Journal Article

Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins

Emara, Mohamed, Packham, Graham, Ghaemmaghami, Amir M., Coelho, Vania, Stevenson, Freda K., Martinez-Pomares, Luisa, Potter, Kathleen N., Johnson, Peter, Levy, Ronald, Krysov, Sergey

2010

Overview

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 Ca²⁺. 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: B lymphocytes / B-Lymphocytes - immunology / Binding sites / Biological Sciences / Blood / calcium / Calcium (intracellular) / Cell Adhesion Molecules - antagonists & inhibitors / Cell Adhesion Molecules - genetics / Cell Adhesion Molecules - immunology / Cell survival / cell viability / Cells / DC-SIGN protein / Dendritic cells / double prime B-cell receptor / Follicular lymphoma / Gene Knockdown Techniques / genes / Glycosylation / Humans / Immune system / Immunity, Innate / Immunoglobulin M / Immunoglobulin M - chemistry / Immunoglobulin M - metabolism / Immunoglobulins / In Vitro Techniques / innate immunity / Intracellular signalling / Lectins / Lectins - immunology / Lectins, C-Type - antagonists & inhibitors / Lectins, C-Type - genetics / Lectins, C-Type - immunology / Lymphocytes B / Lymphoma / Lymphoma, Follicular - etiology / Lymphoma, Follicular - genetics / Lymphoma, Follicular - immunology / Macrophages / Mannose / Mannose - chemistry / Mannose receptors / Mannose-binding lectin / Mannose-Binding Lectin - immunology / Mannose-Binding Lectins - immunology / Models, Immunological / Molecules / Mutation / N-glycans / neoplasm cells / Polysaccharides / Probes / Receptors / Receptors, Antigen, B-Cell - chemistry / Receptors, Antigen, B-Cell - genetics / Receptors, Antigen, B-Cell - metabolism / Receptors, Cell Surface - antagonists & inhibitors / Receptors, Cell Surface - genetics / Receptors, Cell Surface - immunology / Signal Transduction - immunology / Single-Chain Antibodies - chemistry / Single-Chain Antibodies - metabolism / Somatic Hypermutation, Immunoglobulin / somatic mutation / Tumor cells / Tumors / Variable region