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

Abstract

BackgroundAlthough 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 IgG4RD.MethodsWe 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.ResultsSignificant 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 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.ConclusionsAlthough 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.

Unique patterns of glycosylation in immunoglobulin subclass G4‐related disease and primary sclerosing cholangitis

“…32 Recently, a small study reported increased IgG4 G0 N-glycans and IgG4 fucosylated N-glycans in patients with IgG4-RD (n = 12) compared with HCs (n = 8), with IgG4 non-fucosylated N-glycans decreased in those with hypocomplementaemia (n = 7). 33 In line with this, we found a negative correlation between C3 and C4 levels and both IgG4 fucosylation, and IgG1/2/3 hybrid structures. The relevance of this remains uncertain, given that fucosylation and galactosylation are primary mediators of functional changes in IgG for FcγR-mediated and complement-mediated effector functions, respectively.…”

“…In a US cohort, reduced C3 (20%), C4 (19%), or both (11%) were present in 103 IgG4‐RD patients and were associated with a more inflammatory phenotype, higher serum IgG4 levels, and IgG4‐related kidney involvement . Recently, a small study reported increased IgG4 G0 N‐glycans and IgG4 fucosylated N‐glycans in patients with IgG4‐RD ( n = 12) compared with HCs ( n = 8), with IgG4 non‐fucosylated N‐glycans decreased in those with hypocomplementaemia ( n = 7) . In line with this, we found a negative correlation between C3 and C4 levels and both IgG4 fucosylation, and IgG1/2/3 hybrid structures.…”

“…The percentage of Fab glycosylated antibodies was calculated by dividing the amount of IgG in the SNA-enriched fraction by the amount of IgG in the SNA-depleted and SNAenriched fractions as measured by the ELISAs described previously. 33-78] years) were well matched (P = NS). Serum total IgG levels were higher in IgG4-RD and PSC patients compared with HCs (14.7 vs 14.2 vs 9.5 mg/mL; IgG4-RD vs HCs P = 0.004 and DCs vs HCs P = 0.012) ( Fig.…”

The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease

“…Sugimoto et al [84] have analyzed the PEG-precipitated IC from IgG4-RD patients and found that IgG4 could participate in the activation of complements in IgG4-RD patients with hypocomplementemia. To elucidate the inconsistency in complement-activating effect of IgG4 antibody, Konno et al [85] have analyzed the N-linked glycan of IgG4 molecule derived from patients with IgG4-RD. They found decreased galactosylation of IgGs is irrelevant to complement activation whereas IgG4 fucosylation may lead to complement activation, hypocomplementemia and various organ damages in patients with IgG4-RD.…”

A Comparison of Immunoglobulin Variable Region N-Linked Glycosylation in Healthy Donors, Autoimmune Disease and Lymphoma

“…In particular, as detected by Sambucus nigra agglutinin (SNA) affinity chromatography, the presence of variable domain sialylation was increased in both IgG1 and IgG4 subclasses, even when corrected for the inherently higher N-linked glycosylation rates in IgG4 variable regions (46). This observation was corroborated by another study investigating combined variable domain and Fc-glycosylation in IgG4-RD patients (44). Although the role of increased variable domain glycosylation is unclear, it is suggested that increased variable domain sialylation could impart IgG4 immunoglobulins in the context of IgG4-RD with disease-specific immunomodulatory properties through binding of SIGLECs such as CD22 (62).…”