Glycosylation of Surface Ig Creates a Functional Bridge Between Human Follicular Lymphoma and Microenvironmental Lectins

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Oct 13

PMID 20937880

Citations 83

Authors

Vania Coelho

Sergey Krysov

Amir M Ghaemmaghami

Mohamed Emara

Kathleen N Potter

Peter Johnson

Graham Packham

Luisa Martinez-Pomares

Freda K Stevenson

Affiliations

Soon will be listed here.

Abstract

Surface Ig (sIg) of follicular lymphoma (FL) is vital for tumor cell survival. We found previously that the Ig in FL is unusual, because the variable region genes carry sequence motifs for N-glycan addition. These are introduced by somatic mutation and are tumor specific. Unexpectedly, added glycans terminate at high mannose, suggesting a potentially important interaction of FL cells with mannose-binding lectins of the innate immune system. We have now identified mannosylated IgM at the surface of primary lymphoma cells. Recombinant lectin domains of the mannose receptor (MR) or DC-SIGN bind mannosylated Igs in vitro and bind to FL cells, signaling sIgM-associated increases in intracellular Ca(2+). Lectins also bind to normal B cells but fail to signal. In contrast, anti-Ig signaled similarly in both FL and normal B cells. Mannosylation patterns were mimicked by FL Ig-derived single-chain Fvs (scFv), providing probes for potential receptors. Mannosylated scFv bound specifically to the lectin domains of the MR and DC-SIGN and blocked signaling. Mannosylated scFv also bound to DC-SIGN on the surface of dendritic cells. This unique lymphoma-specific interaction of sIg with lectins of innate immunity reveals a potential route for microenvironmental support of tumor cells, mediated via the key B-cell receptor.

Citing Articles

B Cell Differentiation and the Origin and Pathogenesis of Human B Cell Lymphomas.

Weniger M, Seifert M, Kuppers R Methods Mol Biol. 2024; 2865:1-30.

PMID: 39424718 DOI: 10.1007/978-1-0716-4188-0_1.

The role of antibody glycosylation in autoimmune and alloimmune kidney diseases.

Beyze A, Larroque C, le Quintrec M Nat Rev Nephrol. 2024; 20(10):672-689.

PMID: 38961307 DOI: 10.1038/s41581-024-00850-0.

Hyper-N-glycosylated SEL1L3 as auto-antigenic B-cell receptor target of primary vitreoretinal lymphomas.

Elbert M, Neumann F, Kiefer M, Christofyllakis K, Balensiefer B, Kos I Sci Rep. 2024; 14(1):9571.

PMID: 38671086 PMC: 11053041. DOI: 10.1038/s41598-024-60169-5.

Recent advances in understanding the biology of follicular lymphoma.

Nishikori M Int J Hematol. 2024; 121(3):326-330.

PMID: 38536645 DOI: 10.1007/s12185-024-03764-6.

Multi-omic profiling of follicular lymphoma reveals changes in tissue architecture and enhanced stromal remodeling in high-risk patients.

Radtke A, Postovalova E, Varlamova A, Bagaev A, Sorokina M, Kudryashova O Cancer Cell. 2024; 42(3):444-463.e10.

PMID: 38428410 PMC: 10966827. DOI: 10.1016/j.ccell.2024.02.001.

References

Canioni D, Salles G, Mounier N, Brousse N, Keuppens M, Morchhauser F . High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial. J Clin Oncol. 2007; 26(3):440-6. DOI: 10.1200/JCO.2007.12.8298. View

Wallick S, KABAT E, Morrison S . Glycosylation of a VH residue of a monoclonal antibody against alpha (1----6) dextran increases its affinity for antigen. J Exp Med. 1988; 168(3):1099-109. PMC: 2189025. DOI: 10.1084/jem.168.3.1099. View

Dave S, Wright G, Tan B, Rosenwald A, Gascoyne R, Chan W . Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004; 351(21):2159-69. DOI: 10.1056/NEJMoa041869. View

McGreal E, Martinez-Pomares L, Gordon S . Divergent roles for C-type lectins expressed by cells of the innate immune system. Mol Immunol. 2004; 41(11):1109-21. DOI: 10.1016/j.molimm.2004.06.013. View

Cambi A, Gijzen K, de Vries L, Torensma R, Joosten B, Adema G . The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur J Immunol. 2003; 33(2):532-8. DOI: 10.1002/immu.200310029. View

Fiete D, Beranek M, Baenziger J . A cysteine-rich domain of the "mannose" receptor mediates GalNAc-4-SO4 binding. Proc Natl Acad Sci U S A. 1998; 95(5):2089-93. PMC: 19259. DOI: 10.1073/pnas.95.5.2089. View

Kim R, Emi M, Tanabe K, Arihiro K . Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 2006; 66(11):5527-36. DOI: 10.1158/0008-5472.CAN-05-4128. View

Gala F, Morrison S . V region carbohydrate and antibody expression. J Immunol. 2004; 172(9):5489-94. DOI: 10.4049/jimmunol.172.9.5489. View

Mitchell D, Fadden A, Drickamer K . A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands. J Biol Chem. 2001; 276(31):28939-45. DOI: 10.1074/jbc.M104565200. View

10.

Meeker T, Lowder J, Maloney D, Miller R, Thielemans K, Warnke R . A clinical trial of anti-idiotype therapy for B cell malignancy. Blood. 1985; 65(6):1349-63. View

11.

Limpens J, Stad R, Vos C, de Vlaam C, de Jong D, van Ommen G . Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood. 1995; 85(9):2528-36. View

12.

Roulland S, Suarez F, Hermine O, Nadel B . Pathophysiological aspects of memory B-cell development. Trends Immunol. 2007; 29(1):25-33. DOI: 10.1016/j.it.2007.10.005. View

13.

Kuppers R, Klein U, Hansmann M, Rajewsky K . Cellular origin of human B-cell lymphomas. N Engl J Med. 1999; 341(20):1520-9. DOI: 10.1056/NEJM199911113412007. View

14.

Mockridge C, Potter K, Wheatley I, Neville L, Packham G, Stevenson F . Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood. 2007; 109(10):4424-31. DOI: 10.1182/blood-2006-11-056648. View

15.

Tsujimoto Y, Cossman J, Jaffe E, Croce C . Involvement of the bcl-2 gene in human follicular lymphoma. Science. 1985; 228(4706):1440-3. DOI: 10.1126/science.3874430. View

16.

Zabalegui N, Lopez-Diaz de Cerio A, Inoges S, Rodriguez-Calvillo M, Perez-Calvo J, Hernandez M . Acquired potential N-glycosylation sites within the tumor-specific immunoglobulin heavy chains of B-cell malignancies. Haematologica. 2004; 89(5):541-6. View

17.

Alvaro T, Lejeune M, Camacho F, Salvado M, Sanchez L, Garcia J . The presence of STAT1-positive tumor-associated macrophages and their relation to outcome in patients with follicular lymphoma. Haematologica. 2006; 91(12):1605-12. View

18.

Lam K, Kuhn R, Rajewsky K . In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell. 1997; 90(6):1073-83. DOI: 10.1016/s0092-8674(00)80373-6. View

19.

Staudt L, Dave S . The biology of human lymphoid malignancies revealed by gene expression profiling. Adv Immunol. 2005; 87:163-208. PMC: 1351148. DOI: 10.1016/S0065-2776(05)87005-1. View

20.

Gijzen K, Raymakers R, Broers K, Figdor C, Torensma R . Interaction of acute lymphopblastic leukemia cells with C-type lectins DC-SIGN and L-SIGN. Exp Hematol. 2008; 36(7):860-70. DOI: 10.1016/j.exphem.2008.02.003. View