Somatic mutations in B lymphocytes: new perspectives in tolerance research?

This paper extends the concept of clonal anergy developed in the author's laboratory. It has been shown that the primary population of B lymphocytes induced into clonal expansion and IgM antibody formation by mitogens contains many cells capable of autoantibody synthesis, but the affinity of binding to the self constituents, or indeed to foreign antigens, is low. The creation of high affinity antibody, which will still register strongly in an ELISA as an IgG molecule, demands not only the addition of lymphokines to cause isotype switching, but also intentional immunization of the donor mice to permit mutations in V region genes and selection of higher affinity B memory cells. This process appears to begin about 6 days after in vivo immunization. It is postulated that these mutational events occur primarily in germinal centres, and that there must be mechanisms to prevent escape of cells which, by chance, mutate not to higher affinity against an immunogen, but to higher affinity against a self constituent. If such mutants were allowed to enter the long-lived, recirculating pool of B lymphocytes, they might pose a graver threat of autoimmune disease than the low-affinity anti-self cells of the primary repertoire. Therefore, it is suggested that recently mutated germinal centre B cells represent a pool of 'pre-memory' cells, which are immature in the sense of displaying the same kind of sensitivity to negative signalling by antigen that immature B cells from newborn spleen or adult bone marrow display. If so, then the earliest phases of memory generation represent a second window of opportunity for tolerance induction within the B lymphocyte compartment.