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NBME 23 Answers

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

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submitted by sajaqua1(558),
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MHC I utnfcnoi si nrlgtiea to acercn ppuiroesssn. MHC I slpayisd ennsougleoyd nsetzhdeyis posnreit and nesprest thme ot +8CD T sl.cel hTe lauirfe to silapdy HMC ,I or MCH I sdlaypi fo ofe-nnls nda( yb xseeotnin rsnu)ecaco oesniprt gtgsrrie a alluelcr eunmmi es,onspre aeingld ot etrcinotdus fo the ec.ll

hTe paesooterm si esdu rof the danagoirdet of rnwo ,tuo nsee,nscet or odlemrfma nteors.ip sA rcecna vp,ldeoes oemr untostima lead to esnacierd worng rneoi.tps nylO by oeneirspsx fo het eoasptrmeo, ro its xs-oerereopivn,s cna etshe tamtun sopreint eb edddrgae ftas gnohue to not be pesdyladi yb MCH I nda adel to hte ecll egnbi .lkdiel obzoBritme bcklso het as,erptoome so the tmuatn enposirt ear dyidlsape no the re,fascu walinlgo hte iemunm msyset ot egrzoeinc dan llki lphgaaocoilt lslce.

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. +28  
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 +6  
maddy1994  another mechanism is by blocking proteosome u even decrease degration of proapoptotic it enchances apoptosis(from uworld) +5  
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." +  
fatboyslim  I think what OP said contradicts with what @catch-22 cited in the PubMed article. +  

"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(65),

submitted by tinydoc(245),
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OAM fo ospooermte niriihbtso rof MM. :TRDL si atht ehty ascylibal cbklo the opstereomo ormf unifnnigotc so thta molymea clles ctna' lyeccre nsepotri thy(e ekma a not fo htem) nda henw htye tcna' eb edycelcr htey idlbu pu dna hstat cxoti to hte lecl dna ti edis.

doeynb ahtt eht tqsuieon si laayislbc nisakg if teh nibotiiinh fo trmsepsoeoo ints cepscifi to hte elMomya ellcs nad it hiibenidt horet l'slec stomoosreep wtha dlouw be cetfee?fd

CHM slcsa I is ternpes on lal ualcndeet clsle la(l cllse ni hte ybdo xpeetc RBC) nda fcnntoiu to nseptre gdoennouse gtsaenin ot +8CD t sclel ot eb tdereosdy for( xmpalee rVali ADN in na nftceeid ll).ec hTe way teyh od ihts si yb igknta the prtoien it desen to npeerst nad ekiagnbr ti ndow onti uhcm slmlrae peetidp caisnh os( ti nca itf no eth MC.IH fI tihs pset wsa dibeihtni ni ehrot slecl nhet het teh nitearetsnoP of HMC I woutndl be ebal ot netpesr tehir saegintn ot 8CD+ T clles dan rlatNau irllek cels.l sa het inotuqse sm.iiple

hTe eunqiots wsa supre tciykr eucseba fi yuo dot'n wkno owh ooersempto iosbrihtin wkro ehtn oyu tatrs gokinol rof na srawen taht oludw nelapix who yeht oldwu llik outrm lcsel sa elw.l I got ti rwnog t.oo tI redrueiq loewdegkn of eth wya MCH I eptnesrs tdsepe.pi

submitted by krewfoo99(104),
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Why owldu nrfpeoirs be eth nogrw ?rsaenw notWldu mantiolauccu fo oixtc srepotin csaeu eth llce ot rnudoge otpoassip ?

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(79),
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irB,oozmtbe bzcmoafrlii

inacMsehm = tePraoemso nsihi,irbto diencu rasret at GM2- hseap dna ostpspaio.

esU = pluMtlie omlye,am laetmn ecll op.lmhmya

dvA scftefE = arhilPerpe reuhaty,nop preehs tsozre eoiaancirtvt

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. +