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J. Biol. Chem., Vol. 282, Issue 10, 7405-7415, March 9, 2007

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Human Follicular Lymphoma Cells Contain Oligomannose Glycans in the Antigen-binding Site of the B-cell Receptor^*

Catherine M. Radcliffe¹, James N. Arnold², David M. Suter, Mark R. Wormald, David J. Harvey, Louise Royle¹, Yusuke Mimura¹, Yoshinobu Kimura^¶3, Robert B. Sim, Susana Inogès^||, Mercedes Rodriguez-Calvillo^||4, Natalia Zabalegui^||, Ascensión López-Díaz de Cerio^||, Kathleen N. Potter^**5, C. Ian Mockridge^**5, Raymond A. Dwek, Maurizio Bendandi^||6, Pauline M. Rudd⁷, and Freda K. Stevenson^**5

From the Glycobiology Institute, Medical Research Council Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom, the ^¶Department of Biofunctional Chemistry, Graduate School of Natural Science and Technology, Okayama University, Japan, the ^||University Clinic of Navarre and Center for Applied Medical Research, 31008 Pamplona, Spain, and the ^**Molecular Immunology Group, Tenovus Laboratory, Cancer Sciences Division, Southampton University Hospitals Trust, Southampton SO16 6YD, United Kingdom

Expression of surface immunoglobulin appears critical for the growth and survival of B-cell lymphomas. In follicular lymphoma, we found previously that the Ig variable (V) regions in the B-cell receptor express a strikingly high incidence of N-glycosylation sequons, NX(S/T). These potential glycosylation sites are introduced by somatic mutation and are lymphoma-specific, pointing to their involvement in tumor pathogenesis. Analysis of the V region sugars from lymphoma-derived IgG/IgM reveals that they are mostly oligomannose and, remarkably, are located in the antigen-binding site, possibly precluding conventional antigen binding. The Fc region contains complex glycans, confirming that the normal glycan processing pathway is intact. Binding studies indicate that the oligomannose glycans occupying the V regions are accessible to mannose-binding lectin. These findings suggest a potential contribution to lymphoma pathogenesis involving antigen-independent interaction of surface immunoglobulin of the B-cell receptor with mannose-binding molecules of innate immunity in the germinal center.

Received for publication, March 22, 2006 , and in revised form, December 20, 2006.

^* Glycan analysis was supported by the Oxford Glycobiology Institute endowment, and MALDI was supported by Biotechnology and Biological Sciences Research Council funding. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1–S3.

¹ Present address: Dublin-Oxford Glycobiology Laboratory, NIBRT, Conway Institute, University College, Dublin 4, Ireland.

² Supported by a Medical Research Council grant.

³ Supported by Grant-in-Aid from the Ministry of Education, Science, and Culture of Japan.

⁴ Supported by an FIS contract of the Spanish Ministry of Health.

⁵ Supported by Tenovus, UK.

⁶ A Scholar in Clinical Research of the Leukemia and Lymphoma Society.

⁷ To whom correspondence should be addressed: Dublin-Oxford Glycobiology Laboratory, NIBRT, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Tel.: 353-1-7166728; Fax: 353-1-7166713; E-mail: pauline.rudd{at}nibrt.ie.

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