The double edged sword of the immune response: mutational analysis of a murine anti-pneumococcal, anti-DNA antibody.

Abstract

Anti-double-stranded (ds) DNA antibodies are not only an important diagnostic marker for SLE, but also play an important role in tissue injury. Microbial antigen may be a stimulus for the production of these antibodies. We isolated 99D.7E, an IgG2b monoclonal antibody from a nonautoimmune BALB/c mouse that is cross-reactive with both ds-DNA and phosphorylcholine, the dominant hapten on the pneumococcal cell wall. While partially protective against a bacterial challenge, 99D.7E is also pathogenic to the kidney. To identify those molecular motifs that confer on anti-PC antibodies the potential for autoreactivity, we created a panel of 99D.7E mutants with single amino acid substitutions in the heavy chain, and examined the changes in antigen binding and renal deposition. Our results support the hypothesis that charge and affinity for dsDNA are not adequate predictors of the pathogenicity of anti-DNA antibodies. Differential renal damage from anti-dsDNA antibodies may be due to differences in fine specificity, rather than differential affinity for dsDNA. Importantly, high affinity IgG antibodies cross-reactive with bacterial and self antigen exist and can display pathogenic potential, suggesting that defects in peripheral regulation of B cells, activated by foreign antigen but cross-reactive with self antigen, might lead to autoimmune disorders. ( J. Clin. Invest. 1996. 97:2251-2259.)

Abrogation of Lupus Nephritis in Activation-Induced Deaminase-Deficient MRL/lpr Mice

“…Because these mice cannot undergo SHM or CSR, these results directly implicate high-affinity switched Abs in kidney damage and mortality in MRL/lpr mice. Affinity maturation and SHM in the GC reaction have been implicated in the lupus-like syndrome of MRL/lpr mice because many MRL/lpr mice-derived autoantibodies originate from oligoclonal populations of B cells with mutations selected for self-Ag binding (39,41,42,44,46,(57)(58)(59). These results confirm the observation that Abs derived from B cells activated to undergo CSR and SHM play a critical role in the development of kidney disease in MRL/lpr mice.…”

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

“…Similarly, cross-reactivity between foreign antigens and self-antigens can drive the expansion of autoreactive B cells ( Figure 1C). Several autoantibodies exhibit such cross-reactivity: dsDNA autoantibodies cross-react with pneumococcal bacteria and Epstein-Barr virus (29,45) and anti-neutrophil cytoplasm antibodies (ANCAs) recognize the bacterial adhesin FimH (28). However, this cross-reactivity between foreign antigens and intracellular self-antigens still requires the release of intracellular antigens through apoptosis or cross-reactivity to surface antigens in order for autoantibodies to bind and exert their pathogenic activity.…”

“…An example of such cross-reactivity is antidsDNA antibodies in SLE, which have been shown to recognize antigens in the glomerular basement membrane, where these autoantibodies can deposit (44)(45)(46)(47). While the binding of some anti-dsDNA antibodies to glomeruli depends on the presence of nucleosomes containing DNA on the glomerular membrane, the contribution of cross-reactivity to renal pathology has also been demonstrated (48,49).…”

Ventilator-associated lung injury: a search for better therapeutic targets

“…Immune responses are able to incorporate, interpret and integrate anatomical, physical and chemical input, and it became increasingly clear that they could be modulated by parallel pro-and anti-inflammatory signalling cascades acting on local as well as systemic levels. The paradigm shift came with the understanding that these processes, normally directed towards defence and healing, could themselves be capable of causing tissue injury and disease [32][33][34][35][36].…”