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.
Highlights
The ability of IgG antibodies (Abs) to modulate immune responses depends on the Ab subclass and the structure of the N-glycan attached to Asn-297 in the Fc region that affect IgG binding to activating and inhibitory Fcγ receptors (FcγRs) on effector cells [1, 2]
To study how IgG Fc glycosylation is associated with the development of autoimmune pathology, we first used lupus-prone FcγRIIB knockout mice, a model of spontaneous lupus nephritis (Fcgr2b−/− females on the C57BL/6, haplotype b, background) [46, 48,49,50]
Because we recently demonstrated that T cell-independent B cell activation induces immunosuppressive sialylated IgG Abs in vivo [30], we wondered whether the introduction of the 56R allele into lupus-prone Fcgr2b−/− mice may lead to T cell-independent IgG autoAbs and provide a disease-protective effect
Summary
The ability of IgG antibodies (Abs) to modulate immune responses depends on the Ab subclass and the structure of the N-glycan attached to Asn-297 in the Fc region that affect IgG binding to activating and inhibitory Fcγ receptors (FcγRs) on effector cells [1, 2]. The abundance of non-galactosylated (agalctosylated; G0) serum IgG Abs that lack galactose and terminal sialic acid residues positively correlates with the disease severity in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25], whereas alleviated disease activity in RA patients during pregnancy or after anti-TNF treatment is associated with increased levels of sialylated IgG Ab [6, 17, 20, 26,27,28]. With regard to the development of differently Fc glycosylated IgG Abs, it has been shown that immune responses under inflammatory conditions induce plasma cells (PCs) that generate G0 IgG, whereas immune responses under tolerogenic conditions induce more galactosylated and sialylated IgG Abs [29,30,31,32]
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