Gene targeted mice with a simpler immune system. This grant application proposes to investigate the influence of endogenous retroelements on autoimmune disease. Almost half of our genome consists of retroelements-many of them active. We have three lines of evidence for our hypothesis that retroelements can mediate autoimmune disease: (i) The enzyme Trex1 degrades retroelements, and Trex1-deficient patients and mice suffer from autoimmune disease. (ii) Similarly, an integrase inhibitor that accumulates endogenous retroelement cDNA exacerbates lupus and hemolytic anemia in mice. (iii) Apart from its function as a DNA mutator, AID inhibits LINE-1 elements, and AID-deficient patients develop a variety of autoimmune or inflammatory disorders. In this proposal, we will inhibit retroelement replication by transgenesis, and the mice carrying the transgenes ought to have no or ameliorated autoimmune disease.
Instead of dealing only with attacks from microbes from the outside world, the immune system may turn against the very body of which it is a part;when this happens, a so-called autoimmune disease may result. What triggers autoimmunity in the first place, however, has remained a mystery. Mice that accumulate parasite-like DNA, encoded by the body's own genome, in the heart muscle suffer from inflammation of the heart. In other mice, different parasitic elements may be responsible for hemolytic anemia or lupus. This proposal will test which of the many parasitic elements are responsible for autoimmune disease, and whether destroying these parasites as they are formed, or limiting their proliferation, will prevent the disease.
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| Beck-Engeser, Gabriele B; Winkelmann, Rebecca; Wheeler, Matthew L et al. (2015) APOBEC3 enzymes restrict marginal zone B cells. Eur J Immunol 45:695-704 |
| Knittel, Gero; Metzner, Mirjam; Beck-Engeser, Gabriele et al. (2014) Insertional hypermutation in mineral oil-induced plasmacytomas. Eur J Immunol 44:2785-801 |
| Sokol, Martin; Wabl, Matthias; Ruiz, Irene Rius et al. (2014) Novel principles of gamma-retroviral insertional transcription activation in murine leukemia virus-induced end-stage tumors. Retrovirology 11:36 |
| Dabrowska, Magdalena Julia; Ejegod, Ditte; Lassen, Louise Berkhoudt et al. (2013) Gene expression profiling of murine T-cell lymphoblastic lymphoma identifies deregulation of S-phase initiating genes. Leuk Res 37:1383-90 |
| Hartzell, Catherine; Ksionda, Olga; Lemmens, Ed et al. (2013) Dysregulated RasGRP1 responds to cytokine receptor input in T cell leukemogenesis. Sci Signal 6:ra21 |
| Chen, Haoyan; Hayashi, Genki; Lai, Olivia Y et al. (2012) Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease. PLoS Genet 8:e1002514 |
| Metzner, Mirjam; Jack, Hans-Martin; Wabl, Matthias (2012) LINE-1 retroelements complexed and inhibited by activation induced cytidine deaminase. PLoS One 7:e49358 |
| Eilat, Dan; Wabl, Matthias (2012) B cell tolerance and positive selection in lupus. J Immunol 189:503-9 |
| Lutz, Johannes; Heideman, Marinus R; Roth, Edith et al. (2011) Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production. Proc Natl Acad Sci U S A 108:10644-9 |
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