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NBME 23 Answers

nbme23/Block 1/Question#22

An investigator is studying the adverse effects of ...

Presentation of antigens to CD8+ T lymphocytes

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submitted by sajaqua1(354),

MHC I function is integral to cancer suppression. MHC I displays endogenously synthesized proteins and presents them to CD8+ T cells. The failure to display MHC I, or MHC I display of non-self (and by extension cancerous) proteins triggers a cellular immune response, leading to destruction of the cell.

The proteasome is used for the degradation of worn out, senescent, or malformed proteins. As cancer develops, more mutations lead to increased wrong proteins. Only by expression of the proteasome, or its over-expression, can these mutant proteins be degraded fast enough to not be displayed by MHC I and lead to the cell being killed. Bortezomib blocks the proteasome, so the mutant proteins are displayed on the surface, allowing the immune system to recognize and kill pathological cells.

catch-22  Another way to approach it is to think about MHC class I processing. Basically, if you inhibit the proteasome, peptides will not be generated and nothing is available to be loaded onto MHC I (remember MHC I has to be loaded before it's transported to the cell surface). Cells that don't express MHC I get killed by the natural killers. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2214736/ +13  
kai  "In conclusion, we have demonstrated that the proteasome inhibitor bortezomib down-regulates class I and enhances the sensitivity of myeloma to NK cell–mediated lysis" from the conclusion of the NIH paper +4  
maddy1994  another mechanism is by blocking proteosome u even decrease degration of proapoptotic proteins...so it enchances apoptosis(from uworld) +2  

"Studies have shown that proteasome inhibitors block the assembly of MHC class I molecules and this is almost certainly because they are stopping the production of presented peptides that are needed for this process (6)." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094101/

+1/- donttrustmyanswers(9),

 +2  upvote downvote
submitted by tinydoc(135),


MOA of proteosome inhibitors for MM. TLDR: is that they basically block the proteosome from functioning so that myeloma cells can't recycle protiens (they make a ton of them) and when they can't be recycled they build up and thats toxic to the cell and it dies.

beyond that the question is basically asking if the inhibition of proteosomes isnt specific to the Myeloma cells and it inhibited other cells' proteosomes what would be effected?

MHC class I is present on all nucleated cells (all cells in the body except RBC) and function to present endogenous antigens to CD8+ t cells to be destroyed (for example Viral DNA in an infected cell). The way they do this is by taking the protien it needs to present and breaking it down into much smaller peptide chains (so it can fit on the MHCI. If this step was inhibited in other cells then the the Presentation of MHC I wouldnt be able to present their antigens to CD8+ T cells and Natural killer cells. as the question implies.

The question was super tricky because if you don't know how proteosome inhibitors work then you start looking for an answer that would explain how they would kill tumor cells as well. I got it wrong too. It required knowledge of the way MHC I presents peptides.

 +1  upvote downvote
submitted by krewfoo99(42),

Why would perforins be the wrong answer? Wouldnt accumulation of toxic proteins cause the cell to undergo apoptosis ?

ergogenic22  Bortezomib does not directly activate perforin. It directly inhibits the proteasome which → enables CD8+ T cells to initiate apoptosis → via perforin release (in essence a downstream effect). +3  
drzed  Exactly, it triggers the cells to undergo apoptosis which means that it can either be cell mediated (perforin and granzyme via FAS/FASL) OR it could also be through the intrinsic pathway (e.g. mitochondrial; cytochrome c) +  
powerhouseofthecell  Question: But how do CD8 cells have a role in this process exactly in the vignette? Is it saying that when the proteins build up, only then do CD8 cells come and instead of MHC I presenting to proteasomes, they present it to CD8 to initiate apoptosis? +  

Bortezomib, carfilzomib

Mechanism = Proteasome inhibitors, induce arrest at G2-M phase and apoptosis.

Use = Multiple myeloma, mantle cell lymphoma.

Adv Effects = Peripheral neuropathy, herpes zoster reactivation

tyrionwill  under Bortezomib, the proteasome cannot digest viral Ag and presents it to the membrane-bonded MHC-I. Therefore CD8-Tc cannot recognize the host cells containing relapsed VZV. That is probably why shingles is one of the popular side effect of Bortezomib. +