A working model linking differential responses to sIgM engagement to clinical behavior. sIgM expression is strongly down-modulated in M-CLL, associated with a tendency for loss of signaling capacity. In U-CLL, sIgM down-modulation is less dramatic and there is a tendency to retain signaling capacity. “Conversion” of the remaining sIgM to a signal-competent, high-mannose, form of sIgM, most strongly in U-CLL, is a second indicator of antigen engagement. Both subsets of CLL have features of anergic cells, but there is a tendency for retained sIgM signaling in U-CLL, which, in the context of appropriate microenvironment signals, leads to enhanced survival and proliferation, and disease progression. In M-CLL, sIgM responses are strongly down-modulated, leading to indolent disease. sIgD expression does not appear to be down-modulated in response to antigen engagement. Thus, antigen engagement, potentially repetitive, leads to differences in sIgM responses in U-CLL and M-CLL, linked to clinical behavior. Adapted from Packham and Stevenson³³  with permission. PC indicates proliferation center.