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α2,3-Sialylation with Fucosylation Associated with More Severe Anti-MDA5 Positive Dermatomyositis Induced by Rapidly Progressive Interstitial Lung Disease

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Abstract

Dermatomyositis (DM) is a heterogeneous autoimmune disease associated with numerous myositis specific antibodies (MSAs) in which DM with anti-melanoma differentiation-associated gene 5-positive (MDA5 + DM) is a unique subtype of DM with higher risk of developing varying degrees of Interstitial lung disease (ILD). Glycosylation is a complex posttranslational modification of proteins associated with many autoimmune diseases. However, the association of total plasma N-glycome (TPNG) and DM, especially MDA5 + DM, is still unknown. TPNG of 94 DM patients and 168 controls were analyzed by mass spectrometry with in-house reliable quantitative method called Bionic Glycome method. Logistic regression with age and sex adjusted was used to reveal the aberrant glycosylation of DM and the association of TPNG and MDA5 + DM with or without rapidly progressive ILD (RPILD). The elastic net model was used to evaluate performance of glycans in distinguishing RPLID from non-RPILD, and survival analysis was analyzed with N-glycoslyation score by Kaplan–Meier survival analysis. It was found that the plasma protein N-glycome in DM showed higher fucosylation and bisection, lower sialylation (α2,3- not α2,6-linked) and galactosylation than controls. In MDA5 + DM, more severe disease condition was associated with decreased sialylation (specifically α2,3-sialylation with fucosylation) while accompanying elevated H6N5S3 and H5N4FSx, decreased galactosylation and increased fucosylation and the complexity of N-glycans. Moreover, glycosylation traits have better discrimination ability to distinguish RPILD from non-RPILD with AUC 0.922 than clinical features and is MDA5-independent. Survival advantage accrued to MDA5 + DM with lower N-glycosylation score (p = 3e-04). Our study reveals the aberrant glycosylation of DM for the first time and indicated that glycosylation is associated with disease severity caused by ILD in MDA5 + DM, which might be considered as the potential biomarker for early diagnosis of RPILD and survival evaluation of MDA5 + DM.

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Data Availability

The main data supporting the findings of this study are available within the manuscript and its Supplementary materials. All data generated, including both raw images and analyzed datasets for the figures in this study, are available upon request from the corresponding author.

Abbreviations

DM:

Dermatomyositis

MSAs:

Myositis specific antibodies

MDA5 + DM:

DM with anti-melanoma differentiation-associated gene 5-positive

ILD:

Interstitial lung disease

TPNG:

Total plasma N-glycome

RPILD:

Rapidly progressive interstitial lung disease

SLE:

Systemic lupus erythematosus

RA:

Rheumatoid arthritis

IBD:

Inflammatory bowel disease

MALDI-TOF-MS:

Matrix assisted laser desorption/ionization time of flight mass spectrometry

ASS:

Anti-synthetase syndrome

Anti-ARSs:

Anti-synthetases antibodies

HRCT:

High-resolution computed tomography

PaO2 :

Partial pressure of arterial oxygen

SD:

Standard deviation

ROC:

Receiver operating characteristic curves

A:

Antennae

S:

Sialylation

F:

Fucosylation

B:

Bisection

G:

Galactosylation

TM:

High-mannose glycan types

THy:

Hybrid glycan types

TC:

Complex glycan types

AUC:

Area under curve

SA:

Sialic acid

HC:

Healthy controls

NK:

Natural killer

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Acknowledgements

This work was supported by grants from The National Key R&D Program of China (2022YFC3400803), the National Natural Science Foundation of China (32071276), Greater Bay Area Institute of Precision Medicine (IPM2021C005), and National Postdoctoral Program for Innovative Talents (BX20190076).

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  1. Rongrong Zhang and Li Guo share co-first authorship.

Authors and Affiliations

  1. NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Rongrong Zhang, Jichen Sha, Shuwai Chang, Jianxin Gu & Shifang Ren

  2. Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, 200032, China

    Li Guo & Jing Liu

  3. Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China

    Li Guo & Jiangfeng Zhao

  4. State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, 200032, China

    Kaiwen Wang & Jiucun Wang

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  1. Rongrong Zhang
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Contributions

RRZ, LG: carried out the experiments, analysis, interpretation of data and drafted the manuscript. JCS, SWC, JFZ, KWW, JCW: participated in the collection of clinical data. JXG, JL and SFR: conceived the project and revised the intellectual content. All authors contributed to revise the manuscript critically for important intellectual content. All authors read and approved the final manuscript. All authors contributed to drafting the article and revising it critically for important intellectual content. All authors approved the version of the article to be published.

Corresponding authors

Correspondence to Jianxin Gu, Jing Liu or Shifang Ren.

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The authors declare that they have no conflict of Interest.

Ethical Approval

This study was approved by Research Ethics Committee of Renji Hospital (ID: IRB #2016-075), Shanghai, China.

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Written informed consent was obtained from the individual recruited patients of the current study.

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Zhang, R., Guo, L., Sha, J. et al. α2,3-Sialylation with Fucosylation Associated with More Severe Anti-MDA5 Positive Dermatomyositis Induced by Rapidly Progressive Interstitial Lung Disease. Phenomics 3, 457–468 (2023). https://doi.org/10.1007/s43657-023-00096-z

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