Human rheumatoid factor production is dependent on CD40 signaling and autoantigen

High-affinity pathologic rheumatoid factor (RP) B cells occur in autoimmune diseases such as rheumatoid arthritis, but are deleted in healthy individu als, The reasons for the survival and differentiation of these autoreactive B cells in rheumatoid arthritis are not known. Previous studies in mice tr ansgenic for a human IgM RP have shown that peripheral encounter with solub le human IgG leads to deletion of high-affinity RF B cells; however, deleti on can be prevented when concomitant T cell help is provided. This study ai med to further discern the minimal factors necessary not only for the in vi vo survival of RF B cells, but also for their differentiation into Ab-secre ting cells. The combination of MHC class II-reactive T cells and Ag induced the production of RF in human IgM RF transgenic mice, while either stimulu s alone was ineffective, Neutralizing Abs against CD40 ligand (CD40L), but not against IL-4 or IL-15, abrogated IgM-RF production. Moreover, blockade of CD40L-CD40 allowed IgG to delete the RF precursor cells, Most importantl y, activating Abs to CD40 could substitute entirely for T cell help in prom oting the survival of RF precursors and in stimulating RF synthesis in T ce ll deficient animals. The data indicate that CD40 signaling alone can preve nt deletion of RF B cells by Ag and in the presence of IgG is sufficient to trigger RF synthesis. The results suggest that selective induction of apop tosis in high-affinity RF B cells may be achieved by blockade of CD40L-CD40 interaction.