Abstract
The objective of this study was to identify novel acetylation (Ac) modifications of the C1-inhibitor (C1-INH) and explain the association of the levels of autoantibodies against acetylated C1-INH peptides with the risk of developing systemic lupus erythematosus (SLE). Ac modifications of the C1-INH were identified and validated through in-gel digestion, nano-liquid chromatography-tandem mass spectrometry, immunoprecipitation, and Western blotting by using serum protein samples obtained from patients with SLE and age-matched healthy controls (HCs). In addition, the levels of serum C1-INH, Ac-protein adducts, and autoantibodies against unmodified and acetylated C1-INH peptides were measured. C1-INH levels in patients with SLE were significantly lower than those in HCs by 1.53-fold (p = 0.0008); however, Ac-protein adduct concentrations in patients with SLE were significantly higher than those in HCs by 1.35-fold (p = 0.0009). Moreover, immunoglobulin M (IgM) anti-C1-INH367–385 Ac and IgA anti-C1-INH367–385 Ac levels in patients with SLE were significantly lower than those in HCs. The low levels of IgM anti-C1-INH367–385 (odds ratio [OR] = 4.725, p < 0.001), IgM anti-C1-INH367–385 Ac (OR = 4.089, p = 0.001), and IgA anti-C1-INH367–385 Ac (OR = 5.566, p < 0.001) indicated increased risks for the development of SLE compared with HCs.
Highlights
Systemic lupus erythematosus (SLE) is a multisystem, chronic autoimmune disease characterized by a variety of variable clinical manifestations and a heterogeneous group of pathogenic autoantibodies produced through a breakdown of tolerance to nucleic acids and proteins, especially chromatin [1,2]
Novel Ac modifications of the C1-INH in serum were identified from a single pair of each of the nine pooled serum samples (HCs vs. patients with systemic lupus erythematosus (SLE)) by using 1D SDS-PAGE, in-gel digestion, nano-LC-MS/MS, and post-translational modifications (PTMs) finder in-house program through manual examination of modified spectra (Figure 1A,B and Supplementary Figure S1)
The peptide 367 -LEDMEQALSPSVFKAIMEK-385 was identified as SLE specific
Summary
Systemic lupus erythematosus (SLE) is a multisystem, chronic autoimmune disease characterized by a variety of variable clinical manifestations and a heterogeneous group of pathogenic autoantibodies produced through a breakdown of tolerance to nucleic acids and proteins, especially chromatin [1,2].According to the Taiwanese National Health Insurance Research Database, between 2003 and 2008, the average prevalence of SLE in Taiwan was 97.5 new cases (female-to-male ratio, 7.8) per 100,000 persons observed for 1 year; the highest prevalence in women was observed among those aged30–39 years, and that in men was observed among those aged 70–79 years. According to the Taiwanese National Health Insurance Research Database, between 2003 and 2008, the average prevalence of SLE in Taiwan was 97.5 new cases (female-to-male ratio, 7.8) per 100,000 persons observed for 1 year; the highest prevalence in women was observed among those aged. The average SLE incidence rate was 4.87 new cases (female-to-male ratio, 7.0) per 100,000 person-years; the highest incidence rate in women was observed among those aged 40–49 years, and that in men was observed among those aged >70 years. The average standardized mortality rate from SLE was 11.1 new cases (female-to-male ratio, 4.5) per 100,000 person-years [1]. Research reported several autoantibodies for detecting SLE, including antinuclear antibodies, anti-double-stranded DNA antibodies, anti-Smith antibodies, antinucleosome antibodies, antihistone antibodies, antiribosomal P antibodies, antiphospholipid antibodies, anticomplement component 1q antibodies, antiribonucleoprotein antibodies, and antiproliferating cell nuclear antigen antibodies [7]
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