Correspondence

Mechanism of Intravenous Immune Globulin Therapy

N Engl J Med 1999; 341:57-58July 1, 1999

Article

To the Editor:

Yu and Lennon (Jan. 21 issue)1 present an intriguing hypothesis about how intravenous immune globulin (“IVIg”) therapy works in autoimmune diseases. Another possibility is that simultaneous ligation of the Fcγ receptor II and the B-cell receptor inhibits B-cell activation.2 Binding of the Fcγ receptor II by the constant regions (Fc) of IgG molecules inhibits B-cell function through immune tyrosine inhibitory motifs (ITIM) on the cytoplasmic tail of the Fcγ receptor II. This effect induces anergy or apoptosis3 of activated B cells. Such a system could regulate the quantity of IgG in the plasma. When the IgG concentration rises above a certain level, production of immunoglobulin is suppressed until the steady-state serum concentration is restored by catabolism.

Flooding the vascular compartment with intravenous immune globulin probably increases the frequency of ligation of B-cell Fcγ receptor II by the Fc portions of the intravenous immune globulin molecules. The resultant suppression of immunoglobulin production, including the production of pathologic autoantibodies, could induce remission of the disease under treatment. In support of this idea, mice that are deficient in the Fcγ receptor II produce higher-than-normal amounts of antibodies after immunization.

Molecules that selectively ligate the Fcγ receptor II should be as effective as intravenous immune globulin in treating autoantibody diseases. Nature has provided evidence in support of this hypothesis: the nucleocapsid protein of the measles virus markedly suppresses the production of antibodies by human B cells by ligating the Fcγ receptor II.4

Brad Spellberg, M.D.
Harbor–UCLA Medical Center, Torrance, CA 90509

4 References

1. 1

   Yu Z, Lennon VA. Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N Engl J Med 1999;340:227-228
   Full Text | Web of Science | Medline

2. 2

   Ravetch JV. Fc receptors. Curr Opin Immunol 1997;9:121-125
   CrossRef | Web of Science | Medline

3. 3

   Ashman RF, Peckham D, Stunz LL. Fc receptor off-signal in the B cell involves apoptosis. J Immunol 1996;157:5-11
   Web of Science | Medline

4. 4

   Ravanel K, Castelle C, Defrance T, et al. Measles virus nucleocapsid protein binds to FcgammaRII and inhibits human B cell antibody production. J Exp Med 1997;186:269-278
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Spellberg's hypothesis again raises the question of whether IgG synthesis is regulated by its plasma concentration. The presumption that there is a feedback mechanism was the rationale for using immunosuppressant agents in combination with plasmapheresis therapy — to prevent a “rebound” in antibody synthesis. However, it has been solidly established that the synthesis of IgG normally occurs only in response to stimulation by antigens, usually derived from pathogens.1

The discovery that the low-affinity Fcγ receptor II on B lymphocytes can negatively regulate proliferation and secretion of immunoglobulin by B cells2 explains IgG-mediated inhibition of specific immunoglobulin production.3 Antigen-specific suppression of naive B cells occurs if IgG antibody is injected within three days after challenge with intravenous antigen3 and plausibly accounts for the action of anti-D immune globulin injected early in the postpartum period as prophylaxis against maternal Rh immunization.4 This form of B-cell regulation, called coinhibition, depends on the formation of an inactivating tripartite complex, in which the B cell's antigen receptor is coligated with Fcγ receptor IIB by specific antigen–antibody complexes.2 Commercial preparations of immune globulin that are used to treat IgG-mediated autoimmune disease are made from pooled IgG from healthy donors. This IgG is unlikely to contain organ-specific autoantibodies or the corresponding autoantigen required to bridge the autoreactive B cell's antigen receptor to Fcγ receptor IIB. If therapeutic intravenous immune globulin were to bind Fcγ receptor IIB, such a bond would be temporary and monovalent. Engagement of Fcγ receptor IIB alone is insufficient to generate phosphorylation of the cytoplasmic ITIM-signaling domain of Fcγ receptor IIB.5 Finally, activation of memory B cells is thought to be resistant to Fc-dependent negative feedback through the Fcγ receptor IIB.4

We therefore reject the hypothesis that intravenous immune globulin therapy could suppress production of immunoglobulin, including production of pathogenic autoantibodies, on two grounds: first, it is unlikely that pooled, normal human IgG would deliver a negative signal to B cells, regardless of the concentration in the plasma, because the mechanism required for Fcγ receptor IIB to inhibit B cells is antigen-specific, and second, it is doubtful that either memory B cells or plasma cells — the main sources of immunoglobulin — would be subject to negative regulation by a mechanism requiring coligation of membrane antigen receptor and Fcγ receptor IIB.

Zhiya Yu, M.D., Ph.D.
Vanda A. Lennon, M.D., Ph.D.
Mayo Clinic, Rochester, MN 55905

5 References

1. 1

   Junghans RP. IgG biosynthesis: no “immunoregulatory feedback.“ Blood 1997;90:3815-3818
   Web of Science | Medline

2. 2

   Anderson CC, Sinclair NR. FcR-mediated inhibition of cell activation and other forms of coinhibition. Crit Rev Immunol 1998;18:525-544
   Web of Science | Medline

3. 3

   Chan PL, Sinclair NR. Regulation of the immune response. V. An analysis of the function of the Fc portion of antibody in suppression of an immune response with respect to interaction with components of the lymphoid system. Immunology 1971;21:967-981
   Web of Science | Medline

4. 4

   Janeway CA Jr, Travers P. Immunobiology: the immune system in health and disease. 3rd ed. London: Current Biology, 1997.
   

5. 5

   Ono M, Bolland S, Tempst P, Ravetch JV. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc(gamma)RIIB. Nature 1996;383:263-266
   CrossRef | Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   Irina Knezevic-Maramica, Margot S. Kruskall. (2003) Intravenous immune globulins: an update for clinicians. Transfusion 43:10, 1460-1480
   CrossRef

2. 2

   KY Lee, JW Han, JS Lee, KT Whang. (2002) Alteration of biochemical profiles after high-dose intravenous immunoglobulin administration in Kawasaki disease. Acta Paediatrica 91:2, 164-167
   CrossRef

3. 3

   M.M. Kroiss, T. Vogt, M. Landthaler, W. Stolz. (2000) High-dose intravenous immune globulin is also effective in linear IgA disease. British Journal of Dermatology 142:3, 582-582
   CrossRef