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

Applicant Izui Shozo
Number 127644
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 01.10.2009 - 31.03.2013
Approved amount 596'050.00
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Keywords (5)

Autoimmune disease; SLE; Endogenous retroviruses; Lupus suppressive gene; MHC class II molecules

Lay Summary (English)

Lead
Lay summary
The pathogenesis of 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.It has been shown that 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) plays a substantial role in mouse SLE, as documented by accumulation of immune complexes formed of gp70 and anti-gp70 autoantibodies in glomerular lesions of sickened kidneys. Our recent studies revealed a critical role of Toll-like receptor 7 (TLR7), which can be activated by endogenous retroviruses, in the development of autoimmune responses against retroviral gp70 as well as nuclear autoantigens, suggesting the potential causal role of endogenous retroviruses in mouse SLE. We will therefore investigate whether endogenous retroviruses can act as triggering factors for the development of SLE by generating lupus-prone mice deficient in a receptor specific for endogenous retroviruses.The involvement of endogenous retrovirus-related antigens has long been suspected in human SLE, too. Indeed, the presence of retroviral antigens in glomerular lesions of diseased kidneys from SLE patients was reported more than 30 years ago. However, the search for the presence of serum retroviral gp70 in human SLE has, until recently, not been successful. Therefore, using a newly developed monoclonal autoantibody specific for mouse serum retroviral gp70, which also recognizes a serum glycoprotein in humans and stains immune deposits in glomerular lesions of SLE patients' kidneys, we will explore the possible involvement of endogenous retroviral gp70 in human SLE. Our studies should elucidate how and to which extent endogenous retroviruses and their gene products contribute to the pathogenesis of SLE.In view of a critical role of TLR7 in the development of murine SLE, it is important to understand how the expression of TLR7 in immune cells is regulated. We have recently identified a novel locus which regulates the expression of TLR7 and hence the development of murine SLE. The elucidation of the molecular mechanism controlling the expression of TLR7 by this locus should help identify new target molecules central to the development of SLE, and hence contribute to the development of novel therapeutic strategies in human SLE.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Employees

Publications

Publication
Three Sgp loci act independently as well as synergistically to elevate the expression of specific endogenous retroviruses implicated in murine lupus.
Ito Kiyoaki, Baudino Lucie, Kihara Masao, Leroy Valérie, Vyse Timothy J, Evans Leonard H, Izui Shozo (2013), Three Sgp loci act independently as well as synergistically to elevate the expression of specific endogenous retroviruses implicated in murine lupus., in Journal of autoimmunity, 43, 10-7.
Sialylation determines the nephritogenicity of IgG3 cryoglobulins.
Otani Masako, Kuroki Aki, Kikuchi Shuichi, Kihara Masao, Nakata Junichiro, Ito Kiyoaki, Furukawa Jun-ichi, Shinohara Yasuro, Izui Shozo (2012), Sialylation determines the nephritogenicity of IgG3 cryoglobulins., in Journal of the American Society of Nephrology : JASN, 23(11), 1869-78.
Altered Ig levels and antibody responses in mice deficient for the Fc receptor for IgM (FcμR).
Honjo Kazuhito, Kubagawa Yoshiki, Jones Dewitt M, Dizon Brian, Zhu Zilu, Ohno Hiroshi, Izui Shozo, Kearney John F, Kubagawa Hiromi (2012), Altered Ig levels and antibody responses in mice deficient for the Fc receptor for IgM (FcμR)., in Proceedings of the National Academy of Sciences of the United States of America, 109(39), 15882-7.
Sgp3 and TLR7 stimulation differentially alter the expression profile of modified polytropic retroviruses implicated in murine systemic lupus.
Leroy Valérie, Kihara Masao, Baudino Lucie, Brighouse Guy, Evans Leonard H, Izui Shozo (2012), Sgp3 and TLR7 stimulation differentially alter the expression profile of modified polytropic retroviruses implicated in murine systemic lupus., in Journal of autoimmunity, 38(4), 361-8.
Presumptive role of 129 strain-derived Sle16 locus in rheumatoid arthritis in a new mouse model with Fcγ receptor type IIb-deficient C57BL/6 genetic background.
Sato-Hayashizaki Aya, Ohtsuji Mareki, Lin Qingshun, Hou Rong, Ohtsuji Naomi, Nishikawa Keiko, Tsurui Hiromichi, Sudo Katsuko, Ono Masao, Izui Shozo, Shirai Toshikazu, Takai Toshiyuki, Nishimura Hiroyuki, Hirose Sachiko (2011), Presumptive role of 129 strain-derived Sle16 locus in rheumatoid arthritis in a new mouse model with Fcγ receptor type IIb-deficient C57BL/6 genetic background., in Arthritis and rheumatism, 63(10), 2930-8.
Sgp3 and Sgp4 control expression of distinct and restricted sets of xenotropic retroviruses encoding serum gp70 implicated in murine lupus nephritis.
Kihara Masao, Leroy Valérie, Baudino Lucie, Evans Leonard H, Izui Shozo (2011), Sgp3 and Sgp4 control expression of distinct and restricted sets of xenotropic retroviruses encoding serum gp70 implicated in murine lupus nephritis., in Journal of autoimmunity, 37, 311.
The inhibiting Fc receptor for IgG, FcγRIIB, is a modifier of autoimmune susceptibility.
Boross Peter, Arandhara Victoria L, Martin-Ramirez Javier, Santiago-Raber Marie-Laure, Carlucci Francesco, Flierman Roelof, van der Kaa Jos, Breukel Cor, Claassens Jill W C, Camps Marcel, Lubberts Erik, Salvatori Daniela, Rastaldi Maria Pia, Ossendorp Ferry, Daha Mohamed R, Cook H Terence, Izui Shozo, Botto Marina, Verbeek J Sjef (2011), The inhibiting Fc receptor for IgG, FcγRIIB, is a modifier of autoimmune susceptibility., in Journal of immunology (Baltimore, Md. : 1950), 187(3), 1304-13.
TLR7/9-mediated monocytosis and maturation of Gr-1(hi) inflammatory monocytes towards Gr-1(lo) resting monocytes implicated in murine lupus.
Santiago-Raber Marie-Laure, Baudino Lucie, Alvarez Montserrat, van Rooijen Nico, Nimmerjahn Falk, Izui Shozo (2011), TLR7/9-mediated monocytosis and maturation of Gr-1(hi) inflammatory monocytes towards Gr-1(lo) resting monocytes implicated in murine lupus., in Journal of autoimmunity, 37, 171-179.
Investigation into the presence of and serological response to XMRV in CFS patients.
Erlwein Otto, Robinson Mark J, Kaye Steve, Wills Gillian, Izui Shozo, Wessely Simon, Weber Jonathan, Cleare Anthony, Collier David, McClure Myra O (2011), Investigation into the presence of and serological response to XMRV in CFS patients., in PloS one, 6(3), 1-5.
B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas.
Santiuste Inés, Buelta Luis, Iglesias Marcos, Genre Fernanda, Mazorra Francisco, Izui Shozo, Merino Jesús, Merino Ramón (2010), B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas., in Journal of autoimmunity, 35(4), 316-24.
The Sgp3 locus derived from the 129 strain is responsible for enhanced endogenous retroviral expression in macroH2A1-deficient mice.
Baudino Lucie, Changolkar Lakshmi N, Pehrson John R, Izui Shozo (2010), The Sgp3 locus derived from the 129 strain is responsible for enhanced endogenous retroviral expression in macroH2A1-deficient mice., in Journal of autoimmunity, 35(4), 398-403.
IgA-mediated human autoimmune hemolytic anemia as a result of hemagglutination in the spleen, but independent of complement activation and FcαRI.
Chadebech Philippe, Michel Marc, Janvier Daniel, Yamada Kazunori, Copie-Bergman Christiane, Bodivit Gwellaouen, Bensussan Armand, Fournie Jean-Jacques, Godeau Bertrand, Bierling Philippe, Izui Shozo, Noizat-Pirenne France (2010), IgA-mediated human autoimmune hemolytic anemia as a result of hemagglutination in the spleen, but independent of complement activation and FcαRI., in Blood, 116(20), 4141-7.

Associated projects

Number Title Start Funding scheme
105872 Immunopathogenesis of spontaneous murine models of SLE: genetic, cellular and molecular analysis 01.10.2004 Project funding
135229 Pathogenic Role of Defective IgA Galactosylation in a Murine Model of IgA Nephropathy 01.04.2011 Project funding

Abstract

The aim of our research is to gain a comprehensive understanding of the etiology and immunopathogenesis of systemic lupus erythematosus (SLE) at the genetic, cellular and molecular levels. In the present research project, we propose several interrelated lines of investigation with three main objectives: (1) to gain a better understanding of the role of endogenous retroviruses in the pathogenesis of murine and human SLE; (2) to define the molecular basis responsible for the autoimmunity suppressing mechanism linked to the Sgp4 (Serum gp70 production 4) locus in mice; and (3) to elucidate how an Ea transgene encoding the MHC class II I-E alpha-chains suppresses the development of murine SLE.Endogenous retroviruses have been implicated in the pathogenesis of SLE, as documented by deposits of the retroviral envelope glycoprotein, gp70, as immune complexes (IC) in glomerular lesions of lupus mice. Our recent finding that TLR7 plays a critical role in anti-gp70 autoimmune responses strongly suggests an active role of endogenous retroviruses in this autoimmune response. Therefore, we propose to determine the implication of endogenous retroviruses as a triggering factor in murine SLE by experiments aiming at determining the pathogenic role of the Sgp3 (serum gp70 production 3) locus regulating the expression of endogenous retroviruses, at assessing the effect of the Xpr1 (xenotropic and polytropic retrovirus receptor) deficiency on the development of SLE, and at determining the pathogenic effect of replication-competent infectious retroviruses potentially isolated from lupus-prone mice. Moreover, we will also address an important unanswered question: are endogenous retroviruses also implicated in human SLE? Although the search for the presence of serum retroviral gp70 and its IC in human SLE has, until recently, not been successful, we have now observed that a newly established monoclonal autoantibody (mAb) specific for serum retroviral gp70 in mice also recognizes a glycoprotein in human sera, comparable in size to murine gp70, and stains glomerular IC deposits in human SLE kidneys. Using this mAb, we will identify the molecular nature of putative retroviral “gp70” antigens present in human sera, and determine whether the presence of circulating gp70 IC correlates with clinical manifestations.Our recent analysis on C57BL/6 (B6) mice bearing the Sgp4 locus (the second locus regulating the expression of endogenous retroviruses derived from NZB mice) and the Yaa (Y-linked autoimmune acceleration) mutation revealed that the presence of the Sgp4 locus markedly suppressed autoimmune responses characteristic in SLE. Furthermore, on-going analyses suggested a possible functional defect of TLR7 in B cells from B6.Sgp4 congenic mice. To further define the suppressive mechanism associated with the Sgp4 locus, we propose to construct a high-resolution map of the Sgp4 locus by generating the B6.Sgp4 subcongenic mice. Then, the analysis of mRNA expression profiles in splenic B cells from these subcongenic strains should help to facilitate the search and identification of the candidate lupus suppressive gene located in the Sgp4 locus. Finally, by modulating its expression in lupus-prone mice, the suppressive effect of the candidate gene on the development of SLE will be validated.In the third part of the project, we will determine the protective mechanism conferred by the Ea transgene encoding MHC class II I-E alpha-chains (Ea). Based on our recent finding that transgenic Ea chains are transported to the surface of B cells and dendritic cells (DC) in association with an MHC-unrelated molecule(s), we propose to test the hypothesis that the interaction of this putative X protein with Ea chains could play a critical role in the prevention of excessive activation of B cells and DC, thereby contributing to the Ea transgene-mediated suppression of SLE. If an attractive candidate molecule that pairs with Ea chains should be identified through molecular characterization of the putative X protein, we propose to study the effect of overexpression or suppression of the X protein on the development of SLE in lupus-prone mice.
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