title: Genetic elimination of α3(IV) collagen fails to rescue anti-collagen B cells.
abstract: Organ deposition of autoantibodies against the noncollagenous-1 domain of the α3 chain of type IV collagen leads to severe kidney and lung injury in anti-glomerular basement membrane disease. The origin and regulation of these highly pathogenic autoantibodies remains unknown. Anti-α3(IV) collagen B lymphocytes are predicted to mature in vivo ignorant of target antigen because α3(IV) collagen expression is highly tissue restricted and pathogenic epitopes are cryptic. However, a recent analysis of an anti-α3(IV)NC1 collagen autoantibody transgenic mouse model revealed that developing B cells are rapidly silenced by deletion and editing in the bone marrow. To dissect the role of collagen as central tolerogen in this model, we determined B cell fate in autoantibody transgenic mice genetically lacking α3(IV) collagen. We found that absence of the tissue target autoantigen has little impact on the fate of anti-α3(IV)NC1 B cells. This implies a more complex regulatory mechanism for preventing anti-glomerular basement membrane disease than has been previously considered, including the possibility that a second antigen present in bone marrow engages and tolerizes anti-α3(IV)NC1 collagen B cells.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. amy.clark@duke.edu
authors.forename: Amy G
authors.initials: AG
authors.lastname: Clark
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Mackin
authors.forename: Mary H
authors.initials: MH
authors.lastname: Foster
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D017637:Clonal Deletion / Q000502:physiology*; D024141:Collagen Type IV / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D017634:Self Tolerance / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D000939:Epitopes