Response of human B cells to different anti‐immunoglobulin isotypes: Absence of a correlation between early activation events and cell proliferation

Cross‐linking of surface immunoglobulin (sIg) by antibodies against IgM, IgG and IgD activates B cells and in some circumstances can induce cell proliferation. We studied the potential link between anti‐Ig‐induced changes in the cytosolic free Ca²⁺ concentration ([Ca²⁺]_i), inositol phosphate production and the ability to induce cell proliferation in the presence or absence of the phorbol ester 12‐O‐tetradecanoylphorbol 13‐acetete (TPA). Anti‐IgM, but not anti‐IgD or anti‐IgG, induced cell proliferation in the presence but not the absence of TPA. Each of the antibodies induced a rapid increase in [Ca²⁺]_i which appeared to be due to release of Ca²⁺ from internal stores. This was followed by a sustained increase in [Ca²⁺]_i, apparently due to Ca²⁺ uptake from the extracellular medium. Anti‐IgD induced the greatest increase in [Ca²⁺]_i, anti‐IgM induced intermediate changes and anti‐IgG the lowest change. Since inositol 1,3,5‐trisphosphate (IP₃) can release Ca²⁺ from internal stores, we tested the ability of each anti‐Ig isotype to increase concentrations of IP_3. In contrast to the change in [Ca²⁺]_i and proliferation, anti‐IgG induced the most significant increase in IP₃ concentrations. Taken together these data indicate that changes in [Ca²⁺]_i, inositol phosphate production and anti‐Ig‐induced human B cell proliferation are not directly linked. They also demonstrate that changes in [Ca²⁺]_i, inositol phosphate production and activation of protein kinase C are not sufficient to induce proliferation of human B cells. It appears that anti‐IgM induces an additional Ca²⁺‐independent, inositol phosphate‐independent and protein kinase C‐independent activation signal which can collaborate with TPA to induce B cell proliferation. The molecular events involved in this signal remain to be identified.