Changes in N-glycans of IgG4 and its relationship with the existence of hypocomplementemia and individual organ involvement in patients with IgG4-related disease

April Changes in N-glycans of IgG4 and its relationship with the existence of hypocomplementemia and individual organ involvement in patients with IgG4-related disease Naoki Konno 2 3 Mitsuru Sugimoto 2 3 Tadayuki Takagi 2 3 Makiko Furuya 1 3 Tomoyuki Asano 1 3 Shuzo Sato 1 3 Hiroko Kobayashi 1 3 Kiyoshi Migita 1 3 Yoshiaki Miura 0 3 Taichi Aihara 0 3 Atsushi Komatsuda 3 Hiromasa Ohira 2 3 Hiroshi Watanabe 1 3 0 S-Bio, Sumitomo Bakelite Co., Ltd., Hudson, New Hampshire, United States of America, 4 Department of Hematology , Nephrology, and Rheumatology , School of Medicine, Akita University , Akita , Japan 1 Department of Rheumatology, School of Medicine, Fukushima Medical University , Fukushima , Japan 2 Department of Gastroenterology, School of Medicine, Fukushima Medical University , Fukushima , Japan 3 Editor: Aftab A. Ansari, Emory University School of Medicine , UNITED STATES Although increased serum IgG4 level and tissue infiltration of IgG4-positive cells are key events in IgG4-related disease (IgG4RD), and nearly half of IgG4RD patients show hypocomplementemia, the role of IgG4 in the pathogenesis of IgG4RD remains unclear. Many reports show that altered IgG glycosylation, especially IgG with agalactosylated N-linked glycan (G0 N-glycan), have proinflammatory roles including complement activation, implicated in the pathogenesis of various inflammatory diseases. This study determined the concentration of N-linked glycans (N-glycan) released from serum IgG4 in IgG4RD patients and compared the difference of glycosylation changes to those in healthy controls. We also compared the concentration of each IgG4 glycoform between patients with and without hypocomplementemia and individual organ involvement (kidney, pancreas, lymph node) in - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research (C)), Grant Number: JP15K09554. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Although three authors in this study (YM, TA, AK) are employed by Sumitomo Bakelite Background IgG4RD. Methods Results We collected sera from 12 IgG4RD patients and 8 healthy controls. IgG4 was isolated from sera via Melon™ Gel IgG Spin Purification Kit followed by Capture Select IgG4 (Hu) Affinity Matrix. IgG4 N-glycans were analyzed by S-BIO GlycanMap® Xpress methodology. Significant increases of IgG4 G0 N-glycan and IgG4 fucosylated N-glycan (F1 N-glycan) concentrations were observed in IgG4RD compared with healthy controls. Although we observed decreased levels of IgG4 F0 glycan in IgG4RD with hypocomplementemia, there Co. Ltd., this company is not a funding company, but an outsourcing company. Sumitomo Bakelite Co. Ltd. did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: This work was supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research (C)), Grant Number: JP15K09554. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Although three authors in this study (YM, TA, AK) are employed by Sumitomo Bakelite Co. Ltd., it is not a funding company, but an outsourcing company. Sumitomo Bakelite Co. Ltd. also did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Therefore, we feel that three authors belonging to Sumitomo Bakelite Co. Ltd. does not alter our adherence to PLOS ONE policies on sharing data and materials. were no significant differences in the galactosylation and sialyation of IgG4 N-glycans. Furthermore, there were no significant differences in the glycosylation of IgG4 N-glycans between patients with and without individual organ involvement of IgG4RD. Conclusions Although IgG4 has anti-inflammatory properties, IgG4 G0 and F1 glycans were increased in patients with IgG4RD. Our results suggest that decreased galactosylation of IgG4 is not related to complement activation and the differences of individual organ involvement in IgG4RD. IgG4 fucosylation change may be related to complement activation in IgG4RD. Further investigation is needed to clarify the role of IgG4 in IgG4RD. Introduction IgG4-related disease (IgG4RD) is an emerging clinical disorder characterized by increased serum IgG4 concentrations, dense lymphoplasmacytic infiltrate, IgG4-positive plasma cells, and storiform fibrosis [ 1, 2 ]. IgG4RD includes various diseases formerly diagnosed as Mikulicz's Disease [ 3, 4 ], autoimmune pancreatitis [ 5, 6 ], retroperitoneal fibrosis [ 7, 8 ], tubulointerstitial nephritis [9±11], Riedel's thyroiditis [ 12 ], and inflammatory pseudotumor [ 13 ]. Although elevated serum IgG4 levels and infiltration of IgG4-plasma cells in tissues are observed, (...truncated)