Systemiclupuserythematosus(SLE),theprototypicsystemicautoimmunedisease,ischaracterizedby immunesystemhyperactivation,autoantibodyproduction,andmultiorganinflammation.Althoughgenetic predispositioniscriticalfordiseaseexpression,thelowconcordancerateinmonozygotictwins(<40%) suggeststheessentialcontributionofadditionalfactors,mostlyprovidedthroughenvironmentalexposures. Indeed,significantepidemiologicalevidencehaslinkedSLEandothersystemicautoimmunediseaseto crystallinesilicaexposurebutalsotocertainviralinfections.Consideringthecriticalroleofinnateimmune activationinsystemicautoimmunity,wehypothesizedthatsilicainhalation,virusinfection,andgenetic predisposingfactorssynergizebyactivatingdistinctinnateimmunostimulatorypathways,thattogetherleadto moreefficientbreakoftolerance,earlierdiseaseonset,andmoresevereautoimmunemanifestations.In supportofthishypothesis,weprovidepreliminaryevidencethatsilicaandvirusexposuresmoreeffectively induceautoimmunemanifestationsinmousemodelsoflupuswhengivenincombinationthanwhengiven individually.Herewewillusethisexperimentalsystemtodefinethemechanisticbasisoftheinterplay betweenvirusinfectionandsilica,includingthetemporalrequirementsofsilicaexposureandvirusinfection, thecontributionofinnateinflammatorypathwaysdifferentiallyinducedbysilicaandvirus,androlesofthese factorsinbreakingimmunologicaltolerance.
Significantevidenceindicatesthatenvironmentalexposures,mostnotablycrystallinesilicainhalationand virusinfections,contributetothepathogenesisoflupusandothersystemicautoimmune.Herewepropose thatsilica,viruses,andgeneticfactorssynergizebyactivatingdistinctinnateimmunepathwaysthattogether leadtomoreeffectivebreakoftolerance,earlierdiseaseonset,andenhancedseverity.Themechanistic basisofthesesynergisticeffectswillbeinvestigatedusingwell-characterizedmousemodels,including relevantgene-deletedandtransgenicstrains.
