High interleukin-35 expression is associated with the severity of rheumatic mitral stenosis

Front Immunol. 2025 Apr 8:16:1537497. doi: 10.3389/fimmu.2025.1537497. eCollection 2025.

Abstract

Background: Rheumatic mitral stenosis (RMS) is the most common manifestation of rheumatic heart disease, with high morbidity and mortality. Interleukin-35 (IL-35) is a novel anti-inflammatory cytokine associated with many autoimmune diseases. However, the relation between IL-35 expression and RMS remains unknown. We aimed to study IL-35 expression in RMS and its association with disease progression.

Methods: IL-35 concentration was analyzed in blood samples from 40 patients, including 20 moderate, 20 severe RMS, and 20 healthy controls by ELISA. Mitral valve (MV) IL-35 expression was determined by western blot and immunohistochemistry in patients with RMS (22 and 29 cases, respectively) in comparison to control specimens with mitral valve prolapsed (5 cases, respectively).

Results: IL-35 levels were significantly elevated in the blood of the RMS patients compared to those from healthy subjects(p<0.05) and positively correlated with the severity of RMS (r=0.317, p<0.05). The expression of IL-35 and its subunits (p35 and EBI3) was also detected in MV tissues of patients with moderate or severe RMS. The expression of IL-35 and its subunits (p35 and EBI3) had a positive association with the severity of RMS in MV tissues (r=0.528, p<0.01; r=0.561, p<0.001; r=0.456, p<0.01). Co-localization of p35 and EBI3 was seen in MV tissues of RMS patients in a predominantly perivascular pattern.

Conclusion: We show for the first time an increase of IL-35 level in the blood and MV tissues of RMS patients, which is strongly correlated with the severity of RMS. These results suggest that IL-35 plays an important regulatory role in the progression of RMS.

Keywords: EBI3; cytokine; interleukin-35 (IL-35); p35; rheumatic mitral stenosis.

MeSH terms

  • Adult
  • Biomarkers
  • Case-Control Studies
  • Disease Progression
  • Female
  • Humans
  • Interleukins* / blood
  • Interleukins* / metabolism
  • Male
  • Middle Aged
  • Minor Histocompatibility Antigens / metabolism
  • Mitral Valve / metabolism
  • Mitral Valve / pathology
  • Mitral Valve Stenosis* / blood
  • Mitral Valve Stenosis* / diagnosis
  • Mitral Valve Stenosis* / etiology
  • Mitral Valve Stenosis* / immunology
  • Mitral Valve Stenosis* / metabolism
  • Mitral Valve Stenosis* / pathology
  • Rheumatic Heart Disease* / blood
  • Rheumatic Heart Disease* / diagnosis
  • Rheumatic Heart Disease* / immunology
  • Rheumatic Heart Disease* / metabolism
  • Severity of Illness Index
  • Young Adult

Substances

  • interleukin-35, human
  • Interleukins
  • EBI3 protein, human
  • Biomarkers
  • Minor Histocompatibility Antigens

Grants and funding

The author(s) declare that financial support was received for the research and/or publication of this article. The research was supported by the Applied Basic Research Foundation of Yunnan Province (2017 FE467 (-096) and 202401AY070001-161), Clinical Medicine Center for Cardiovascular Disease of Yunnan Province (ZX2019-08-01), the Yunnan Provincial Clinical Medicine Research Special Program - Research Project on the Application of Diagnostic and Therapeutic Technologies and Capacity Enhancement Centered on Innovative Cardiovascular Diagnosis and Treatment Devices (202405AJ310003).