Human Plasma IgG N -Glycome Profiles Reveal a Proinflammatory Phenotype in Chronic Thromboembolic Pulmonary Hypertension

Abstract

BACKGROUND: The pathological mechanism of chronic thromboembolic pulmonary hypertension (CTEPH) is not fully understood, and inflammation has been reported to be one of its etiological factors. IgG regulates systemic inflammatory homeostasis, primarily through its N -glycans. Little is known about IgG N -glycosylation in CTEPH. We aimed to map the IgG N -glycome of chronic thromboembolic pulmonary hypertension to provide new insights into its pathogenesis and discover novel markers and therapies. METHODS: We characterized the plasma IgG N -glycome of patients with chronic thromboembolic pulmonary hypertension in a discovery cohort and validated our results in an independent validation cohort using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Thereafter, we correlated IgG N -glycans with clinical parameters and circulating inflammatory cytokines in patients with CTEPH. Furthermore, we determined IgG N -glycan quantitative trait loci in chronic thromboembolic pulmonary hypertension to reveal partial mechanisms underlying glycan changes. RESULTS: Decreased IgG galactosylation representing a proinflammatory phenotype was found in CTEPH. The distribution of IgG galactosylation showed a strong association with NT-proBNP (N-terminal pro-B-type natriuretic peptide) in CTEPH. In line with the glycomic findings, IgG pro-/anti-inflammatory N -glycans correlated well with a series of inflammatory markers and gene loci that have been reported to be involved in the regulation of these glycans or inflammatory immune responses. CONCLUSIONS: This is the first study to reveal the full signature of the IgG N -glycome of a proinflammatory phenotype and the genes involved in its regulation in CTEPH. Plasma IgG galactosylation may be useful for evaluating the inflammatory state in patients with CTEPH; however, this requires further validation. This study improves our understanding of the mechanisms underlying chronic thromboembolic pulmonary hypertension inflammation from the perspective of glycomics.

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study

“…36 Moreover, our preliminary research found that the IgG N-glycome in CTEPH presented a proinflammatory phenotype (upregulated IgG-Gal ratio representing decreased IgG galactosylation) compared with healthy controls, and the IgG-Gal ratio is positively correlated with the level of NT-proBNP. 35 In the current study, we found that patients in the CHIP group showed a severe inflammatory state, reflected by the upregulated IgG-Gal ratio, compared with that in the non-CHIP group, suggesting a probable relationship between CHIP and the secreted IgG antibody phenotype. However, the causality and directionality of the link between the proinflammatory functions of IgG and CHIP require further investigation.…”

“…In addition, our previous study suggested that the IgG N-glycan characteristics of patients with CTEPH presented an obvious proinflammatory phenotype (decreased proportion of IgG-Gal leading to a higher IgG-Gal ratio). 35 Decreased IgG galactosylation has been reported to be a hallmark of inflammation. 36 In the present study, baseline IgG glycan characteristics were analyzed in patients with and without CHIP mutations.…”

Prognostic value of plasma IgG N-glycome traits in patients with pulmonary arterial hypertension: an observational cohort study

“…Especially, clinical IgG N-glycosylation analysis does not rely as heavily on mild serum/plasma storage conditions and timely analysis (glycans are even stable at 50 °C for two weeks) as many other omics analyses. 54 It is worth mentioning that the high-throughput workflow for IgG N-glycome profiling applied in the present study has been widely used in various studies, [24][25][26][27]55 enabling the candidate glycan biomarker to be more convenient for further clinical application.…”

“…The formulas used for the calculation: Galactosylation = H3N4F1/(H4N4F1 + 2*H5N4F1); Bisecting N- acetylglucosamine = H3N5F1 + H4N5F1 + H5N5F1; Fucosylation = H3N4F1 + H4N4F1 + H3N5F1 + H5N4F1 + H4N5F1 + H5N5F1 (H = hexose; N = N-acetylhexosamine; F = deoxyhexose [fucose]). 24,27 GlycoWorkbench software (version 1.1.3480) was used to annotate the N-glycan structures.…”

“…[18][19][20][21] IgG loss of terminal galactose could trigger a proinflammatory response. 22,23 It is noteworthy that our team has previously demonstrated dysregulation of the plasma IgG N-glycome in patients with chronic thromboembolic pulmonary hypertension 24 and the identified abnormal IgG N-glycan traits may play a crucial role in the pathogenesis and progression of this condition. 24 Nevertheless, the glycosylation characteristics of IgG and their prognostic value in patients with PAH have not yet been explored.…”