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NBME 23 Answers

nbme23/Block 1/Question#22 (47.4 difficulty score)
An investigator is studying the adverse ...
Presentation of antigens to CD8+ T lymphocytes🔍
tags: immuno 

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submitted by sajaqua1(520),
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CHM I fctiuonn is tnerlgia ot ceacrn opes.srsipnu MCH I aslyipsd nneoguyosdel eiyhesznsdt tpsonier nda ssperetn emht ot +8CD T sll.ce eTh ilefaru ot daliyps MHC I, or CMH I pliaysd fo s-fonlen (dan by ensoxntei n)ucseroac pinsorte stgergri a aculllre nummie sonee,rsp ldngaei to tteiocnsrud of eht .lecl

Teh smratpeoeo si udes ofr eth grieoadntad of nrow o,tu tnnseec,es ro fedalromm ietprson. sA acncer e,opsledv mero ottamunsi alde to necrdaesi gnwro psie.rton nOly by nsiopsrxee of eht eo,ptraomes or tsi xevoesnp,s-erori anc hetes ntatmu iseprotn eb gdedrdae tsfa gunohe to nto be pdsdelayi by MCH I adn aled ot eth llec gnebi bmoetoBzri lbocks the smep,taroeo so hte mtatun oepnrsit era pdsiadlye no the c,ufesra ainlwogl hte nmuime smetsy ot cigernoez dan lilk oaialtgpcolh .llsec

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) +3  
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(56),

submitted by tinydoc(223),
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OAM fo omseptoore hrnioitsib rof MM. TD:RL si hatt ethy caslalbiy bkocl the rtmopoeeos mfor goiniutcnfn so hatt emymoal leslc ntac' ceyercl einsrtop t(yeh meka a nto of ehm)t nad when ehyt t'acn be ydereccl ythe udibl pu adn ahtts icxot ot het clel dna it .ised

oydnbe atth the osquinet si slyaacilb gisnka fi eht bohtiiinin of eerpstsooom stin cscfipie to eht lmaeMyo cesll dna ti deibtniih rhtoe cle'sl moptsoseoer hwat ouwdl eb fed?tefce

CHM alcss I is etsnepr on all acnluteed lscle (all clesl ni hte boyd epxcet C)RB nad uctoninf ot tperesn sdnoegueon esigtann ot +8DC t lsecl to be sytddeeor (orf aelmxpe Vrial DAN ni na fdneitce lle.)c ehT wya yhte do iths si by aigtnk eht oiretpn ti eedns to rntespe nda ekgbnria ti nowd noti cumh elarlms ditpepe iacnsh so( ti nac tif no the ICH.M If shit tesp was tiindbhei in eroht llces tnhe eth het aetsninPotre fo CMH I tnoldwu be aebl to eterspn hiter ateginns to +D8C T clels and Nultara lkilre le.scl as eth esontqui elm.isip

hTe enstqoiu asw speru trkyic abcuees fi ouy ont'd wonk owh oeorsotmep iotsibhrni korw tenh uoy tarts okgnlio ofr an aerswn ahtt wdlou anxlpei woh hety oudlw ikll urtmo ecsll sa w.lle I tog it rngow oto. It qierrued knlgdewoe fo eth ywa CMH I ssetnrep eiptde.sp

submitted by krewfoo99(90),
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yhW wlodu psoiefnrr be teh rgnow rnsa?ew uotdlWn ncmltauuoaic fo tioxc oispnret seuac het lcle to egnduro asitopops ?

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? +  

submitted by abhishek021196(50),

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. +