title: Lymphotoxin pathway-directed, autoimmune regulator-independent central tolerance to arthritogenic collagen.
abstract: Ectopic expression of peripherally restricted Ags by medullary thymic epithelial cells (mTECs) is associated with negative selection. Autoimmune regulator (AIRE) is considered to be the master regulator of these Ags. We show in this study that the ectopic expression of type II collagen (CII) in mTECs and the corresponding central tolerance to CII are AIRE independent but lymphotoxin dependent. The failure to properly express CII in mTECs of Lta(-/-) and Ltbr(-/-) mice leads to overt autoimmunity to CII and exquisite susceptibility to arthritis. These findings define the existence of additional pathways of ectopic peripheral Ag expression, parallel to and independent of AIRE, which may cover an extended spectrum of peripheral Ags in the thymus.
authors.affiliation: Department of Pathology and Committee in Immunology, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Chin
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Zhu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Christiansen
authors.forename: Wenhua
authors.initials: W
authors.lastname: Liu
authors.forename: Carl
authors.initials: C
authors.lastname: Ware
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.forename: Linjie
authors.initials: L
authors.lastname: Guo
authors.forename: Shuhua
authors.initials: S
authors.lastname: Han
authors.forename: Biao
authors.initials: B
authors.lastname: Zheng
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D024043:Collagen Type II; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C505887:Ltb protein, mouse