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Immunopathogenesis of spontaneous murine models of SLE: genetic, cellular and molecular analysis

English title Immunopathogenesis of spontaneous murine models of SLE: genetic, cellular and molecular analysis
Applicant Izui Shozo
Number 105872
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.10.2004 - 30.09.2009
Approved amount 798'334.00
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Keywords (6)

Autoimmune disease; Systemic lupus erythematosus; Autoimmune hemolytic anemia; the Yaa mutation; Serum retroviral gp70 autoantigen; IgG Fc receptor

Lay Summary (English)

Lead
Lay summary
The pathogenesis of systemic lupus erythematosus (SLE) is a complex process in which many genetic factors play essential roles. Although considerable progress has been made in the past, further identification of the genetic defects predisposing to SLE is important for the understanding of the pathogenesis and for the development of more targeted treatments of this disease.A unique mutation has been described in a lupus-prone strain of mice, BXSB. Since this mutant gene is located on the Y chromosome, and is able to dramatically accelerate the progression of SLE in mice, it is called Yaa (Y-linked autoimmune acceleration). The Yaa mutation was recently identified to be a translocation from the end of the X chromosome onto the Y chromosome. Since this region of the X chromosome contains the gene encoding Toll-like receptor 7 (TLR7), which may play an important role in the development of autoimmune responses against nuclear and retroviral autoantigens characteristics in SLE, we will determine whether TLR7 gene duplication is the cause of the Yaa defect by assessing the development of SLE in TLR7-deficient lupus-prone mice bearing the Yaa mutation.The pathogenic role of the surface glycoprotein gp70, one of the gene products of endogenous retroviruses (i.e. a family of RNA viruses integrated into the host’s DNA) in mouse SLE has been well established. Therefore, it is extremely important to determine whether endogenous retroviruses are also implicated in human SLE. However, the search for the presence of serum retroviral gp70 in human SLE has, until recently, not been successful. One likely explanation for this failure was the lack of appropriate antibodies to detect specifically retroviral gp70 antigens implicated in human SLE. This is the reason why we developed an antibody specific for mouse serum retroviral gp70, which also recognizes a serum glycoprotein in humans and stains immune deposits accumulated in glomerular lesions of SLE patients’ kidneys. This strongly argues in favor of a possible role of endogenous retroviral gp70 antigens in human SLE, which we wish to investigate further.In view of a potential role of endogenous retroviruses in human SLE, a complete understanding of the role of retroviruses in mouse SLE is important. Therefore, we will address two additional questions: 1) how does endogenous retroviral gp70 become particularly immunogenic to stimulate the production of anti-gp70 autoantibodies? and 2) do endogenous retroviruses act as a potential triggering factor leading to immune dysregulation and hence to the development of autoimmune responses in SLE?The results obtained from the proposed project should facilitate the elucidation of the molecular nature of the Yaa mutation and elucidate how and to which extent endogenous retroviruses and their gene products are involved in the pathogenesis of SLE. Clearly, such knowledge will help identify target molecules critically involved in the development of SLE, and hence contribute to the development of novel diagnostic, prognostic and therapeutic strategies in human SLE.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
127644 Immunopathogenesis of spontaneous murine models of SLE: genetic, cellular and molecular analysis 01.10.2009 Project funding
128666 Gamma Irradiator for Research in Immunology, Infectious Diseases, Stem Cell Biology, and Neurobiology 01.12.2009 R'EQUIP
65274 Immunopathogenesis of spontaneous models of SLE: genetic, cellular and molecular analysis 01.10.2001 Project funding

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