Transplantation of autoimmune regulator-encoding bone marrow cells delays the onset of experimental autoimmune encephalomyelitis.
The autoimmune regulator (AIRE) promotes "promiscuous" expression of tissue-restricted antigens (TRA) in thymic medullary epithelial cells to facilitate thymic deletion of autoreactive T-cells. Here, we show that AIRE-deficient mice showed an earlier development of myelin oligonucleotide glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). To determine the outcome of ectopic Aire expression, we used a retroviral transduction system to over-express Aire in vitro, in cell lines and in bone marrow (BM). In the cell lines that included those of thymic medullary and dendritic cell origin, ectopically expressed Aire variably promoted expression of TRA including Mog and Ins2 (proII) autoantigens associated, respectively, with the autoimmune diseases multiple sclerosis and type 1 diabetes. BM chimeras generated from BM transduced with a retrovirus encoding Aire displayed elevated levels of Mog and Ins2 expression in thymus and spleen. Following induction of EAE with MOG(35-55), transplanted mice displayed significant delay in the onset of EAE compared with control mice. To our knowledge, this is the first example showing that in vivo ectopic expression of AIRE can modulate TRA expression and alter autoimmune disease development.
Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Hyun-Ja
HJ
Ko
Sarah A
SA
Kinkel
François-Xavier
FX
Hubert
Zeyad
Z
Nasa
James
J
Chan
Christopher
C
Siatskas
Premila
P
Hirubalan
Ban-Hock
BH
Toh
Hamish S
HS
Scott
Frank
F
Alderuccio
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001324:Autoantigens / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002460:Cell Line; D003001:Cloning, Molecular; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D013950:Thymus Gland / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D000096927:AIRE Protein
D001324:Autoantigens; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D014157:Transcription Factors; D000096927:AIRE Protein; C445081:myelin oligodendrocyte glycoprotein (35-55)