Lymphotoxin pathway-directed, autoimmune regulator-independent central tolerance to arthritogenic collagen.
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.
Chin
Robert K
RK
Department of Pathology and Committee in Immunology, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Zhu
Mingzhao
M
Christiansen
Peter A
PA
Liu
Wenhua
W
Ware
Carl
C
Peltonen
Leena
L
Zhang
Xuejun
X
Guo
Linjie
L
Han
Shuhua
S
Zheng
Biao
B
Fu
Yang-Xin
YX
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
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