We have generated a new model for systemic autoimmune disease in mice deficient in FcgammaRIIB, an IgG-binding receptor that inhibits antibody production and inflammatory responses. These mice develop a spontaneous disease that resembles lupus in humans but only in certain genetic backgrounds. Our goal is to identify susceptibility/resistance genetic loci that are responsible for the background differences in this system. We have performed an analysis of 200 mice derived from the cross between a resistant strain and a lupus susceptible strain and have identified three new resistance loci. New mouse lines have been generated in which these resistance loci are transferred to the RII-/-B6 background to allow further genetic mapping and eventual gene identification. In the characterization of the autoimmune-prone RII-/-B6 mice, we have observed that they can be aggravated or attenuated in their disease by crossing to certain modifier strains. We have observed enhanced disease in RII-/- B6 Yaa mice that correlates with a change in autoantibody specificity. By comparing these new models of disease we aim to dissect the requirements for the autoimmune pathology. These newly discovered genes will possibly uncover potential routes for modifying ongoing disease in lupus or other autoimmune diseases and will serve as predictors of disease susceptibility, progression and severity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000912-05
Application #
7303912
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Tarasenko, Tatyana; Kole, Hemanta K; Bolland, Silvia (2008) A lupus-suppressor BALB/c locus restricts IgG2 autoantibodies without altering intrinsic B cell-tolerance mechanisms. J Immunol 180:3807-14
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Tarasenko, Tatyana; Dean, Jonathan A; Bolland, Silvia (2007) FcgammaRIIB as a modulator of autoimmune disease susceptibility. Autoimmunity 40:409-17
Deane, Jonathan A; Bolland, Silvia (2006) Nucleic acid-sensing TLRs as modifiers of autoimmunity. J Immunol 177:6573-8
Pisitkun, Prapaporn; Deane, Jonathan A; Difilippantonio, Michael J et al. (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312:1669-72
Bolland, Silvia (2005) A newly discovered Fc receptor that explains IgG-isotype disparities in effector responses. Immunity 23:2-4
Bolland, Silvia; Yim, Young-Sun; Tus, Katalin et al. (2002) Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(-/-) mice. J Exp Med 195:1167-74
Bolland, S; Ravetch, J V (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13:277-85