Generalized resistance to thymic deletion in the NOD mouse; a polygenic trait characterized by defective induction of Bim.
The cause of common polygenic autoimmune diseases is not understood because of genetic and cellular complexity. Here, we pinpoint the action of a subset of autoimmune susceptibility loci in the NOD mouse strain linked to D1mit181, D2mit490, D7mit101, and D15mit229, which cause a generalized resistance to thymic deletion in vivo that applies equally to Aire-induced organ-specific gene products in the thymic medulla and to systemic antigens expressed at high levels throughout the thymus and affects CD4(+), CD4(+)8(+), and CD4(+)25(+) thymocytes. Resistance to thymic deletion does not reflect a general deficit in TCR signaling to calcineurin- or ERK-induced genes, imbalance in constitutive regulators of apoptosis, nor excessive signaling to prosurvival genes but is distinguished by failure to induce the proapoptotic gene and protein, Bim, during in vivo encounter with high-avidity autoantigen. These findings establish defects in thymic deletion and Bim induction as a key mechanism in the pathogenesis of autoimmunity.
Liston
Adrian
A
Immunogenomics Laboratory, John Curtin School of Medical Research and The Australian Phenomics Facility, The Australian National University, Canberra, 2601, Australia.
Lesage
Sylvie
S
Gray
Daniel H D
DH
O'Reilly
Lorraine A
LA
Strasser
Andreas
A
Fahrer
Aude M
AM
Boyd
Richard L
RL
Wilson
Judith
J
Baxter
Alan G
AG
Gallo
Elena M
EM
Crabtree
Gerald R
GR
Peng
Kaiman
K
Wilson
Susan R
SR
Goodnow
Christopher C
CC
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D015704:CD4 Antigens / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D020412:Multifactorial Inheritance / Q000235:genetics*; D040081:Protein Array Analysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000002:abnormalities / Q000276:immunology* / Q000473:pathology*
D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D015704:CD4 Antigens; D002352:Carrier Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D015375:Receptors, Interleukin-2