Autoinnnune disease in mice due to integration of an endogenous retrovirus in an apoptosis gene

Academic Article

Abstract

  • The MRL-lpr/lpr mouse strain is a model of systemic autoimmune disease. In this model, intrinsic defects of intrathymic T cell development include defective deletion of self-reactive T cells and expression of endogenous retroviruses. Defective deletion of self-reactive T cells in the thymus has been proposed to be due to a germline mutation in the Fas apoptosis gene. Using different fragments of a Fas cDNA probe, we determined that the lpr/lpr mutation is a 5.3-kb insertion of DNA within the second intron of the Fas gene. cDNA corresponding to this region was then derived from thymic RNA from MRL-lpr/lpr and MRL- +/+ mice using the polymerase chain reaction. All thymic KNA samples from MRL-lpr/lpr mice yielded a unique product that was 168 bp larger than that of MRL- +/+ mice. Complete sequence analysis indicated that this inserted sequence had 98% homology with a sequence from the 3’ long terminal repeat of the early transposon (Egh). RNA analysis indicated higher expression of ETn RNA in the thymus of MRL-lpr/lpr than MRL- +/+ mice. The interdependence of ETn expression and abnormal Fas expression was then analyzed in a CD2-Fas transgenic mouse model in which a full-length murine Fas cDNA under the regulation of the CD2 promoter and enhancer was used to correct defective Fas expression in T cells of MRL-lpr/lpr mice. In these mice, reduced thymic ETn expression was observed, confirming that high ETn expression is rdated to abnormal Fas expression. These results establish a link between endogenous retrovirus expression, abnormal Fas expression, and autoimmune disease. © 1993, Rockefeller University Press., All rights reserved.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Wu J; Zhou T; He J; Mountz JD
  • Start Page

  • 461
  • End Page

  • 468
  • Volume

  • 178
  • Issue

  • 2