Goldammer et al's recent study1 provides interesting data that appear to contradict the still widely held notion that there is an immunoglobulin G (IgG) feedback regulatory system and a resultant rebound in IgG synthesis following serum apheresis. Indeed, there is much evidence to corroborate that impression, as perhaps best exemplified by Junghans.2 But in the ongoing debate regarding the existence of a serum IgG level homeostasis mechanism, 2 points should be emphasized.
First, although designing a human study to determine the effects of apheresis on IgG production is certainly difficult, the nearly exclusive enrollment of patients with autoimmune diseases is a potential confounding factor. The applicability of this study to the idea that there is not likely a need to prophylax against rebound postapheresis IgG synthesis is a reasonable conclusion, although the small number of patients in the study is problematic. But the diseased state of these patients' immune systems calls into question the applicability of the data to the existence of an immunoregulatory feedback mechanism in healthy patients. Moreover, no matter what arguments can be made that it has not affected the results, the fact that nearly all of the patients were being treated with immunosuppressive therapy is also potentially confounding.
Second, given our extensive knowledge about the pathophysiology of the immune response to individual antigens,3 common sense tells us that what has been observed to be a steady-state serum immunoglobulin level is likely to result from the rise and decay of Ig in the normal immune response to an antigen. Given the number of antigens an individual encounters and the more-or-less steady state of that exposure, along with the lack of a clear cellular mechanism for monitoring Ig levels, it is more likely that the serum Ig level is governed by overlapping antigen exposures and the decay of the concomitant immune responses rather than a feedback mechanism.
Again, the data in Goldammer et al are a helpful reminder that we should question prophylaxing against rebound Ig production. The data are sound in the apheresis setting, but the problems of extrapolating to the existence of an immunoregulatory feedback mechanism should be addressed.
Lack of feedback mechanism in regulation of IgG synthesis
Dr Ely points out that the inclusion of patients with autoimmune diseases might be a confounding factor when investigating the regulation of antibody synthesis. Although all patients included suffered from different autoimmune diseases, most of them (7 of 8) had a normal free light chain (flc) level prior to enrollment. Since flc concentration reflects current antibody synthesis, a general activation of Ig production, possibly triggered by the underlying disease, was excluded. Furthermore, a different result in normal controls (ie, the existence of an immunoregulatory feedback mechanism with an increase of antibody synthesis after immunoglobulin depletion) would imply a specific suppression of antibody synthesis in patients with autoimmune diseases. This would have been plausible if all patients were concomitantly treated with drugs suppressing antibody synthesis. But actually only 4 of 8 patients received oral immunosuppressants in a dose high enough to influence antibody synthesis. Although steroids seem to have a stimulating1-1 as well as inhibitory1-2 effect on antibody synthesis, the dose of prednisolone administered to 1 patient (7.5 mg/d) was most likely too low to interact with antibody synthesis.1-3 Due to the uncertainty concerning the influence of steroids on antibody synthesis, however, we subjected a second patient with a higher steroid monotherapy of 15 mg/d to the immunosuppressive group. In fact, according the action of immunosuppressive drugs, only the 3 patients receiving mycophenolate mofetil were treated with drugs potentially affecting immunoglobulin synthesis. Thus, it is very likely that the results will be similar in healthy individuals. We nevertheless agree with Dr Ely that our results should be confirmed in healthy controls before they can be generalized.
Concerning the low number of patients included, we believe that a physiologic effect, such as a feedback mechanism, will be similar in all humans and not differ from patient to patient. Thus, the lack of such a mechanism in a small group will predict a similar lack in the general population.
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