Autoimmunity, apoptosis defects and retroviruses

Academic Article

Abstract

  • Autoimmune disease in both mice and humans is associated with increased expression of endogenous retroviruses in the thymus and T cells, and loss of self-tolerance by T cells. The basic genetic defect underlying autoimmune disease has been identified as a mutation of the Fas apoptosis antigen in MRL-lpr/lpr mice or a mutation of the Fas ligand in C3H-gld/gld mice. In MRL- lpr/lpr mice, the lpr mutation results from a 5.3 kb insertion of the ETn retrotransposon in the second intron of the Fas gene. In contrast to normal mice, which express a 2.2 kb normal size Fas cDNA, MRL-lpr/lpr mice express multiple Fas RNA transcripts ranging from 2-10.5 kb. In addition, a 5.7 kb full-length ETn transcript is highly expressed in the thymus of younger MRL- lpr/lpr mice. To determine if high ETn expression was dependent on abnormal Fas expression, CD2-fas transgenic mice were produced using the full-length murine Fas cDNA under the regulation of the CD2 promoter and enhancer. This resulted in normalization of Fas expression and also elimination of expression of the ETn retrotransposon. The ETn regulatory sequence contains potential DNA binding sites found in the enhancers of many genes activated during early T cell development in the thymus including enhancer regions for the TCR, CD3 and IL-2 genes. Therefore we propose that ETn expression is increased during early T cell development in the thymus, or after T cell activation, and that the integration of ETn in the Fas apoptosis gene leads to abnormal T cell apoptosis or development. Human autoimmune disease has also been found to result from production of a soluble inhibitor of apoptosis. The full-length cDNA and genomic clones for human Fas were cloned and sequenced. Patients with SLE produced high levels of an alternatively spliced soluble Fas (sFas) RNA lacking the transmembrane (exon 6) resulting in high circulating levels of the Fas molecule. This human sFas molecule was able to inhibit apoptosis in vitro at levels found in serum of SLE patients (200 ng/ml). The same levels of mouse sFas were able to inhibit apoptosis in vivo in mice resulting in a 3-fold increase in spleen size, and altered thymocyte maturation consisting of increased production of CD4-CD8- T cells and decreased CD4+CD8+ T cells. Regulation of Fas signaling in human T cells also plays a role in abnormal apoptosis. Fas signaling is mediated by the hematopoietic stem cell phosphatase, (Hcph) and is inhibited in the Hcph deficient Molt-4 T cell, the phosphatase deficient motheaten (me/me) mice and by the tyrosine phosphatase inhibitor pervanadate. Multiple pathways of Fas apoptosis were also shown to exist, as Fas induced apoptosis is increased in the liver of me/me mice, and signaling likely also involves an sphingomylinase-ceramide activated kinase pathway as utilized by the TNF-R. Fas ligand has been recently cloned in mice and humans, and is homologous to TNF-α. The Fas ligand defect in autoimmune C3H-gld/gld mice is due to a point mutation resulting in a single amino acid change in the hydrophobic region of the Fas ligand trimer. These results indicate that T cell apoptosis can be dramatically increased or decreased by cellular interactions which in turn regulate either the levels of production or signaling activity of the Fas and Fas ligand. Retroviruses and their products can influence apoptosis by altering expression of Fas or Fas-L, or altering apoptotic signaling after Fas/Fas-L interactions. Further insights into the regulation of apoptosis molecules will be important in normalizing this activity when it is decreased as in the case of autoimmune disease, or when it is in excess, as is the case with HIV disease.
  • Author List

  • Mountz JD; Cheng J; Su X; Wu J; Zhou T
  • Start Page

  • 183
  • End Page

  • 201
  • Volume

  • 374