Nephritogenic autoantibodies in lupus: current concepts and continuing controversies

In summary, we suggest that the following statements regarding lupus nephritis are best supported by the existing data. 1) Lupus nephritis is an immunologically complex disorder. Autoantibodies directed against multiple epitopes on chromatin, including but not limited to dsDNA, may contribute to nephritis. 2) The presence of charged residues within autoantibody heavy chain CDR regions, particularly CDR3, may be essential to the property of nephritogenicity. 3) Chromatin/antichromatin immune complexes (formed either in the circulation or in situ in the GBM) are likely the proximal cause of lupus nephritis. Cross-reactive autoantibodies or antibodies reacting directly to glomerular antigens are less likely to play a major pathogenic role. 4) The induction of lupus nephritis may relate to the propensity of chromatin or its components to bind to the GBM by virtue of the interactions of histones with type IV collagen and heparan-sulfated glycosaminoglycans. Nonetheless, as indicated above, there are numerous issues that remain to be addressed and clarified with respect to lupus nephritis. Insight into these issues is not only of theoretical interest, but may lead to new approaches to diagnostic testing and more specific therapies to replace currently use nonspecific immunosuppressive drugs, which have substantial toxicities.