Generalized resistance to thymic deletion in the NOD mouse: A polygenic trait characterized by defective induction of Bim

Adrian Liston, Sylvie Lesage, Daniel H.D. Gray, Lorraine A. O'Reilly, Andreas Strasser, Aude M. Fahrer, Richard L. Boyd, Judith Wilson, Alan G. Baxter, Elena M. Gallo, Gerald R. Crabtree, Kaiman Peng, Susan R. Wilson, Christopher C. Goodnow

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)817-830
Number of pages14
JournalImmunity
Volume21
Issue number6
DOIs
StatePublished - Dec 2004
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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