Bullouspemphigoidisanautoimmunedisordercharacterizedbytheemergenceoflarge,fluid-filled blistersontheskinofaffectedpatients.ItiscausedbypathogenicantibodiesthattargetBP180,acomponent ofthehemidesmosomesthatattachbasalkeratinocytestothebasementmembraneoftheepidermis.The antibodiespromoteinflammationandneutrophilrecruitment,leadingtothedestructionofhemidesmosomes andseparationoftheepidermisfromthedermis.Bullouspemphigoidisthemostcommonblistering autoimmunedisorderoftheskin,and10.8%ofpatientsintheUnitedStatesdiewithinoneyearofdiagnosis. Eveninpatientssuccessfullytreatedforbullouspemphigoid,recurrenceiscommon.Thus,noveltherapeutics tobettertreatandpreventrecurrenceofbullouspemphigoidareneeded. OurpreliminarydatashowsthattheNLRP3inflammasomepathwayanditsendproduct,the inflammatorycytokineIL-1b?,arerequiredforneutrophilrecruitmentandblisterformationinawell-established mousemodelofbullouspemphigoid.Similarly,weobservedthatmicedeficientinthekeratinocyte-specific proteingasderminAhadsignificantlylowerlevelsofIL-1b?withintheskinandwereresistanttoblister formation.GasderminAisamemberofafamilyofproteinsthatincludesgasderminD,whichwasrecently showntomediateIL-1b?releaseandlyticcelldeathdownstreamofinflammasomeactivationinimmunecells. Therefore,wehypothesizethatgasderminAsimilarlyactsdownstreamofinflammasomeactivationwithin keratinocytestopromoteinflammationoftheskinandbullouspemphigoidpathology.
In AIM1, wewilldetermineinwhichcelltypestheNLRP3inflammasomeisactivatedinthemouse modelofbullouspemphigoidusingbonemarrowtransplantsandcelltype-specificIL-1b?knockouts,andwewill assesstheroleofterminalcomponentsofcomplementinactivatingNLRP3usingmicedeficientinmembrane attackporeformation.
In AIM2, wewillcomparetheroleandactivationmechanismofgasderminAand gasderminDinthemousemodelofbullouspemphigoidusingmicedeficientingasderminAandgasderminD intheinvivomodelofbullouspemphigoid,andbyreconstitutinggasderminactivationpathwaysinvitro. Thisgrantissignificantbecauseitwillprovidefoundationalknowledgethatmayaidinthedevelopment ofnoveltherapeuticsthattargetinflammasomesandgasderminstotreatbullouspemphigoid.Furthermore, thisgrantwillmorebroadlyprovideinsightsintothefunctionsofkeratinocytesasactiveparticipantsofinnate immunityandgasderminsasmediatorsofinflammationintheskin.Notably,toourknowledge,thiswouldbe thefirstin-depthcharacterizationofgasderminAasamediatorofskininflammation.Thus,insightsgained fromthisgrantmayimproveourunderstandingofthepathogenesisofbullouspemphigoidandother inflammatoryconditionsoftheskinaswellasourunderstandingofhowtheskinprotectsagainstinfection.

Public Health Relevance

Bullouspemphigoidisthemostcommonblisteringautoimmunediseaseoftheskin.Thisgrantwillcharacterize theroleofinflammasomesandgasdermins,includingthepreviouslyuncharacterizedproteingasderminA,in promotingthedevelopmentofbullouspemphigoid.Knowledgegainedfromthisgrantwillprovideinsightsinto mechanismsdrivinginflammationwithintheskinandmayaidinthefuturedevelopmentofnoveltherapeutics totreatbullouspemphigoid.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AI142990-03
Application #
10090561
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2019-01-24
Project End
2022-01-23
Budget Start
2021-01-24
Budget End
2022-01-23
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599