Sialylated Autoantigen-Reactive IgG Antibodies Attenuate Disease Development in Autoimmune Mouse Models of Lupus Nephritis and Rheumatoid Arthritis

Abstract

Pro- and anti-inflammatory effector functions of IgG antibodies (Abs) depend on their subclass and Fc glycosylation pattern. Accumulation of non-galactosylated (agalactosylated; G0) IgG Abs in the serum of rheumatoid arthritis and systemic lupus erythematosus (SLE) patients reflects severity of the diseases. In contrast, sialylated IgG Abs are responsible for anti-inflammatory effects of the intravenous immunoglobulin (pooled human serum IgG from healthy donors), administered in high doses (2 g/kg) to treat autoimmune patients. However, whether low amounts of sialylated autoantigen-reactive IgG Abs can also inhibit autoimmune diseases is hardly investigated. Here, we explore whether sialylated autoantigen-reactive IgG Abs can inhibit autoimmune pathology in different mouse models. We found that sialylated IgG auto-Abs fail to induce inflammation and lupus nephritis in a B cell receptor (BCR) transgenic lupus model, but instead are associated with lower frequencies of pathogenic Th1, Th17 and B cell responses. In accordance, the transfer of small amounts of immune complexes containing sialylated IgG Abs was sufficient to attenuate the development of nephritis. We further showed that administration of sialylated collagen type II (Col II)-specific IgG Abs attenuated the disease symptoms in a model of Col II-induced arthritis and reduced pathogenic Th17 cell and autoantigen-specific IgG Ab responses. We conclude that sialylated autoantigen-specific IgG Abs may represent a promising tool for treating pathogenic T and B cell immune responses in autoimmune diseases.

CDG and immune response: From bedside to bench and back

“…All these variables can influence the functionality of immune organs, cells and molecules. Glycans are practically present in all components of the immune system . However, their distribution is not random.…”

“…Here, the pivotal and widespread role of glycosylation is made evident by the array of molecules of the immune system that are glycosylated. These include immunoglobulins, adhesion molecules (eg, integrins and selectins), PRRs (eg, toll like receptors—TLRs—and lectins) and complement molecules, cytokines, chemokines and (many of) their receptors …”

Profiling of Naturally Occurring Antibodies to the Thomsen-Friedenreich Antigen in Health and Cancer: The Diversity and Clinical Potential

“…Immunoglobulins (Igs) are glycosylated molecules, and by now, it is clear that the N-glycans of the Fc-fragment strongly influence IgG-Fcγ receptor interactions and thus the Fcmediated effector mechanisms [101,102]. Several studies have demonstrated that NAbs usually exhibit a sialylated pattern which confers an anti-inflammatory nature, in contrast to Ag-specific adaptive Abs that are either agalactosylated or asialylated and exhibit proinflammatory properties [103][104][105]. Compared to healthy individuals, there is a marked change of serum Ig glycosylation in individuals with autoimmune diseases, infections, and tumors [106][107][108][109][110][111][112][113].…”

Loss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in Rheumatoid Arthritis

“…Some elegant studies have shown the potential impact of glycan regulation in multiple aspects of RA pathophysiology, for example reduced sialylation of N-glycans is a feature of pathogenic immunoglobulins in RA patients and their glycosylation profile shows predictive potential for disease progression [13][14][15][16][17] . Besides, galectins, a family of proteins that bind to galactose-containing glycans, are key modulators of synovial inflammation [18][19][20] .…”