A Study of Differential Glycosylation of IgG on Fcγ Receptor Mediated Neutrophil Recruitment Model of SLE Nephritis
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AbstractThe goal of this research was to evaluate cellular binding interactions to glycoengineered IgGs to further investigate the role neutrophils play in the pathogenesis of Lupus nephritis in an SLE nephritis model. Lupus nephritis is characterized by inflammation of the glomeruli, which is part of the nephron, the basic structural and functional filtering unit of the kidney (Nephron, 2017). Lupus nephritis is caused by SLE nephritis , which is marked by high levels of circulating IgG-immune complexes formed between autoantibodies and antigens, such as DNA and smRNP (LFA, 2017). Up to 60% of SLE patients develop kidney injury, referred to as lupus nephritis, which can worsen overtime leading to kidney failure that requires dialysis or a kidney transplant (Lupus and Kidney Disease, 2017).
Statistics show how SLE Nephritis and LN occur disproportionally among non-White populations in the United States, with roughly 73 affected per 100,000 persons (Hoover et al.,2016). The prevalence is several times greater in Black SLE patients compared to Whites, with the proportion being 116.1 vs 34.8 per 100,000 persons (Hoover et al.,2016). In a national study between 2000 and 2004, it was determined that incidence rates of LN were 3.8 times higher in Blacks, 3.7 times higher in Asians, 2.3 in Native Americans, and 1.9 in Hispanics patients compared to Whites patients (Feldman et al., 2016).
Research for SLE Nephritis in recent years has significantly advanced our knowledge in understanding auto inflammatory mechanisms that govern the onset of auto immune diseases like LN. Structural glycosylation sites located at Asn 297 in the CH2 domains of Fc regions have been used to study its influence on antibody functions, and disease linked glycoform changes. By evaluating the binding affinity of neutrophils and Jurkat cells expressing FcγRIIA (JIIA) and/or FcγRIIIB (JIIIB) to immune complexes generated with glycoengineered IgGs, a broader understanding of Fc glycosylation is garnered in hopes of broading the range of new therapeutic advances.
Here, we show sialylation of the N-glycans of anti-endoglin IgG increases binding to activating FcγRs on neutrophils. Our data suggests that inhibition of both FcγRIIA and FcγRIIIB, as located on neutrophils, is required to prevent neutrophil binding to sialylated antibody. Our study also revealed that IgG1 sialylation had no effect on FcγRIIIB mediated binding, while sialylated IgG1 (S2) containing immune complexes exhibited greater binding to FcγRIIA expressing cells compared to the G0 and G2 glycoforms. Together these data demonstrate that sialylation may decrease or increase immune responses depending on its target, which in the context of inflammation, offers new possible ways to further explore sialylation modulation.
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