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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041570-14
Application #
8465786
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Nasseri, M Faraz
Project Start
1997-09-30
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
14
Fiscal Year
2013
Total Cost
$359,444
Indirect Cost
$126,794
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Knittel, Gero; Metzner, Mirjam; Beck-Engeser, Gabriele et al. (2014) Insertional hypermutation in mineral oil-induced plasmacytomas. Eur J Immunol 44:2785-801
Hartzell, Catherine; Ksionda, Olga; Lemmens, Ed et al. (2013) Dysregulated RasGRP1 responds to cytokine receptor input in T cell leukemogenesis. Sci Signal 6:ra21
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
Pyrz, Magdalena; Wang, Bruce; Wabl, Matthias et al. (2010) A retroviral mutagenesis screen identifies Cd74 as a common insertion site in murine B-lymphomas and reveals the existence of a novel IFNgamma-inducible Cd74 isoform. Mol Cancer 9:86
Lum, Amy M; Wang, Bruce B; Beck-Engeser, Gabriele B et al. (2010) Orphan receptor GPR110, an oncogene overexpressed in lung and prostate cancer. BMC Cancer 10:40
Metzner, Mirjam; Schuh, Wolfgang; Roth, Edith et al. (2010) Two forms of activation-induced cytidine deaminase differing in their ability to bind agarose. PLoS One 5:e8883
Liao, Jia-Jun; Huang, Mei-Chuan; Fast, Katharine et al. (2009) Immunosuppressive human anti-lymphocyte autoantibodies specific for the type 1 sphingosine 1-phosphate receptor. FASEB J 23:1786-96
Nielsen, Anne Ahlmann; Kjartansdottir, Kristin Ros; Rasmussen, Mads Heilskov et al. (2009) Activation of the brain-specific neurogranin gene in murine T-cell lymphomas by proviral insertional mutagenesis. Gene 442:55-62
Beck-Engeser, Gabriele B; Eilat, Dan; Harrer, Thomas et al. (2009) Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir. Proc Natl Acad Sci U S A 106:20865-70

Showing the most recent 10 out of 22 publications