Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus

Abstract

In addition to the redundancy of the receptors for the Fc portion of immunoglobulins, glycans result in potential ligands for a plethora of lectin receptors found in immune effector cells. Here we analysed the exposure of glycans containing fucosyl residues and the fucosylated tri-mannose N-type core by complexed native IgG in longitudinal serum samples of wellcharacterized patients with systemic lupus erythematosus. Consecutive serum samples of a cohort of 15 patients with systemic lupus erythematosus during periods of increased disease activity and remission were analysed. All patients fulfilled the 1982 American College of Rheumatology classification criteria. Sera of 15 sex-and age-matched normal healthy blood donors served as controls. The levels and type of glycosylation of complexed random IgG was measured with lectin enzyme-immunosorbent assays. After specifically gathering IgG complexes from sera, biotinylated lectins Aleuria aurantia lectin and Lens culinaris agglutinin were employed to detect IgG-associated fucosyl residues and the fucosylated tri-mannose N-glycan core, respectively. In sandwich-ELISAs, IgG-associated IgM, IgA, C1q, C3c and C-reactive protein (CRP) were detected as candidates for IgG immune complex constituents. We studied associations of the glycan of complexed IgG and disease activity according to the physician's global assessment of disease activity and the systemic lupus erythematosus disease activity index 2000 documented at the moment of blood taking. Our results showed significantly higher levels of Aleuria aurantia lectin and Lens culinaris agglutinin binding sites exposed on IgG complexes of patients with systemic lupus erythematosus than on those of normal healthy blood donors. Disease activity in systemic lupus erythematosus correlated with higher exposure of Aleuria aurantia lectin-reactive fucosyl residues by immobilized IgG complexes. Top levels of Aleuria aurantia lectin-reactivity were found in samples taken during the highest activity of systemic lupus erythematosus. Our results show that native circulating IgG complexes from active systemic lupus erythematosus patients expose fucosyl residues and their glycan core is accessible to soluble lectins. Two putative mechanisms may contribute to the increased exposure of these glycans: (1) the canonical N-glycosylation site of the IgG-CH2 domain; (2) an IgG binding non-IgG molecule, like complement or C-reactive protein. In both cases the complexed IgG may be alternatively targeted to lectin receptors of effector cells, e.g. dendritic cells. Lupus (2015) 24, 569-581.

Association of Systemic Lupus Erythematosus With Decreased Immunosuppressive Potential of the IgG Glycome

“…In a very recent study of a small number of SLE patients (n = 15), Sjowall and colleagues showed increased binding of lectins recognizing fucose to complexed natural IgG in patients with active disease . This contradicts our observation that IgG fucosylation is decreased in SLE patients.…”

Sweet but dangerous – the role of immunoglobulin G glycosylation in autoimmunity and inflammation

“…22 In 2015, we reported on the impact of fucosyl exposure on native circulating IgG complexes in patients with SLE. 43 Our results showed significantly higher levels of AAL and LCA binding sites exposed on IgG complexes of patients with SLE than on those of normal healthy donors (Figure 1). Moreover, disease activity in patients positively correlated with exposure of AAL-reactive fucosyl residues on immobilized IgG complexes.…”

Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy

“…Similarly, complexes consisting of antibodies against CRP have been described in lupus nephritis [38]. In contrast to SLE [23], CRP itself appears to associate with IgG in RA. CRP is elevated chronically in RA and has shown to contribute to bone destruction [39].…”

“…Composition of native immunoglobulin (Ig)G complexes and their putative glycosylation sites. This scheme shows (1) the canonical glycans attached to the IgG–CH2‐domain, (2) the glycans attached to some VH and CH1 domains, (3) putative sites of hyper‐glycosylation, (4) increased accessibility for lectin binding of the canonical glycans attached to the CH2‐domains and (5) that glycans can also be exposed by IgG‐associated molecules exemplified by IgA, IgM, C1q, C3d and C‐reactive protein (CRP).…”