Superantigen-induced B-cell deletion

Abstract

Superantigens (SAgs) are powerful microbial toxins that interact with lymphocyte antigen receptors to produce adverse effects on host immune responses. Studies of the interaction between SAgs and T-cell receptors (TCRs) have offered a valuable insight into TCR-mediated stimulation, and revealed possible roles for SAgs in the pathogenesis of a range of diseases, from toxic shock syndrome to autoimmune diseases. Although SAgs are also known to interact with B-cell receptors (BCRs), studies have largely been limited to in vitro analysis.Now, Silverman and colleagues1xA B-cell superantigen induced persistent ‘hole’ in the B-1 repertoire. Silverman, G.J. et al. J Exp Med. 2000; 192: 87–98Crossref | PubMed | Scopus (46)See all References1 report the in vivo effects of the interaction between one of the best-studied SAgs, Staphylococcus aureus protein A (SpA), and the BCR. SpA interacts with BCRs encoded by the VH clan III genes via a highly conserved variable region framework surface. Although many genes from clan III-related VH families encode antibodies that bind to SpA, those encoded by the S107 family in particular have greater binding affinity.Silverman and colleagues demonstrate that treating neonatal and adult mice with SpA leads to the T-cell independent deletion of a large supra-clonal set of susceptible B cells (those expressing VH clan III antibody genes), leaving a ‘hole’ in the B-cell repertoire. By studying different forms of SpA, they showed that the magnitude of the loss of SpA-reactive B cells correlates with the binding avidity of the Fab-binding interaction, a finding that is consistent with previous observations that high-affinity ligands are most effective at inducing B-cell tolerance.SpA treatment led to a near-complete loss of constitutively expressed S107-expressing B-cell clones and natural IgM, which, given the greater binding affinity of antibodies encoded by genes of the S107 family, suggests that the loss of these cells is due, at least in part, to their higher binding affinity for the SAg. When the mice were no longer exposed to SpA, numbers of conventional splenic B cells (B-2 cells) returned to normal. However, there was a persistent deficit in VH clan III-derived peritoneal B-1 cells, which constitutively produce natural IgM antibodies that are associated with housekeeping and anti-microbial functions. Previous studies suggest that they convey a repertoire that has been naturally selected during the evolution of the adaptive immune system, indicating that there are many advantages to the pathogen in knocking out these cells. VH clan III genes are well conserved across the animal kingdom, being particularly well represented in mammalian immune systems; in humans, more than 30% of B cells are targeted by SpA.Other B-cell-specific ligands are known to induce persistent holes in the B-cell repertoire, but such interactions probably represent a fraction of the large supra-clonal set affected by SAg exposure. The interaction with SpA is also likely to be particularly important because it affects immune responses to other immunogens by interacting with supra-clonal sets via VH family-specific interations. The authors suggest that these findings could help to elucidate the role that the SAg properties of HIV-1-associated retroviral products might play in the increased susceptibility of HIV patients to infection by other pathogens, notably the high frequency of pneumococcal sepsis.