The ?Developmental Origin of Health and Disease? hypothesis posits that susceptibility to a number of non- communicable diseases can be influenced by in utero exposures (nutritional, environmental, inflammatory). Whilethishypothesisisincreasinglyaccepted,particularlyfordiseaseswithanimmuneetiology(i.e.allergic, autoimmune),themechanismsinvolvedremainunresolved.Amajorknowledgegapthatlimitsprogressinthis areaistheremainingpaucityofinformationregardingthe?normal?immuneprocessesthatoccurduringcritical pre-andperinatalperiods,andhowthisdevelopmentmaybeinfluencedbyfetalexposures.Onefetalexposure witharepeatedandrobustimpactonlong-termhealthisinflammationoftheplacenta?termedchorioamnionitis (chorio),which,inseverecases,leadstoinflammationoffetalmembranesandincreasedlevelsofinflammatory mediatorsinboththeamnioticfluidandtheneonates?cordbloods.Ourpreliminarydatashowinhumaninfants thatexposuretoseverechorio(1)isassociatedwithrespiratorymorbidityduringearlyinfancy,and(2)leadsto increasedlevelsoftheTh17-associatedtranscriptionfactorRORCinthecirculationinthefirstmonthoflife.To getdeeperinsightsintotheunderlyingmechanisms,wehavedevelopedanexperimentalmodelofchoriointhe Rhesus macaque, which presents with very high level of similarities with human chorio. Intra-amniotic (IA) injectionofLPSintopregnantanimalsleadstomassiveneutrophilicinfiltrationandup-regulationofinflammatory cytokinesinthechorio-decidua,andsignificantchangesinthefetalimmunesystem,including(1)severelung inflammation;?(2)alterationoftheregulatoryTcell(Treg)/Th17balanceinthespleen,withtheincreasedaccrual of ?inflammatory Tregs?;? and (3) increased proportion of activated type 3 innate lymphoid cells (ILC3) in the mucosalareas.LPS-inducedfetalinflammationwaslargelydrivenbyIL-1-dependentmechanisms. Thesedataleadustohypothesizethatexposuretochorioinducesalterationsofthefetalsystemicandmucosal immunesystem,notablythroughalterationsofTregsandILCs,thatpredisposetopost-nataldiseases,including respiratoryproblems.Wewill(1)analyzeindepththeaccrualoffetalinflammatoryTregsinthecontextofchorio, usingsinglecellRNAseq,methylationprofilinganduniquefunctionalassays;?(2)analyzehowfetalinflammation directs the ontogeny and functional development of ILC3 through detailed phenotyping of ILC and their progenitorsforhoming/adhesionmolecules,analysisofthetranscriptomeoffetalNHPILCbyscRNAseq,and the use of unique ILC3 functional assays we have developed;? and 3) determine how fetal inflammation longitudinallyimpactsaccumulationofinflammatoryTregsorILC3precursordevelopment,andneonatalimmune function,bymonitoringcontrolandchorio-exposedneonatesfrombirthto4monthsofage,characterizing1)the normalcourseofrecruitmentofinflammatoryTregsandILC3invariouscompartments,and2)immuneresponses tocommonneonatalvaccinesandenvironmentalallergens.
Susceptibility to a number of non-communicable diseases are influenced by in utero exposures (nutritional, environmental,inflammatory).However,themechanismsinvolvedremainunresolved.Amajorknowledgegap thatlimitsprogressinthisareaistheremainingpaucityofinformationregardingthe?normal?immuneprocesses that occur during critical pre- and perinatal periods, and how this development may be influenced by fetal exposures. Ourdatashowthatinuteroplacentalinflammationaltersthefetalimmunesystem,whichcouldpredisposeto post-natal diseases, including respiratory problems. We will use the experimental model of pregnant rhesus macaquetostudytheunderlyingmechanisms,aswellastodeterminehowfetalinflammationimpactsneonatal immuneresponsesafterbirth.
| Chougnet, Claire A (2018) Human fetal immune cells fight back. Sci Transl Med 10: |
| Kleinman, Adam J; Sivanandham, Ranjit; Pandrea, Ivona et al. (2018) Regulatory T Cells As Potential Targets for HIV Cure Research. Front Immunol 9:734 |
