Block 5 Revision - StudentVIP

Block5Revision

AnatomyAnatomyoflymphaticdrainage–12/4/16

1. DescribethecomponentsofthelymphaticsystemandthefunctionsofthesecomponentsThelymphaticsystemiscomprisedoftwosemi-independentparts:thelymphaticvesselsandlymph;andlymphaticorgansandtissues.Lymphaticvesselsplaytwokeyroles.Firstly,theydrainexcessinterstitialfluidbackintotheblood,returningsomelostplasmaproteinsintheprocess.Secondly,theytransportdietarylipidsfromtheintestinetothebloodthroughspecialisedlymphaticcapillariescalledlacteals.Lymphaticorgansandtissuesplayanimportantroleinfightinginfectionsthroughimmuneresponsesandareessentialforboththeadaptiveandinnateimmunesystem.Lymphaticorgansandtissuesareclassedintoprimaryorgansandtissuesandsecondaryorgansandtissues.PrimarylymphaticorgansandtissuesarewherestemcellsdivideandmatureintoBorTlymphocytes.Itincludestheredbonemarrow(produceslymphocytes,Bcellmaturation)andthethymus(Tcellmaturationundertheeffectsofthymosin).Secondarylymphaticorgansandtissuesarewheremostimmuneresponsesoccur.Theyincludelymphnodes(areasofconcentratedlymphocytesinaspecialarrangement),spleen(similartolymphnodebutlargeandfilledwithblood,playsaroleinfilteringandpurifyingtheblood)andlymphaticnodules(whicharecongregationsoflymphatictissue,includingthetonsils,Peyer’spatchesandmucosaassociatedlymphoidtissue[MALT]).

Primarylymphaticorgansandtissues–BandTcellproductionandmaturation

Secondarylymphaticorgansandtissues–sitesofimmuneresponse

Bonemarrow• Lymphocyteproduction• Bcellmaturation

Lymphnodes• Concentratedlymphocytesin

specialconfigurationThymus

• Tcellmaturation(thymosin)Spleen

• Similartolymphnodes,butfilledwithblood

• Bloodfilteringandpurification Lymphaticnodules

• NOTencapsulated• Congregationsoflymphatic

tissue• Tonsils• Peyer’spatches• Mucosaassociatedlymphoid

tissue(MALT)

2. ExplaintheformationoflymphandthemechanismoflymphtransportInthesystemicandpulmonarybloodcapillaries,themeanofinterstitialandluminaloncoticandhydrostaticpressurecanresultinmovementofblood(minuscellsandlargeproteins)outofthecapillariesandintotheinterstitium.Thelymphatic

capillariesarecloselyassociatedwiththeinterstitiumandexcessfluidflowsintothemtoeventuallyenterthelymphaticvessels.Thelymphaticvesselsofthepulmonarycirculationmeetatthelymphaticductwheretheyemptyintosystemicbloodcirculationatthesubclavianvein.Thelymphaticcapillariesplayakeyroleintheformationoflymph.Foundthroughoutthebodyexceptinavasculartissues(cartilage,epidermis,cornea),theyareporousandblind-endedandtheopeningsintothemarebetweentwotissuecells.Theseopeningshaveaone-wayvalvethatmeansthatfluidenteringthemfromtheinterstitiumcannotre-entertheinterstitium.

Onceinthelymphaticsystem,therearenopumpssospecialmechanismsforflowarerequired.Therearelotsofvalvesinthelymphaticvesselstoensurethatflowisonlyone-way.Theexitofthelymphofthelymphaticductisintoalow-pressurearea(thesubclavianvein–5mmHg)togiveapressuregradient.Therearealsospecialdrivingforcestokeeplymphmovingthroughthelymphaticcirculation.Thesmoothmuscleinthevesselwallassistsinpumpingthelymphthroughthevessels.Theskeletalmuscleneighbourassistsinmilkingoutlymph.Respirationcausesthethoraciccavitypressuretodecreaseandtheabdominalcavitypressuretoincrease,thuscreatingapressuregradienttodriveflowbackintothethoraciccavity(thatis,wherethethoracicductandthesubclavianveinarelocated).

3. Summarisethedrainageroutesofmajorlymphaticvesselsandlocationofmajor

clustersoflymphnodesThereare10principalgroupsoflymphnodes.Thefirsttwogroupsliealongsidekeymidlinestructures:thetrachea(trachealnodes,x1)andtheaorta/celiactrunk/SMA/IMA(deepnodes,x1).Thenextthreearewheretheupperlimbs(axillarynodesinaxilla,x2)andlowerlimbs(inguinalnodesalonginguinalligament,x2;femoralnodesalongfemoralvein,x2)attachtothetrunk.Thelasttwogroupsarewheretheheadandneckattachestothetrunk(cervicalnodesalongcourseofinternaljugularvein,x2;pericranialringalongbaseofhead,x2).

4. Compareandcontrastthelocation,histologicalstructureandfunctionsofprimary

andsecondarylymphaticorgans

Seepracticalmanual

5. Relatetheanatomyofthelymphaticsystemwithclinicalscenarios:cancermetastasis,lymphoedemaHavingagoodunderstandingofthelymphaticsystemisimportantascertainareasofthebodydrainthroughcertainpathways.Therefore,thelymphaticspreadofcancercanbepredicted,ortraced.Threeexamplesaretheoesophagus,testesandscrotum,andtheupperlimbandbreast.

Partofoesophagus Drainsinto SitesofmetastasesUpper1/3 Deepcervicalnodes Middle1/3 Superiorandposterior

mediastinalnodes

Lower1/3 Leftgastricnodes->coeliacnodes

StomachDuodenumSpleenOmenta

Testicularandscrotalcancershavedifferentsurgicaltreatmentsduetothedifferencesintheirlymphaticdrainage.Thetestesdrainintothepara-artic/lumbarnodes,whereasthescrotumdrainsintothesuperficialinguinalnodes.Assuch,orchiectomy(removalofthetestes)shouldbedonethroughtheinguinalroute(NOTcuttingthroughthescrotumbutgoingthroughtheinguinalcanal)toavoidtumourspillageintotheinguinaldrainageroute(i.e.itavoidsthecancerpossiblyreachingthesuperficialinguinal).Differentareasofthebreastdrainintodifferentnodes(e.g.thelateralbreastdrainsintothepectorallymphnode).Itisimportanttocheckforlymphnodeenlargementwhendoingabreastexamasthisisoneofthemostcommonsitesofmetastasis.Infact,itisnecessaryforabreastcancertospreadtoatleastthesentinellymphnodeintheaxillabeforespreadinganywhereelsethroughthelymphaticroute.Post-mastectomylymphoedemaoccurswhentherehasbeentotalexcisionoftheaxillarylymphnodesthatoccurswithamastectomy.Becausethelymphaticdrainageiseffectivelycutoff,thereisnopressuregradientforthelymphtodrainsothefluidremainsintheinterstitium.Thiswillgiveaseverenon-pittingoedemaintheaffectedlimb.

PhysiologyHaematopoeisisanditsregulation–23/3/16

1. DefinehaematopoeisisHaematopoeisisistheprocessinwhichbloodcellsareformedinthebodyfromstemcells.

2. ContrasthaematopoieticstemcellsandprogenitorcellsHaematopoieticstemcells(HSCs)havedifferentpropertiestoprogenitorcells.

Feature HSC ProgenitorcellHaematopoeiticcapacity(time)

Perpetual–canreconstituteandmaintainhaematopoeisisoveralongperiodoftime

Non-perpetual–cannotreconstituteandmainhaematopoesisoveralongperiodoftime

Proliferativecapacity Extensiveproliferativecapacity

Limitedproliferativecapacity

Self-renewal Canself-renew Limitedornoself-renewalcapacity

Pluripotency/unipotency Pluripotency–cangiverisetocellsofmanylineages(e.g.erythrocyte,granulocyte,Blymphocyte)

Multipotencyorunipotency–commitedtoalineage(e.g.lymphoid)

Activity Quiescent Activelycycling

3. DescribethesitesofhaemopoeisisbeforeandafterbirthBeforebirth Afterbirth4-5weeks:AortaGonadMesonephros(AGMregion)

Bonemarrow(pelvicbones,ribs,spine,skull,proximalpartofarmandlegbones)

4-6weeks:yolksac 6-22weeks:foetalliver 16weeks-9months:bonemarrow

4. Describeerythropoiesis,includingitsregulation,process,featuresandpurposeof

redbloodcells

Erythropoeisisistheprocessthroughwhichredcellsaregeneratedinthebonemarrow.RedcellsareessentialforcarryingoxygentotissuesonHb.Theyareverysimplecells.Theydonothavenucleiandthereforecannotdooxidativemetabolism,relyinginsteadonglycolysisandthepentosephosphateshunt.Theyaresusceptibletofreeradicalsastheydonothavethepathwaysusuallypresenttoremovefreeradicals.TheythereforerelyonthePPPtogenerateantioxidantsandifapersonhasG6PDdeficiencytheredcellsaremorelikelytolyseunderconditionsofstress,resultinginhyperbilirubinaemiaandjaundice.Erythropoeisisisregulatedbyerythropoietin,whichisreleasedfromthekidneywhenlowO2tensionissensedbytheproximaltubule.EpoisinternalisedbytheEporeceptor(aJAKcytokinereceptor)intothemarrowprogenitorcellsanderythroidprecursorswhereithasanumberofeffects,includingthedifferentiationofHSCsintopronormoblasts.ItdoesthisbyALAsynthetaseformation,adenylylcyclaseactivationandtransferrinreceptorsynthesis.Epoisthenbrokendownwithinthereceptorsothatthereceptorcanberecycled.ErythropoesisisalsoregulatedbyIL-3whichpromotesthegrowthandreproductionofallthedifferenttypesofcommittedstemcells.OtherregulatoryfactorsincludeIGF-1,IL-6,andglucocorticoids,allowingincreaseinproductionofredbloodcellsduringtimesofacuteorchronicstress.Thiscanbedonebyincreasingtheactivityofthecommittedprogenitorcellsorthroughproductionofmoreprogenitorcells.Theprocessoferythropoiesisisshowninthediagrambelow.Basically,itgoesfromproerythroblasttonormoblasttoreticulocytetoerythrocyte(blast->cyte)andtakesabout7days.RBCsthensurviveinthecirculationforaround120days.Theyarethenbrokendownbymacrophagesinthespleenwhentheybecomesenescent.

5. OutlinetheroleofJAK2inhaemopoeisisJAKisanintegralpartofacytokinereceptorthatsitsonthemembraneofmanycells,includingbonemarrowprogenitorcells.Whenthecytokine(e.g.Epo)bindstotheoutermembraneportionofthereceptor,thiscausesaconformationalchangeinthereceptorthatresultsinJAKphosphorylatingthecytoplasmicdomainofthereceptor.Whenthereceptorisphosphorylated,thisallowsthebindingofSTAT

Proerythroblast

Basophilicnormoblast

Polychromaticnormoblast

Orthochromaticnormoblast

Reticulocyte

Erythrocyte

Day115-20umBasophiliccytoplasm(polyribosomes)MitosisNucleuswithinnucleoliNoHb

Day214-17umMitosisBasophiliccytoplasmNucleolidisappearsDay310-15umPolychromasia(basophilicandeosinophilic)ChromatinlumpsHbappearsNucleuscondenses

Day47-10umPyknotic(shrunken)nucleusEosinophiliccytoplasmMitosesabsentExtrusionofnucleusHbismaximumDay5-77.3umEnterscirculationReticulumofbasophilicmaterialinthecytoplasm(clumpedribosomes,RER)

Day7-1207.2umHb

proteintothecytoplasmicdomain.OnceSTATproteinisbound,JAKphosphorylatestheSTATprotein,allowingtheproteinstoassociateintoadimertoenterthenucleusandregulategenetranscription.‘

6. OutlinethestructureofthehaemoglobinmoleculeHaemoglobinhas2alphaglobinchainsand2betaglobinchains,eachofwhichcarries1unitofheme.Eachunitofhemecarriesanironatom.Thehaemoglobinmoleculecanthereforecarry4O2.ItundergoesconformationchangewhenO2associatesordisassociates,resultingintheO2saturationcurve.

7. Describegranulopoeisis,includingitsregulation,process,featuresandpurposeofthewhitebloodcellsGranulopoiesisistheprocessbywhichgranulocytesareformedfromthemyeloidstemcell.Granulocytesincludeneutrophils,monocytes,eosinophilsandbasophils.Thesecellshavedifferentfeatures(staindifferently,differentnuclei)androleswithintheimmunesystemincludingphagocytosisreleaseofgranulesandchromatinswhenneutrophilslysetoformanextracellularfibrilmatrixasaphysicalbarriertostoppathogenspread.Phagocytosiscanbedonebydirectlybindingthebacterium,bindingthebacterium+C3bontheC3breceptor,bindingofthebacterium+antibody+C3bontotheirC3breceptorandFcreceptor.Theyreachsitesofinflammation,tissuedamageandimmunereactionsbytheprocessofchemotaxis,wheretheyfollowsignalssuchasC5atocrosstheendotheliumandbasementmembraneofthecapillarybloodvesseltoreachtissue.GranulopoeisisisregulatedbyGCSF(granulocytecolonystimulatingfactor)whichisproducedbytheendothelium,macrophagesandotherimmunecellsfromageneonchromosome17.ItbindstoGCSFreceptorsonmyeloidprogenitorswhereitistheninternalised.GCSFisusedinthebasalproductionofgranulocytes.AnotherimportantregulatorisIL6whichissecretedbymonocytesandfibroblastsduringacutestress(e.g.infection).IL6isusedintheemergencyproductionofgranulocytes.Thefollowingdiagramdescribesthestagesofgranulopoeisis.Theprocesstakesover14days.

Myeloblast

Promyelocyte

Myelocyte

Metamyelocyte

Bandcell

Granulocyte

CommittedcellDiameter14-18nmOvalnucleuswithmultiplenucleoliNogranules

18-30umOvalnucleusCondensedchromatinPurple-stainingnonspecificazurophilicgranules

12-15umPresenceofsmallerspecificorsecondarygranulesCytoplasmbecomeslessbasophilic

12-15umNomoregranuleproductionReducedcellsizeNucleusbecomesflattenedChromatincondensation

Nucleushorse-shoeshapedCellsizedecreases

NucleussegmentedintolobesCellsizedecreasesEntersthebloodstream