A substantial proportion of the adult BALB/c available B cell repertoire consists of multireactive B cells.

A variety of studies have documented multireactive antibodies in both the preimmune and naturally activated repertoire, but the relationship of these primarily IgM multireactive antibodies to antigen-specific primary and secondary response antibodies is currently not defined. In order to characterize the BALB/c preimmunization specificity repertoire and the baseline of naturally activated antibodies from which the immune response to a specific antigen (hen egg-white lysozyme, HEL) develops, panels of polyclonally activated blast-derived hybridomas (BlAbs) and natural antibody hybridomas (NAbs) from the spleens of unimmunized mice were screened for binding to a panel of nine complex antigens. Over half of the IgM-secreting BlAbs produced antibodies that were antigen-reactive; of these, over half were multireactive, i.e. capable of binding more than one complex antigen. There was no bias towards self vs foreign or thymus-dependent vs thymus-independent antigens. The frequency of antigen-reactive NAbs was about half the frequency of antigen-reactive antibodies found among the BlAbs. However, over half of the antigen-reactive NAbs were also multireactive, and the reactivity profile within the antigen-reactive subset of NAbs was similar to that within the antigen-reactive subset of BlAbs. These results suggest that the available repertoire of adult spleen cells contains a high proportion of multireactive antibodies, and that a subset of the available repertoire is randomly activated, yielding a small proportion of natural antibodies which closely reflect a random sampling of the available repertoire. Although monospecific precursor cells are rare, monospecific IgM BlAbs were found for all antigens in the panel except staphylococcal nuclease and mouse IgG. Monospecific as well as multireactive HEL-binding BlAbs were found at frequencies comparable to other protein antigens in the panel, and HEL-reactive NAbs were also present. On the other hand, it has previously been shown that HEL-reactive IgM antibodies (including multireactive antibodies whose specificities include HEL) are rare or absent in both the primary and secondary response to HEL. This cannot be attributed to an absence of available precursor B cells, and most likely reflects an early recruitment of HEL-reactive clones into the peripheral B cell pool. The possibility that polyreactive B cells may serve as precursors for some HEL-specific IgG antibodies is discussed.