Abstract
The interactions of antibodies with myeloid Fcγ receptors and the complement system are regulated by an Asn297-linked glycan in the Fc portion of IgG. Alterations of serum IgG-Fc glycosylation have been reported in various autoimmune diseases, and correlate with treatment response and disease activity. We hypothesized that IgG-Fc glycosylation is altered in immune thrombocytopenia (ITP) and associates with response to anti-CD20 monoclonal antibody treatment (rituximab). IgG-Fc glycosylation was analyzed by liquid chromatography-mass spectrometry. We found that IgG-Fc glycosylation was identical between refractory ITP patients (HOVON64 trial; N = 108) and healthy controls (N = 120). Two months after rituximab treatment, we observed a shift in Fc glycosylation, with a mean 1.7% reduction in galactosylation for IgG1 and IgG4 and a mean 1.5% increase for bisection in IgG1, IgG2/3 and IgG4 (adjusted p < 1.7 × 10−3 and p < 2 × 10−4, respectively). Neither baseline nor longitudinal changes in IgG-Fc glycosylation after rituximab were associated with clinical treatment response. We conclude that IgG-Fc glycosylation in refractory ITP is similar to healthy controls and does not predict treatment responses to rituximab. The observed changes two months after treatment suggest that rituximab may influence total serum IgG-Fc glycosylation. Overall, our study suggests that the pathophysiology of refractory ITP may differ from other autoimmune diseases.
Highlights
The interactions of antibodies with myeloid Fcγ receptors and the complement system are regulated by an Asn297-linked glycan in the Fc portion of IgG
In contrast to our hypothesis, we unexpectedly found that refractory immune thrombocytopenia (ITP) patients showed no skewing of IgG-Fc glycosylation, which is observed - in particular with a low total serum IgG-galactosylation - in other autoimmune diseases[9,10,11,13,16]
Our findings may suggest that the pathophysiological mechanisms in ITP are different from other antibody-mediated autoimmune diseases, where IgG-glycosylation shows clear associations with disease onset and progression(in particular autoimmune hemolytic anemia9)
Summary
The interactions of antibodies with myeloid Fcγ receptors and the complement system are regulated by an Asn297-linked glycan in the Fc portion of IgG. We hypothesized that IgG-Fc glycosylation is altered in immune thrombocytopenia (ITP) and associates with response to anti-CD20 monoclonal antibody treatment (rituximab). The total serum IgG-Fc glycosylation is skewed in multiple autoimmune diseases, such as rheumatoid arthritis[7,8], autoimmune hemolytic anemia[9], systemic lupus erythematosus[10], Guillain-Barre syndrome[11], vasculitis[12,13] and inflammatory bowel disease[14]. Across these studies, the strongest association with autoimmune diseases is a reduction in Asn-297 galactosylation, followed by sialylation, which are linked because galactosylated glycan structures are substrates for sialyltransferases[6]. The effect of B cell depleting antibody therapy, such as rituximab, has not been studied
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