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Science 14 September 2007:
Vol. 317. no. 5844, pp. 1554 - 1557
DOI: 10.1126/science.1144603
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Reports

Anti-Inflammatory Activity of Human IgG4 Antibodies by Dynamic Fab Arm Exchange

Marijn van der Neut Kolfschoten,1 Janine Schuurman,2 Mario Losen,3 Wim K. Bleeker,2 Pilar Martínez-Martínez,3 Ellen Vermeulen,1 Tamara H. den Bleker,1 Luus Wiegman,2 Tom Vink,2 Lucien A. Aarden,1 Marc H. De Baets,3,4 Jan G.J. van de Winkel,2,5 Rob C. Aalberse,1* Paul W. H. I. Parren2*

Antibodies play a central role in immunity by forming an interface with the innate immune system and, typically, mediate proinflammatory activity. We describe a novel posttranslational modification that leads to anti-inflammatory activity of antibodies of immunoglobulin G, isotype 4 (IgG4). IgG4 antibodies are dynamic molecules that exchange Fab arms by swapping a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule, which results in bispecific antibodies. Mutagenesis studies revealed that the third constant domain is critical for this activity. The impact of IgG4 Fab arm exchange was confirmed in vivo in a rhesus monkey model with experimental autoimmune myasthenia gravis. IgG4 Fab arm exchange is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 antibodies.

1 Sanquin Research—AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands.
2 Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands.
3 Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands.
4 Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium.
5 Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands.

* To whom correspondence should be addressed. E-mail: r.aalberse{at}sanquin.nl (R.C.A.); p.parren{at}genmab.com (P.W.H.I.P.)

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Effective Induction of Cell Death on Adult T-Cell Leukaemia Cells by HLA-DR{beta}-Specific Small Antibody Fragment Isolated from Human Antibody Phage Library.
S. Muraoka, Y. Ito, M. Kamimura, M. Baba, N. Arima, Y. Suda, S. Hashiguchi, M. Torikai, T. Nakashima, and K. Sugimura (2009)
J. Biochem. 145, 799-810
   Abstract »    Full Text »    PDF »
Human IgG4 Binds to IgG4 and Conformationally Altered IgG1 via Fc-Fc Interactions.
T. Rispens, P. Ooievaar-De Heer, E. Vermeulen, J. Schuurman, M. van der Neut Kolfschoten, and R. C. Aalberse (2009)
J. Immunol. 182, 4275-4281
   Abstract »    Full Text »    PDF »
Human IgG2 Antibody Disulfide Rearrangement in Vivo.
Y. D. Liu, X. Chen, J. Z.-v. Enk, M. Plant, T. M. Dillon, and G. C. Flynn (2008)
J. Biol. Chem. 283, 29266-29272
   Abstract »    Full Text »    PDF »
IgG1 and IgG4 are the predominant subclasses among auto-antibodies against two citrullinated antigens in RA.
R. Engelmann, J. Brandt, M. Eggert, K. Karberg, A. Krause, G. Neeck, and B. Mueller-Hilke (2008)
Rheumatology 47, 1489-1492
   Abstract »    Full Text »    PDF »
Human IgG2 Antibodies Display Disulfide-mediated Structural Isoforms.
J. Wypych, M. Li, A. Guo, Z. Zhang, T. Martinez, M. J. Allen, S. Fodor, D. N. Kelner, G. C. Flynn, Y. D. Liu, et al. (2008)
J. Biol. Chem. 283, 16194-16205
   Abstract »    Full Text »    PDF »


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Science. ISSN 0036-8075 (print), 1095-9203 (online)