These two authors contributed equally to this work.
Effect of immunoglobulin G (IgG) interchain disulfide bond cleavage on efficacy of intravenous immunoglobulin for immune thrombocytopenic purpura (ITP)
Article first published online: 5 OCT 2010
© 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology
Clinical & Experimental Immunology
Volume 162, Issue 3, pages 415–424, December 2010
How to Cite
Machino, Y., Ohta, H., Suzuki, E., Higurashi, S., Tezuka, T., Nagashima, H., Kohroki, J. and Masuho, Y. (2010), Effect of immunoglobulin G (IgG) interchain disulfide bond cleavage on efficacy of intravenous immunoglobulin for immune thrombocytopenic purpura (ITP). Clinical & Experimental Immunology, 162: 415–424. doi: 10.1111/j.1365-2249.2010.04255.x
- Issue published online: 10 NOV 2010
- Article first published online: 5 OCT 2010
- Accepted for publication 28 July 2010
- Fc receptors;
- idiopathic thrombocytopaenia purpuria/thrombocytopenia;
- intravenous immunoglobulin therapy;
- protein structure/folding
Intravenous immunoglobulin (IVIG) has been used widely to treat immune thrombocytopenic purpura (ITP), but the mechanisms of its action remain unclear. We investigated the affinity for Fcγ receptors (FcγRs) and the thrombocytopenia-ameliorating effect of S-sulfonated gammaglobulin (SGG) and S-alkylated gammaglobulin (AGG), in comparison with unmodified gammaglobulin (GG), in a mouse ITP model. Cleavage of immunoglobulin (Ig)G interchain disulfide bonds by either S-sulfonation or S-alkylation did not decrease the affinity for FcγRIIA (CD32A) and FcγRIIB (CD32B), but did decrease the affinity for FcγRIA (CD64A) and FcγRIIIA (CD16A), presumably because of changes in H-chain configuration. The interchain disulfide bond cleavage decreased the affinity much more for mouse FcγRIV than for mouse FcγRIIB. The ability of AGG to ameliorate ITP was greatly diminished, while SGG, whose disulfide bonds are reconstituted in vivo, was as effective as GG. These results suggest that the interchain disulfide bonds are important for therapeutic effect. It is also suggested that the interaction of IVIG with the inhibitory receptor FcγRIIB is insufficient for effective amelioration of ITP and that, at least in this model, direct binding of IVIG to FcγRIIIA is also required.