TY - JOUR
T1 - Generalized resistance to thymic deletion in the NOD mouse
T2 - A polygenic trait characterized by defective induction of Bim
AU - Liston, Adrian
AU - Lesage, Sylvie
AU - Gray, Daniel H.D.
AU - O'Reilly, Lorraine A.
AU - Strasser, Andreas
AU - Fahrer, Aude M.
AU - Boyd, Richard L.
AU - Wilson, Judith
AU - Baxter, Alan G.
AU - Gallo, Elena M.
AU - Crabtree, Gerald R.
AU - Peng, Kaiman
AU - Wilson, Susan R.
AU - Goodnow, Christopher C.
N1 - Funding Information:
We thank M. Jordan for advice; G. Hoyne and O. Siggs for critically reading this manuscript; L. Wicker, E. Unanue, and D. Peterson for generous gifts of mice and antibody; D. Buckle and D. Howard for microsatellite analysis; G. Osborne and S. Gruninger for FACS expertise; H. Wilson for assistance with Affymetrix hybridisation; K. Sullivan, R. Gambell, and the staff of Australian Phenomics Facility for curating the mouse colony; and K. Pulsford, D. Howard, and S. Ewing for genotyping. We also thank D. Huang (Walter and Eliza Hall Institute) for assistance in raising the anti-Bim mAb. This work was supported by grants from the National Health and Medical Research Council (NHMRC) and the Juvenile Diabetes Research Foundation. L.A.O. is a recipient of the R.D. Wright Biomedical Career Development Award (NHMRC).
PY - 2004/12
Y1 - 2004/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.immuni.2004.10.014
DO - 10.1016/j.immuni.2004.10.014
M3 - Article
C2 - 15589170
AN - SCOPUS:10344231974
SN - 1074-7613
VL - 21
SP - 817
EP - 830
JO - Immunity
JF - Immunity
IS - 6
ER -