Blood, 15 October 2002, Vol. 100, No. 8, pp. 3055-3056
CORRESPONDENCE
To the editor:
Observing autoimmune patients may not be appropriate
for testing "normal" immunoregulatory mechanisms
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.
Scott Ely
Correspondence: Department of Pathology, Weill Medical College
of Cornell University, 525 E 68th St, New York, NY 10021
References
1.
Goldammer A, Derfler K, Herkner K, Bradwell AR, Horl WH, Haas M.
Influence of plasma immunoglobulin level on antibody synthesis.
Blood.
2002;100:353-355[Abstract/Free Full Text].
2.
Junghans RP.
IgG biosynthesis: no "immunoregulatory feedback."
Blood.
1997;90:3815-3818[Free Full Text].
3.
Janeway CA, Travers P, Walport M, Shlomchick M.
Immunobiology: the immune system in health & disease. 5th ed. New York, NY: Garland Publishing; 2001.
Response:
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 as well as
inhibitory2 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.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.
Martin Haas
Correspondence: Department of Internal Medicine III, Division of
Nephrology and Dialysis, University Hospital Vienna, Währinger
Gürtel 18-20, 1090 Vienna, Austria; e-mail:
martin.haas{at}akh-wien.ac.at
References
1.
Cooper DA, Duckett M, Petts V, Penny R.
Corticosteroid enhancement of immunoglobulin synthesis by pokeweed mitogen-stimulated human lymphocytes.
Clin Exp Immunol.
1979;37:145-151[Medline]
[Order article via Infotrieve].
2.
Akdis CA, Blesken T, Akdis M, Alkan SS, Heusser CH, Blaser K.
Glucocorticoids inhibit human antigen-specific and enhance total IgE and IgG4 production due to differential effects on T and B cells in vitro.
Eur J Immunol.
1997;27:2351-2357[Medline]
[Order article via Infotrieve].
3.
Frequin ST, Barkhof F, Lamers KJ, Hommes OR, Borm GF.
CSF myelin basic protein, IgG and IgM levels in 101 MS patients before and after treatment with high-dose intravenous methylprednisolone.
Acta Neurol Scand.
1991;86:291-297.
