Ectopic Lymphoid Structures Support Ongoing Production of Class-Switched Autoantibodies in Rheumatoid Synovium 英文参考文献.docVIP

o PL SMEDICINE EctopicLymphoidStructuresSupportOngoing ProductionofClass-SwitchedAutoantibodiesin RheumatoidSynovium Frances Humby1[,Michele Bombardieri1[,Antonio Manzo1,Stephen Kelly1,Mark C.Blades1,Bruce Kirkham2, JoSpencer3,Costantino Pitzalis1* 1 William Harvey Research Institute, Barts and the London School of Medicine, Charterhouse Square, London, United Kingdom, 2 Department of Rheumatology, Kings College London, Guy’s Hospital, St ThomasStreet, London, United Kingdom, 3 Division of Infection,Immunity and InflammatoryDiseases, Kings College London, Guy’s Hospital,StThomasStreet,London,UnitedKingdom Funding:Thisworkwassupported bygrantsfromGuy’sandStThomas’ Charity(FH),theArthritisResearch Campaign(MB)andINNOCHEM (InnovativeChemokine-based ABSTRACT Background TherapeuticStrategiesforAuto- immunityandChronicinflammation) EUFrameworkProgramme6(AM). Fundersdidnothaveanyrolein studydesign,datacollectionand analysis,decisiontopublishorinthe preparationofthemanuscript. Follicular structures resembling germinal centres (GCs) that are characterized by follicular dendritic cell (FDC) networks have long been recognized in chronically inflamed tissues in autoimmune diseases, including the synovium of rheumatoid arthritis (RA). However, it is debated whether these ectopic structures promote autoimmunity and chronic inflammation driving the production of pathogenic autoantibodies. Anti-citrullinated protein/peptide antibodies(ACPA)arehighlyspecificmarkersofRA,predictapoorprognosis,andhavebeen suggestedtobepathogenic.Therefore,themainstudyobjectivesweretodeterminewhether ectopiclymphoidstructuresinRAsynovium:(i)expressactivation-inducedcytidinedeaminase (AID),theenzymerequiredforsomatichypermutationandclass-switchrecombination(CSR)of Iggenes;(ii)supportongoingCSRandACPAproduction;and(iii)remainfunctionalinaRA/ severecombinedimmunodeficiency(SCID)chimeramodeldevoidofnewimmunecellinflux intothesynovium. CompetingInterests:Theauthors havedeclaredthatnocompeting interestsex