Remarkable selective glycosylation of the immunoglobulin variable region in follicular lymphoma

Abstract

Follicular lymphoma (FL) generally expresses immunoglobulin (Ig) with somatically mutated variable (V) region genes. Surprisingly, these almost always carry introduced motifs available for N-glycosylation (Asn-X-Ser/Thr). Introduced motifs are uncommon on normal B cells, but are on other germinal center (GC)-associated B-cell malignancies suggesting a site-specific role. They are not evident in mutated chronic lymphocytic leukemia (CLL) or myeloma. Recently, we found that the glycosylation sites are unusual in containing oligomannose glycans, which are apparently displayed on tumor cell surface IgM. This suggests a potential interaction with a mannose receptor in the GC. However, natural N-glycosylation sites exist in germline (GL) V region genes, particularly the V4-34 gene expressed by normal B cells and by some malignancies, including CLL, potentially undermining the selective importance for FL. To compare oligosaccharide addition at the introduced and natural sites, we expressed V region genes as single chain Fv (scFv) and analyzed the added glycans. In contrast to introduced sites, which were oligomannosylated, the natural GL motif in the V4-34 sequence had no added sugars. The remarkable selective glycosylation within the heavy chain V region gene of FL apparently permits only limited processing to oligomannose at somatically mutated motifs, creating a feature exploitable by GC lymphomas.