Analysis of the Correlation Between the Expression of T-Helper Type 17 Cell-Related Cytokines and Valve Damage in Rheumatic Heart Disease

Abstract

Introduction: Rheumatic heart disease (RHD) results from chronic inflammation and fibrosis of heart valves following untreated rheumatic fever, yet its immunopathology, particularly involving T helper 17 (Th17) cells and their cytokines, is not fully understood. Th17 cells are prominent drivers of inflammation and have been linked to various autoimmune diseases, suggesting their potential role in RHD-related valve damage. This study examines Th17-associated cytokines-interleukin (IL)-17, IL-6, IL-23, and IL-21-in RHD. IL-17 is known to amplify inflammation by inducing pro-inflammatory cytokines and recruiting neutrophils, likely exacerbating valve damage, while IL-6 plays a role in Th17 differentiation and may promote chronic inflammation linked to fibrosis. IL-23 sustains Th17 cells, thereby perpetuating the inflammatory cycle in RHD, and IL-21 influences Th17 cells and B cell responses, potentially linking adaptive immunity to valve pathology. Clarifying the roles of these cytokines could offer insights into novel therapeutic targets for mitigating inflammation and preventing disease progression in RHD.

Methods: This study included 20 patients with RHD undergoing mitral valve replacement (Group O) and 20 patients with degenerative mitral valve prolapse (Group C) as controls. We utilized immunohistochemical staining and hematoxylin and eosin staining to assess the expression of Th17 cell-related cytokines in heart valves. To explore the relationship between cytokine expression and valve damage, Spearman correlation analysis was conducted. For inter-group comparisons, we employed the Mann-Whitney U test and Wilcoxon rank-sum test for non-parametric data, facilitating the evaluation of significant differences in cytokine levels and other relevant variables.

Results: In Group O, the percentage of IL-17-positive cells in mitral valve tissue was 51.6 ± 18.4%, with an immunohistochemistry score of 3.7 ± 2.2. IL-21-positive cells constituted 54.2 ± 16.5% with a score of 5.2 ± 1.3, IL-6-positive cells were at 29.4 ± 17.3% (score of 3.9 ± 1.5), and IL-23-positive cells accounted for 33.7 ± 17.9% (score of 4.3 ± 1.6). All these cytokine levels were significantly higher in Group O compared to Group C (P < 0.05), and the expression levels of IL-17, IL-21, IL-6, and IL-23 in valve tissue positively correlated with heart valve damage (P < 0.05). The main findings indicated that patients with RHD had significantly elevated levels of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-10, compared to healthy controls. These elevated cytokine levels were associated with the severity of valve damage in RHD patients, suggesting a critical role of the inflammatory response in the progression of valve injury; specifically, higher concentrations of TNF-α correlated with more severe mitral regurgitation, while increased levels of IL-6 were linked to a higher grade of mitral stenosis.

Conclusion: The study reveals a significant association between Th17 cell-related cytokine expressions and valve damage in RHD patients, suggesting that targeting these cytokines may offer a promising strategy for treatment and prevention while highlighting their potential as biomarkers for assessing valve damage and the importance of managing inflammation to mitigate further cardiac complications.

Keywords: inflammatory response; mitral valve replacement; rheumatic heart disease; th17 cells; valve damage.

Figure 1. Contrast of IL-17 between groups

A: positive cell count; B: immunohistochemical score; *P < 0.05 vs. Group C; χ² = 12.60; p-value = 0.0004 Mean comparisons were conducted using the t-test; comparisons for categorical variables were carried out using the chi-square test.

Figure 2. Contrast of IL-17 between groups

A: positive cell count B: immunohistochemical score; *P < 0.05 vs. Group C; χ² = 13.79; p-value = 0.0002 Mean comparisons were conducted using the t-test; comparisons for categorical variables were carried out using the chi-square test.

Figure 3. Contrast of IL-6 expression between groups

A: positive cell count; B: immunohistochemical score; *P < 0.05 vs. Group C; χ² = 10.82; p-value = 0.001 Mean comparisons were conducted using the t-test; comparisons for categorical variables were carried out using the chi-square test.

Figure 4. Contrast of IL-23 expression between groups

A: positive cell count; B: immunohistochemistry score; *P < 0.05 vs. Group C; χ² = 9.90; p-value = 0.0016 Mean comparisons were conducted using the t-test; comparisons for categorical variables were carried out using the chi-square test

Figure 5. Immunohistochemistry scores for cytokines in mitral valve tissue

Figure 6. Proportion of positive cells for cytokines in mitral valve tissue