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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 aesalmon(91),
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etmSlpycnoe = rome ltebcusipes ot seepaunactld sigarosmn

I tpu .E iolc sa ist alpetusndeca tbu ttah twasn' eth tosm htgri ewnsra I ges?us

submitted by sajaqua1(585),
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CMH I ocinfunt is gtrinela ot cnerac supnesp.rsoi MHC I lyaispsd ondyleenugso ziyedsshent erpstino nad terpesns them to D8+C T .clsel heT freuail to sydilpa CHM ,I or CHM I asyildp of ns-eflno a(dn yb nonetxeis oes)naurcc pntoesri gritersg a lralluec euimnm psnoese,r igaendl ot tcornsuitde fo het ecll.

eTh oeompersta is dseu ofr hte daanirgedot of wnro ut,o tnseeen,cs ro romdamlfe ter.onsip sA rccaen deve,oslp omer nmutsoiat dlea to eansdcier norwg rentsoip. lOyn by sipsnoreex of hte t,ospaeomre ro ist ir-vsn,oerpoexse cna etesh mutant trnespoi eb adedredg afst ohnegu to ont be adlesidyp by HMC I dna dlea ot het elcl iengb e.llidk tBbozireom lskboc the oretm,aepos os the amnutt rnpesoti rae pedidsayl no teh ,auercsf olgialnw teh unimem semsyt to iczegnreo nad lilk ocipgoalthla lscle.

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. +31  
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) +6  
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. +  
an1  OP said "Only by expression of the proteasome, or its over-expression, can these mutant proteins be degraded fast enough to not be displayed by MHC I". UW QID 11674 says that a protein undergoes degradation by the ubiquitin proteasome pathway, after which it goes to the ER and then is presented to the cell surface for MHC 1 response leading to apoptosis via performs and granzymes. Having a proteasome inhibitor would actually prevent the MHC response because no proteins are displayed. Also note that the question says which process will be affected, there is no mention of increase or decrease. So yes, the MHC 1/ CD8 pathways is affected, but it's actually down regulated. An absence of MHC 1 leads to NK cell mediated death. +  

"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(69),

submitted by tinydoc(262),
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MAO fo otpeoersmo rsotiinibh rof .MM LD:RT si hatt yhet abaillsyc bclko eht eotmsoeorp orfm iunfniotncg os that amelomy secll tna'c cleyrec niestopr yhe(t mkea a tno of m)teh and hnwe hety 'tacn be ceydrcle ehyt bulid pu dna tthas cxtio to hte clle and ti dise.

edoybn atht eth tuqoesin si bacisyall gikasn fi het oinhinbiit fo rsoeoespmto itns ispeifcc to het myaMoel sclle dna it niihtdbei heotr llsec' poemtsooser what doluw be ffcteee?d

MHC alcss I si netepsr on all nuedlcate slcel (lla lcles ni hte oydb xpctee RB)C nda oucinfnt ot tnepsre esgdneouon nainsetg to CD8+ t clles to be dedetrsyo (rof elxmpae ilraV ADN in an etifnecd llc.)e Teh yaw yeht do hsit si by tgnkia the toprien ti nesed ot rpeestn dan agibernk it dnow inot cumh mlaserl ppediet ahincs s(o ti acn tfi on eth MCHI. fI stih teps asw ehiibdtin ni herot lecls enht eht eht oPsneenttiar fo CHM I wntudlo be laeb to spernet rtihe etannisg to +D8C T ellcs dna Naluart lkielr lclse. as het nesitouq pem.iisl

Teh sionuqet wsa repus rcytik aebsecu if ouy 'tdno ownk how omsoerepot thiionrisb korw hnte you rttsa golonki orf na srnawe ahtt ouwdl anieplx who hyet doulw klli otumr slelc as llwe. I gto it onrwg oot. It qeiurdre geoedklwn fo eht ywa CHM I ssnrtpee epdit.sep

submitted by krewfoo99(114),
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Wyh uwdol nsifroerp eb eth norwg sr?ewna lWduont acuualictonm fo oitcx rnesopit aesuc teh elcl ot oduegrn tsaspooip ?

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) +1  

submitted by abhishek021196(102),
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trob,zBoiem cmlfzbroaii

aMhseimnc = eorPatomse iitinos,hrb dicenu taesrr ta -M2G aesph dna appo.ostis

eUs = lltepuMi o,memyal temanl elcl m.maohlyp

vdA cetffsE = prlareeihP unrapty,hoe pesher rsoezt ttvoenariiac

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. +  

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