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.

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.

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 Hex2HexNAc2NeuAc2 [α2,6/α2,6] + Man3GlcNAc2, α2,6-linked sialylated N-glycans, showed the treatment response group to have an area under the curve of 0.802 (p < 0.05).

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 KEY MESSAGEAbnormal 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported in part by JSPS KAKENHI Grant Numbers JP23K14751 (Y.F.) and JP23H00420 (M.K.). This work was supported in part by JSPS KAKENHI Grant Numbers JP22H03502 (J.F.). Part of this study was conducted under the Human Glycome Atlas Project (HGA). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Nagoya University Hospital Institutional review board (reference number: 2014-0424, 2019-0170). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Emails: fs0504dream{at}gmail.com (S.F.); yuki.fukami{at}med.nagoya-u.ac.jp (Y.F.); hanamatsu.hisatoshi.y8{at}f.mail.nagoya-u.ac.jp (H.H.); yokota.ikuko{at}gmail.com (I.Y.); furukawa.junichi.n0{at}f.mail.nagoya-u.ac.jp (J.F.); mhane{at}nuagr1.agr.nagoya-u.ac.jp (M.H.); kitajima{at}agr.nagoya-u.ac.jp (K.K.); chi{at}agr.nagoya-u.ac.jp (C.S.); hiraga.keita.n5{at}f.mail.nagoya-u.ac.jp (K.H.); y.satake0316{at}gmail.com (Y.S.); satyagi0317{at}gmail.com (S.Y.); koike{at}cc.saga-u.ac.jp (H.K.); katsuno.masahisa.i1{at}f.mail.nagoya-u.ac.jp (M.K.)