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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(530),
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MHC I nftcuoin si elrnigta ot naccer .peuisnpossr HCM I lysasdip ydulngsoenoe esyeniztdsh ieopntrs adn sprneets tehm to DC+8 T slc.le hTe uelfira to daplysi HMC I, ro HCM I lyspdai fo lno-nfse a(dn yb nnsxeioet nu)oarescc eptnosir rtgersig a lurcalel uimemn rnspeeos, dniegal ot creiotusndt of hte lecl.

eTh tseomerpao si dseu rfo eth teadrodniag fo wnro uo,t n,eescenst ro faodermlm pesn.rito sA racnce eo,ldesvp rmeo atnmoiust aled ot canresied norgw pto.nries lOny yb pnosrxeies fo the esopoare,tm ro sti vs,or-ioesprneex cna htsee nuamtt inrtpoes eb greadded satf gunheo ot ton eb pdlyisdae by CMH I dna aled ot hte lecl geibn .elikld eBomriozbt olbksc het reo,tsemopa os the natumt eoistrnp are alsiyddpe no teh sfce,rau nawllgoi eht uiemnm ytmsse to enrgzocie and llki ptoilacahlog ell.cs

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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AOM fo tpeosremoo irishtbnio fro M.M RLD:T si atht etyh allybscia lkbco eth oseepmroot fmor nntifiugocn os ahtt ylommea lslce tca'n cceyrel spotienr h(ety eamk a tno fo tmhe) adn hwne hyet an'ct eb cyrdelec ythe budli pu and htast txcio ot eth llce adn it dei.s

dbnyeo atht het uoiqtsen si alsciyalb sankgi fi hte hininoiibt fo seesrtoompo nits seifcpci ot the moleyaM lcels dan ti etdihinib oehrt ecll's smooptrseoe wath woudl be ceetf?efd

CMH lcass I is npsreet no lal dutaecnle lecls all( clles in eht ydob epetxc C)RB dan inuoctnf ot pnesert enudgonseo inengtsa to +D8C t llces to eb doeerdtsy (for elxepam iarVl NAD in na tfneiecd )lle.c Teh way yeht od tish is yb tkinga hte ripntoe it endes ot tesnrpe dna kgaibrne it ondw into mhuc ralmsle edietpp shniac (os it cna fti on hte .HMCI fI ihts ptse saw ehibtidni in hetor eclls hetn eth het staPrtnenoie of HMC I owtdunl eb aleb ot steprne theri tisengan ot +8DC T elcsl nad Natralu lirekl llcse. as hte nusoqeit liiespm.

Teh snqeouit was srupe tikcry bcueesa if you odt'n owkn how potsmeoreo tnbsihoiir rokw ehtn oyu tsrat loigkno rfo na eawnrs that wluod plnexia owh tehy ouwld llik tmrou lslec as l.ewl I tgo it gorwn It dqirreue nlodewkge fo eht ywa MCH I rsesetpn sdtep.ipe

submitted by krewfoo99(93),
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yWh udwol poesirnrf be hte grown wr?nsae luoWntd muaoitcalcnu of xotci inoertsp acesu eth llce to rguoedn ootsippsa ?

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(59),

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. +