Structural features of nephritogenic lupus autoantibodies.
We have identified monoclonal antibodies derived from MRL-lpr/lpr lupus-prone mice that produced nephritis after passive transfer to normal mice. Our present goal was to elucidate the structural and immunochemical features of nephritogenic Ig that facilitate immune deposition. For this purpose the antigen binding properties, capacity to form immune deposits, and nucleotide sequence of a genetically related autoantibody subgroup were compared. The prototype, H147 (an IgG encoded by 7183/81X VH gene), produced glomerular and tubular basement membrane, mesangial immune deposits, and proliferative glomerulonephritis after passive transfer to normal mice. For comparison three other 7183/81X encoded anti-DNA IgG (H257, H171, and H8a) were evaluated (predicted heavy chain aa homology >75%). H257 produced similar types of immune deposits as H147, and this was associated with nephritis; H8a produced predominantly mesangial deposits, whereas H171 did not produce significant deposits. Although their antigen binding profile to a panel of soluble autoantigens was variable, only H147 and H257 bound to both mesangial and aortic endothelial cell surfaces. V gene sequence analysis of the IgG suggests that individual residues, motifs, and conformations influence the autoantigen binding specificities that contributed to the observed differences in immune deposit formation.
Vargas
M T
MT
Department of Medicine and The Penn Kidney Research Foundation, The University of Pennsylvania School of Medicine, Philadelphia 19104-6144, USA.
Gustilo
K
K
D'Andrea
D M
DM
Kalluri
R
R
Foster
M H
MH
Madaio
M P
MP
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000737:chemistry* / Q000276:immunology; D001483:Base Sequence; D003001:Cloning, Molecular; D005920:Glomerular Mesangium / Q000276:immunology / Q000378:metabolism; D006825:Hybridomas / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics; D007668:Kidney / Q000293:injuries; D008181:Lupus Nephritis / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D017421:Sequence Analysis
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007135:Immunoglobulin Variable Region