Abstract
Immunoglobulin G (IgG) fragment crystallizable (Fc) N-glycosylation has a large influence on the affinity of the antibody for binding to Fcγ-receptors (FcγRs) and C1q protein, thereby influencing immune effector functions. IgG Fc glycosylation is known to be partly regulated by genetics and partly by stimuli in the microenvironment of the B cell. Following allogeneic hematopoietic stem cell transplantation (HSCT), and in the presence of (almost) complete donor chimerism, IgG is expected to be produced by, and glycosylated in, B cells of donor origin. We investigated to what extent IgG glycosylation in patients after transplantation is determined by factors of the donor (genetics) or the recipient (environment). Using an IgG subclass-specific liquid chromatography–mass spectrometry method, we analyzed the plasma/serum IgG Fc glycosylation profiles of 34 pediatric patients pre-HSCT and at 6 and 12 months post-HSCT and compared these to the profiles of their donors and age-matched healthy controls. Patients treated for hematological malignancies as well as for non-malignant hematological diseases showed after transplantation a lower Fc galactosylation than their donors. Especially for the patients treated for leukemia, the post-HSCT Fc glycosylation profiles were more similar to the pre-HSCT recipient profiles than to profiles of the donors. Pre-HSCT, the leukemia patient group showed as distinctive feature a decrease in sialylation and in hybrid-type glycans as compared to healthy controls, which both normalized after transplantation. Our data suggest that IgG Fc glycosylation in children after HSCT does not directly mimic the donor profile, but is rather determined by persisting environmental factors of the host.
Highlights
The N-glycan attached to the conserved glycosylation site of the fragment crystallizable (Fc) region of immunoglobulin G (IgG) has a large influence on the structure and function of the antibody [1, 2]
The IgG Fc glycosylation profiles of 34 pediatric hematopoietic stem cell transplantation (HSCT) patients were followed over time, starting with a sample prior to the HSCT and followed by two longitudinal samples, 6 and 12 months postHSCT
While the B cells in children after HSCT are mainly of donor origin [36] and patients were investigated after reaching independency of IgG supplementation, we found that IgG Fc glycosylation in our pediatric cohort did not reflect the glycosylation pattern of the donors
Summary
The N-glycan attached to the conserved glycosylation site of the fragment crystallizable (Fc) region of immunoglobulin G (IgG) has a large influence on the structure and function of the antibody [1, 2]. The presence or absence of specific monosaccharides have proven to be crucial both in modulating the affinity of IgG binding to Fcγ-receptors (FcγRs) and in the activation of the complement system. For IgG Fc binding to complement factor C1q, galactosylation plays a primary role and is associated positively with binding affinity and downstream complementdependent cytotoxicity (CDC) [3, 4]. In adults, total IgG-Fc galactosylation is decreased in rheumatoid arthritis and active tuberculosis infections [7, 8], and in different types of cancer, like ovarian cancer and colorectal cancer [9, 10]. Gp120-specific antibodies in HIV-infected patients show a decrease in fucosylation as compared to the total pool of IgG in these patients [11]
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