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NBME 23 Answers

nbme23/Block 1/Question#22 (50.6 difficulty score)
An investigator is studying the adverse ...
Presentation of antigens to CD8+ T lymphocytes🔍,📺
tags: immuno 

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submitted by sajaqua1(535),
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HMC I ftnonciu si nrgelita ot anercc MCH I dyiplsas ylusdeongeon yiztesdesnh prositen dan eprensts tmhe ot C8D+ T .sclel heT flureai to sylipad MHC I, ro CMH I yslpdia of lenos-nf d(na yb senitoexn )ecocrnasu roentpsi trggseir a lelulacr enimum nesr,seop lgdneia to tdicrteunso of hte ellc.

heT temroaoesp is sued fro het dnatadigore of norw to,u snetec,nes ro rmmalfedo nopsitre. sA eraccn lpeoe,svd eomr stuoaitmn adel ot dencaeisr grown yOnl yb peseionrsx fo eth seaortoep,m ro its enois,ovperesxr- acn teehs tamtnu osnretip eb rdeagedd fsat nogeuh ot ton eb pdaylsied by CHM I dna adle ot the lecl ngeib .eklldi rotobeziBm oblcks eth rtpmeoeao,s os hte nmutat ipnroset ear adldpesyi no teh ,arefsuc lowiangl teh niumme yemsts to egznroice adn kill atlialhcgpoo el.lcs

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. +27  
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) +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." +  

"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(59),

submitted by tinydoc(233),
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OMA of eospooermt nsiboiitrh rof .MM RDL:T is that they bailsclay olkcb teh etmosorope rfom otnicnginfu so ttha lmyeaom esllc 'acnt ycrcele nitrepso (yhet kmea a ont of mht)e adn nhew ehyt cn'ta be eccyrdel ythe ilbud pu nda ahtst coitx to teh clel dan ti ides.

nyedob atth the nsoqitue is caiylbsla kngasi if teh hiniintboi fo opotosrmees inst pcfcisei ot teh laoymeM lcsel dan ti iidiehtnb ehort 'lescl eoeosspotrm what owudl be edcfftee?

HMC lsacs I si tnesrpe on lla ncutadele selcl la(l sclel in hte ybdo exepct )RBC adn tnfoiunc to rtpesne sodenueogn nsinteag ot DC8+ t sllce to be eosdytder o(fr eampelx rliaV DAN ni na detfecni .lec)l heT yaw teyh do isht si by ntiakg het otreinp it esned to neetrsp dna krbneagi ti nowd noti uchm arllesm ptpidee casinh s(o ti cna tif no teh IC.HM If hsti step saw ideitbihn ni ohrte lclse hetn the teh eoeantriPsnt of CMH I twoldnu be beal to seepntr iehtr sgnetina ot D8C+ T lscle nda ulrataN rkleil cse.ll sa teh utqoenis lpis.iem

hTe sounteiq swa suepr ckitry uecsbea if uyo 'ntod onwk ohw msepoteoor irbiostihn kwor then uoy trsta nikgloo for an rsenwa that wluod alepxin owh yeth udwol kill uormt cslel as lwe.l I tgo it gwron o.ot It rrdqeeui lngkewdeo of het way MHC I stensrpe pepie.dts

submitted by krewfoo99(93),
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hyW lowdu irprofens be hte owngr e?wsarn ulnoWdt maouuantlicc fo xtioc erstpoin useca het elcl ot derougn aoosppist ?

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(66),

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. +