Serum Glycobiomarkers Defining Therapeutic Response to Intravenous Immunoglobulin in Chronic Inflammatory Demyelinating Polyneuropathy

Background

Glycosylation plays a crucial role in various pathologic conditions, including inflammation. This study conducted a comprehensive glycan analysis of serum to determine how glycan biomarkers are associated with the pathophysiology of chronic inflammatory demyelinating polyneuropathy (CIDP) and the effects of its treatment.

Methods

We comparatively analyzed N - and O -glycans in the pretreatment serum of 27 treatment-naïve patients with typical CIDP and age- and sex-matched 20 healthy controls (HC) using mass spectrometry. We determined the association between clinical parameters and glycans. Treatment response was defined according to the degree of improvement in the modified Rankin Scale 2 weeks after the first dose of intravenous immunoglobulin (IVIg), and the serum glycan and neurofilament light chain (NfL) levels were assessed at the baseline.

Results

Compared with the HC, the CIDP group demonstrated significantly lower levels of serum total N -glycans (CIDP, median 973.3 [IQR 836.2–1131.3] pmol/µL; HC, 1125.0 [1005.0–1236.2] pmol/µL; p < 0.05), especially sialylated N -glycans (CIDP, 898.0 [752.2–1037.2] pmol/µL; HC, 1064.4 [942.7–1189.8] pmol/µL; p < 0.01). In contrast, the O -glycan levels did not differ significantly between the two groups. Treatment response was associated with low N -glycan levels but not with the serum NfL levels. For individual glycans, low levels of Hex ₂ HexNAc ₂ NeuAc ₂ [α2,6/α2,6] + Man ₃ GlcNAc ₂ , α2,6-linked sialylated N -glycans, showed the treatment response group to have an area under the curve of 0.802 (p < 0.05).

Conclusions

Low levels of sialylated N -glycans may serve as a novel biomarker reflecting pathophysiology and therapeutic resistance in typical CIDP.

KEY MESSAGE

• What is already known on this topic

Abnormal conformational changes in glycans of serum proteins are associated with the pathogenesis of inflammatory diseases. In a demyelinating mouse model, N -glycans suppress the activity of inflammatory helper T- and B-cells. A decrease in sialylated N -glycans of serum IgG-Fc in the serum of patients with CIDP correlates with disease severity, suggesting the potential of serum glycans as biomarkers for CIDP.

• What this study adds

In the patients with typical CIDP, serum total N -glycans, especially sialylated types, were significantly decreased, indicating a reduction in sialylated N -glycans derived from glycoproteins in CIDP. Moreover, lower levels of total N -glycans, particularly α2,6-sialylated N -glycans, were associated with reduced responsiveness to initial IVIg treatment.

• How this study might affect research, practice or policy

The study’s findings provide a new approach to exploring the immunological and therapeutic aspects of the role of glycans in CIDP. The decrease in serum total N -glycans, specifically sialylated types, may reflect an inflammatory pathophysiology in CIDP. Furthermore, it is suggested that these changes may serve as novel biomarkers to predict response to initial IVIg treatment.