Human antiglomerular basement membrane autoantibody disease in XenoMouse II

Background. Previous studies have identified regions within α3(IV) collagen in human antiglomerular basement membrane (anti-GBM) disease, however, information pertaining to the nature of the pathogenic human autoantibodies has been limited by a lack of a relevant disease model. Availability of engineered mice that produce antibodies (that is, XenoMouse II™ strains) provides an ideal opportunity to examine the human antibody response. Methods. XenoMouse II™ mice that produce human IgG2 (γ2κ) in response to antigenic challenge were immunized with various forms of α3(IV)NC1 GBM collagen, including native bovine α3(IV) NCl collagen, E. coli expressed r α3(IV)NCl, and mammalian fetal kidney 293 cell expressed r α3(IV)NC1 preparations. The mice were evaluated for autoantibody (Ab) production and nephritis. Results. All immunized XenoMouse II animals produced human anti-GBM Ab associated with proliferative glomerulonephritis, linear IgG deposits along the murine GBM and tubular basement membrane (TBM), C3 deposits (weaker). A fully human mAb (Ig γ2κ), produced from a mouse immunized with native bovine α3(IV)NCl collagen produced basement membrane deposits, nephritis and proteinuria on transfer to normal XenoMouse II. Furthermore, monoclonal antibodies (mAb) shared idiotypic properties with polyclonal autoantibodies derived from patients with anti-GBM disease, supporting a structural relationship among the antibodies. Conclusions. The results further support the importance of α3(IV)NCl collagen in the pathogenesis of anti-GBM disease. Moreover, to our knowledge this is the first demonstration that experimentally induced, pathogenic human autoantibodies result in disease. This new model of anti-GBM disease, therefore, provides the means and unique reagents to both decipher the molecular basis of the human anti-GBM autoantibody response and the opportunity to test specific therapies aimed at modulation of either B cells producing human autoantibodies or the human pathogenic antibodies themselves, in vivo, prior to trial in patients with the spontaneous form of the disease.