Pathogenic and protective properties of cross reactive antibodies: The double-edged sword of the immune response

Abstract

Anti-DNA antibodies contribute to pathogenesis in the autoimmune disease systemic lupus erythematosus (SLE). Extensive previous studies of these antibodies derived from lupus patients and lupus prone mice have identified certain amino acid motifs important for DNA binding. In addition, the analysis of these antibodies has shown they use variable (V) region gene segments that are used to encode protective anti-microbial antibodies. In order to understand the structure of the anti-DNA antibodies that can be made in nonautoimmune mice but are part of a "forbidden" autoantibody repertoire, I analyzed anti-DNA producing hybridomas from BALB/c mice.;Most of these hybridomas were made from spleen cells of mice that had been immunized with phosphorylcholine coupled to KLH (PC-KLH), as PC is structurally related to DNA. Analysis of the variable regions of these antibodies reveals that they use the same VH gene segments used in generating autoantibodies in autoimmune mice, although there is a lower frequency of somatic mutation present. The VL gene usage is diverse. To address whether these autoantibodies are pathogenic like autoantibodies from lupus prone mice, pathogenicity studies were performed in SCID mice. The results demonstrate that anti-DNA antibodies made in nonautoimmune mice cause proteinuria and deposit in renal glomeruli. Many of these autoantibodies cross react with PC. Canonical anti-PC antibodies, bearing the T15 idiotype, are known to protect against a lethal pneumococcal infection. These cross-reactive antibodies also protect SCID mice against pneumococcal infection, even though they are genetically unrelated to canonical anti-PC antibodies.;These data suggest that anti-DNA antibodies can arise following immunization with a bacterial antigen. Furthermore, these studies suggest that the anti-PC response in nonautoimmune mice is genetically restricted in order to maintain self tolerance.