Autoimmune glomerulotubular nephropathy in mice

Abstract

We produced an autoimmune glomerulotubular nephropathy in Swiss-Webster mice using human glomerular antigen in Freund's complete adjuvant. The disease is associated with circulating antibody to both mouse and human glomerular basement membranes (GBM) and tubular basement membranes (TBM). All mouse IgG subgroups are deposited initially in a linear pattern along the GBM and TBM. IgG deposition remains linear, while that of the other subgroups assumes a granular GBM pattern with continued linear TBM deposits. Despite tissue deposition of antibody capable of C-3 fixation, no C-3 is found in vivo along the GMB or TBM, nor is there C-3 fixation in vitro. This appears to be related to spatial limitations of IgG molecule attachment to basement membranes. A unique ultrastructural lesion of the GMB developed, characterized by periodic expansions of the lamina rara externa to form a beaded pattern. Eluate of nephritic kidneys contained all subgroups of IgG, but mainly IgG1 fixed in vitro to mouse kidney and in vivo when injected intravenously into normal mice. Fixation of other IgG subgroups in vivo may have resulted from antibody formation to abnormally formed GBM, thereby accounting for the peculiar ultrastructural findings and tissue fixation characteristics of the eluted immunoglobulin. Abnormal proteinuria without glycosuria or lysozymuria developed in test animals as compared to controls. Our model is similar in certain aspects to previously described models of Stebley nephritis, but differs because of the total involvement of TBMs, unique ultrastructural lesions, and dissimilarity to other reports of this model in mice.