Vaccine25(2007)5467–5484ReviewInductionofsecretoryimmunityandmemoryatmucosalsurfacesPerBrandtzaeg∗LaboratoryforImmunohistochemistryandImmunopathology(LIIPAT),InstituteandDepartmentofPathology,UniversityofOslo,Rikshospitalet-RadiumhospitaletMedicalCentre,N-0027Oslo,NorwayReceived28August2006;receivedinrevisedform8November2006;accepted1December2006Availableonline15December2006AbstractMucosalepitheliacompriseanextensivevulnerablebarrierwhichisreinforcedbynumerousinnatedefencemechanismscooperatingintimatelywithadaptiveimmunity.LocalgenerationofsecretoryIgA(SIgA)constitutesthelargesthumoralimmunesystemofthebody.Secretoryantibodiesfunctionbothbyperformingantigenexclusionatmucosalsurfacesandbyvirusandendotoxinneutralizationwithinepithelialcellswithoutcausingtissuedamage.SIgAisthuspersistentlycontainingcommensalbacteriaoutsidetheepithelialbarrierbutcanalsotargetinvasionofpathogensandpenetrationofharmfulantigens.Resistancetotoxin-producingbacteriasuchasVibriocholeraeandenterotoxigenicEscherichiacoliappearstodependlargelyonSIgA,andsodoesherdprotectionagainsthorizontalfaecal–oralspreadofentericpathogensunderna¨ıveorimmunizedconditions—withasubstantialinnateimpactbothoncross-reactivityandmemory.Likenaturalinfections,livemucosalvaccinesoradequatecombinationsofnon-replicatingvaccinesandmucosaladjuvants,giverisenotonlytoSIgAantibodiesbutalsotolongstandingserumIgGandIgAresponses.However,thereisconsiderablydisparitywithregardtomigrationofmemory/effectorcellsfrommucosalinductivesitestosecretoryeffectorsitesandsystemicimmuneorgans.Also,althoughimmunologicalmemoryisgeneratedaftermucosalpriming,thismaybemaskedbyaself-limitingresponseprotectingtheinductivelymphoidtissueinthegut.Theintranasalrouteofvaccineapplicationtargetingnasopharynx-associatedlymphoidtissuemaybemoreadvantageousforcertaininfections,butonlyifsuccessfulstimulationisachievedwithouttheuseoftoxicadjuvantsthatmightreachthecentralnervoussystem.Thedegreeofprotectionobtainedaftermucosalvaccinationrangesfromreductionofsymptomstocompleteinhibitionofre-infection.Inthisscenario,itisoftendifficulttodeterminetherelativeimportanceofSIgAversusserumantibodies,butinfectionmodelsinknockoutmicestronglysupportthenotionthatSIgAexertsadecisiveroleinprotectionandcross-protectionagainstavarietyofinfectiousagents.Nevertheless,relativelyfewmucosalvaccineshavebeenapprovedforhumanuse,andmorebasicworkisneededinvaccineandadjuvantdesign,includingparticulateorlive-vectoredcombinations.©2006ElsevierLtd.Allrightsreserved.Keywords:ImmunoglobulinA(IgA);PolymericIgreceptor;Secretorycomponent;SecretoryIgA;SecretoryIgM;IgG;Mucosalimmunity;Secretoryimmunity;Immuneexclusion;Mucosalvaccines;MALT;GALT;NALT;BALT;Gutmucosa;NasalmucosaContents1.Introduction.......................................................................................................54682.Secretoryimmunity................................................................................................54683.Stimulationofmucosalimmunity...................................................................................54693.1.Immune-inductivelymphoepithelialtissue.....................................................................54693.2.PrimingofmucosalBandTcells.............................................................................54693.3.DisperatemicrobialactivationofmucosalBcells.....
