Consequences of superantigen binding and signaling to B lymphocytes. (A) Superantigen-induced cell death through BCR engagement. Upon engagement by a superantigen, the BCRs are recruited into complexes that include CD19, CD21, and other coreceptors, which results in signaling events for cellular activation. When these interactions occur in the absence of a “second signal,” they can cause a series of intracellular events that could lead to changes in mitochondrial membrane potential and ultimately to the release of cytochrome c and proapoptotic factors that can lead to DNA fragmentation and nuclear fragmentation. (B) Susceptibility and outcome of B-cell superantigen exposure. (Bi) Superantigen can interact with all clones of a particular family (green) no matter their conventional Ag specificity. Conventional Ags, however, can interact with only certain clones having defined binding specificities (brown) and of a particular family (green). (Bii) On initial exposure to a superantigen, the BCRs of all susceptible clones are recruited into complexes, followed by clustering of the CD21 and CD19 coreceptors and the resulting activation of the B cell, associated with up-regulation of CD69 and CD86 expression. Later activation events include up-regulation of CD40, CD54, CD80, and CD95. Migration of B cells to the spleen is observed at early time points. Several outcomes follow, a main one being apoptosis, although with an appropriate second signal such as CD40 ligand or IL-4, survival and proliferation may result. Based on B-cell responses to conventional Ags, differentiation of clones into memory cells, functional inactivation (anergy), or receptor editing may occur. Used with permission from Malavasi et al.⁴²