title: Polyclonal Immunoglobulin G N-Glycosylation in the Pathogenesis of Plasma Cell Disorders.
abstract: The pathological progression from benign monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma (SMM) and finally to active myeloma (MM) is poorly understood. Abnormal immunoglobulin G (IgG) glycosylation in myeloma has been reported. Using a glycomic platform composed of hydrophilic interaction UPLC, exoglycosidase digestions, weak anion-exchange chromatography, and mass spectrometry, polyclonal IgG N-glycosylation profiles from 35 patients [MGUS (n = 8), SMM (n = 5), MM (n = 8), complete-response (CR) post-treatment (n = 5), relapse (n = 4), healthy age-matched control (n = 5)] were characterized to map glycan structures in distinct disease phases of multiple myeloma. N-Glycan profiles from MGUS resembled normal control. The abundance of neutral glycans containing terminal galactose was highest in SMM, while agalactosylated glycans and fucosylated glycans were lowest in MM. Three afucosyl-biantennary-digalactosylated-sialylated species (A2G2S1, A2BG2S1, and A2BG2S2) decreased 2.38-, 2.4-, and 4.25-fold, respectively, from benign to active myeloma. Increased light chain sialylation was observed in a longitudinal case of transformation from MGUS to MM. Bisecting N-acetylglucosamine was lowest in the CR group, while highest in relapsed disease. Gene expression levels of FUT 8, ST6GAL1, B4GALT1, RECK, and BACH2 identified from publicly available GEP data supported the glycomic changes seen in MM compared to control. The observed differential glycosylation underlined the heterogeneity of the myeloma spectrum. This study demonstrates the feasibility of mapping glycan modifications on the IgG molecule and provides proof of principle that differential IgG glycosylation patterns can be successfully identified in plasma cell disorders.
authors.affiliation: NIBRT-The National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock Co., Dublin A94 X099, Ireland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mittermayr
authors.affiliation: NIBRT-The National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock Co., Dublin A94 X099, Ireland.|Department of Haematology, Mater Misericordiae University Hospital , Dublin D07 R2WY, Ireland.|National Institute for Cellular Biotechnology, Dublin City University , Dublin D09 NR58, Ireland.
authors.forename: Giao N
authors.initials: GN
authors.lastname: Lê
authors.affiliation: NIBRT-The National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock Co., Dublin A94 X099, Ireland.
authors.forename: Colin
authors.initials: C
authors.lastname: Clarke
authors.affiliation: NIBRT-The National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock Co., Dublin A94 X099, Ireland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Millán Martín
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University , Dublin D09 NR58, Ireland.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Larkin
authors.affiliation: Department of Haematology, Mater Misericordiae University Hospital , Dublin D07 R2WY, Ireland.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Gorman
authors.affiliation: NIBRT-The National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock Co., Dublin A94 X099, Ireland.
authors.forename: Jonathan
authors.identifier: 0000-0001-8950-0156
authors.initials: J
authors.lastname: Bones
mesh_terms: D000368:Aged; D005260:Female; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000097:blood* / Q000473:pathology; D011134:Polysaccharides / Q000097:blood; D006023:Glycoproteins
chemical_list: D007074:Immunoglobulin G; D011134:Polysaccharides; C046179:glycosylated IgG; D006023:Glycoproteins
keywords: IgG N-glycosylation; glycan analysis; multiple myeloma; plasma cell disorders; polyclonal IgG