AUTOANTIBODIES INTERACT DIRECTLY WITH DISTINCT GLOMERULAR AND VASCULAR CELL-SURFACE ANTIGENS

We have identified monoclonal anti-DNA antibodies derived from lupus p rone MRL-lpr/lpr mice that produce glomerular immune deposits and neph ritis after passive transfer to normal mice. Particularly noteworthy i s that the location of immune deposition varied among nephritogenic Ig , and this was associated with distinctive histologies and clinical di sease profiles. Although their autoantigen binding properties differed , they were highly cross-reactive, in a manner similar to Ig deposited in glomeruli of lupus mice. This antigen binding profile was also typ ical of other previously described nephritogenic autoantibodies that b ound directly to glomerular antigens to initiate immune deposit format ion. In this study, we questioned whether ligation of different glomer ular antigens by individual autoantibodies could contribute to the obs erved differences in the location of immune deposits. To examine this possibility, monoclonal anti-DNA antibodies (IgG2a) that produced glom erular immune deposits in different locations were evaluated. H221 pro duced mesangial, intracapillary (that is, intraluminal or within the c apillary lumen) and subendothelial deposits associated with heavy prot einuria, whereas H147 produced mesangial, subendothelial and linear ba sement membrane deposits associated with proliferative glomerulonephri tis. Initially, the capacity of H221 and H147 to bind directly to glom erular and vascular cell surfaces was evaluated. As demonstrated by FA GS, H221 bound preferentially to mesangial cells whereas H147 bound pr eferentially to endothelial cells. To identify possible target cell su rface antigens, Western blots, immunoprecipitation of surface labeled cells, and 2D gel electrophoresis were employed. H221 reacted with a 1 08 kDa protein on mesangial cells not identified by H147, whereas H147 reacted with a 45 kDa protein on endothelial cells not identified by H221. These results support the hypothesis that some nephritogenic lup us autoantibodies initiate immune deposit formation through direct int eraction with glomerular antigens. Furthermore, they suggest that the site of immune deposition is determined by both antigen binding proper ties of the relevant antibody and the location of its target ligand wi thin the glomerulus. In a given individual, therefore, the predominant autoantibody-glomerular antigen interaction may influence the morphol ogic and clinical phenotype expressed. Variation in the predominant in teraction may also contribute to variations in disease expression amon g individuals with lupus nephritis.