The alternative interpretation proposed by Dr Baumgrath, namely that the effect of BLyS inhibition on germinal center formation occurs indirectly, through inhibition of IgM secretion, was noted in our discussion (see page 40 bottom left)1: “…TACI-Fc–treated mice showed a marked deficit in both IgM and IgG production. Thus, it is possible that BLyS and TACI operate early on in B cell activation, and blocking their function impairs all phases of the humoral response.” Notwithstanding, TACI-Fc inhibits interactions that are crucial for germinal center formation regardless of the underlying mechanism.

The studies that Dr Baumgrath refers to show that a complete lack of IgM secretion attenuates or delays germinal center formation in mice after immunization with a suboptimal dose of antigen2,3; however, absence of secreted IgM clearly did not abolish this event, as properly organized splenic germinal centers with peanut-agglutinin–staining B cells were readily detectable. Moreover, mice deficient in secreted IgM showed no defect in germinal center formation in response to a higher dose of antigen, as compared to heterozygous controls2. Hence, IgM secretion is not essential for germinal center formation, although it may augment this process. On the other hand, we found that TACI-Fc treatment after immunization (with an even higher dose of antigen) prevented germinal center formation completely, despite inhibiting IgM secretion only partially1. On the basis of these observations, it is likely that TACI-Fc prevents germinal center formation independently of its inhibitory effect on IgM secretion.