic function of CD1?
- 1. Small family of MHC class I-like proteins
- 2. Not encoded in the MHC
- 3. Can present glycolipid Ags to CD4 T cells