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NBME 23 Answers

nbme23/Block 1/Question#22 (49.4 difficulty score)
An investigator is studying the adverse ...
Presentation of antigens to CD8+ T lymphocytes🔍
tags: immuno 

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submitted by sajaqua1(531),
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MCH I nntcuofi si lartgine ot acrcne CMH I ypasslid oulsgodeynne diestsnehyz osrtepni dan rentessp ehmt to D8C+ T s.llce heT irfaule to lpdysia MCH I, or HCM I dailpsy of ofsle-nn dn(a by xeoiesnnt unceasrc)o rieotspn eiggsrtr a lacuellr mumnie eeosps,rn gnlaide ot nduritoesct fo the e.cll

eTh soamptreeo is euds ofr eth toidgandaer of norw t,uo etcn,sseen or mdfmorale erno.stip As nccera ps,eedovl orem ttsmonuia elad to iesdacrne onrwg pnroist.e nyOl yb piosexensr of het ootprae,esm or its enrpss-rv,eoeoix anc hsete tutman pneirots eb aededgrd staf ugneoh to ont be piddlsyea by MCH I nad dela to the ecll egbin ireoBmotzb sckblo eht oees,trmpoa os the tnuamt nestprio ear ediyapsdl no eth ,esruacf awgnilol hte iemmun tseyms ot znergocei adn illk hclglpotoaia llse.c

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. +25  
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 +5  
maddy1994  another mechanism is by blocking proteosome u even decrease degration of proapoptotic it enchances apoptosis(from uworld) +4  
azibird  But CD8+ and NK cells kill via perforin! Why is this answer wrong? Is it because it's not the primary effect? +2  
testready  "The proteasome is the major source of proteolytic activity involved in the generation of peptides for presentation by major histocompatibility complex class I molecules. We report the new observation that bortezomib down-regulates HLA class I on MM cells, resulting in increased NK cell–mediated lysis." +  

"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)."

+3/- donttrustmyanswers(58),

submitted by tinydoc(231),
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OAM of sooermetop sibintoirh rfo MM. L:TRD is htta yhet bisayallc lbcko teh rsmooetpeo mfro igtonnucnfi os htat lmmoyea lslce ca'tn yerclce sitrnepo het(y maek a ton of htme) nad when ethy ca'nt eb redlccye ehyt bilud up dan hstat ictxo ot the cell and ti e.sdi

neyobd htat het utensqio is asilaylcb iagkns if the iioniitbnh fo mopooeterss stni scicipef ot the yeMmloa ellcs nda it iiihtdnbe ehort ecsl'l epersootmos hatw dwoul be cefeetf?d

HMC cssla I si trpense no all naculedet csell (all celsl in hte doyb texpec BC)R and ftonicnu to tsenerp nundegeoso sgnetani ot C+D8 t llesc ot be deyteodrs fr(o maepexl Varli DNA in an edceitfn l.cel) Teh ywa hyet od shti is by tangki het itronpe ti nesed ot enestpr adn rngbkeai ti dnwo iton hucm laesrlm edteppi asinch (so ti nac tif on hte .CHIM fI hist step was edbiitnih in rhteo lelsc then eth eth reenoPintsat fo HMC I ltwondu eb aebl to entpres rhite ginatesn ot 8C+D T clesl dan uratlNa lielrk .lcels as hte enuitosq spim.ile

Teh insuetoq saw repus cikrty bcuease if uyo d'ont nwko ohw eosrotoemp ioiisbhrnt work neht uoy atstr ioglonk for an ersnwa thta dwluo xnealip ohw htye ldouw ilkl toumr lslec sa wl.le I tgo ti gornw oo.t tI ederiruq nkweedogl of eth awy HCM I ptnsrsee tspep.edi

submitted by krewfoo99(93),
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hyW uoldw rfenosrip eb eht rognw nerwas? odltnuW aclumionctua fo tocxi snoiprte uasec teh lelc ot rgoeund iptpsaoos ?

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). +4  
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? +  
flexatronn  @powerhouseofthecell so it all goes back to basic immuno (i got this wrong and put apoptosis as well) but after reviewing relevant anki cards, i now get it. So proteasomes break down tagged proteins within the cell (endogenous). The breakdown products get taken up by transport associated with antigen processing (TAP) and brought to the rough ER. The breakdown products are then loaded onto MHC I molecules and brought to the surface of the cell. When thinking about MHC I, think about CD8+ T cells (FA MHC 1 x 8 = CD8. Now to summarize, when using a proteasome inhibitor, you're blocking that tagging and MHC I loading process. As stated before, CD8 recognizes MHC I (which won't happen when using these drugs) +  

submitted by abhishek021196(61),

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. +