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Background <p>Soluble CD13 (sCD13), generated through cleavage of membrane-bound CD13 by matrix metalloproteinase-14 (MMP14), exhibits proinflammatory, angiogenic, and arthritogenic properties. Its known receptors include bradykinin receptor B1 (B1R) and protease-activated receptor 4 (PAR4). Building on our previous findings that the sCD13-B1R axis contributes to fibrosis in systemic sclerosis (SSc), we investigated whether plasma sCD13 levels and gene expression by peripheral blood cells are associated with clinical features of SSc.</p> Methods <p>Plasma sCD13 levels were quantified by ELISA in SSc patients and healthy controls enrolled at the University of Michigan Scleroderma Program. Three independent patient cohorts were analyzed to assess associations with disease subtype, vascular complications, and early-stage disease. Public transcriptomic datasets were used to evaluate the expression of CD13-related genes in peripheral blood cells. Statistical analyses included t-tests, one-way ANOVA, chi-square tests, and correlation analyses, with significance defined as <i>p</i> &lt; 0.05.</p> Results <p>Plasma sCD13 levels were significantly elevated in SSc patients compared to healthy controls but showed no association with vascular complications or baseline severity of skin disease as shown by mRSS, interstitial lung disease, pulmonary function, and autoantibody profiles. In early-stage SSc, higher baseline sCD13 predicted greater improvement in skin fibrosis over one year (<i>r</i> = -0.42, <i>p</i> = 0.001), and longitudinal decline in sCD13 corelated with changes in DLCO% (<i>r</i> = 0.53, <i>p</i> = 0.04). Transcriptomic analysis revealed upregulation of <i>ANPEP</i> (CD13), <i>MMP14</i>, and <i>F2RL3</i> (PAR4) in SSc blood, with strong positive correlations between <i>ANPEP</i> and both <i>MMP14</i> and <i>F2RL3</i>. In addition, <i>ANPEP</i> and <i>MMP14</i> expression correlated with <i>TGFB1</i> and <i>IL6</i>, key cytokines in SSc pathogenesis. Single-cell data further localized <i>ANPEP</i> and <i>MMP14</i> expression to myeloid cells, particularly CD14⁺ and CD16⁺ monocytes and dendritic cells.</p> Conclusions <p>Our results demonstrate that circulating sCD13 reflects dynamic disease activity rather than static severity in SSc. Its expression in myeloid cells and linkage to fibrotic cytokines suggest an active role in disease pathogenesis. While systemic sCD13 alone may have limited biomarker utility, longitudinal monitoring and integration with tissue-level markers could enhance prediction of disease trajectory and therapeutic response.</p>

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Soluble CD13 in systemic sclerosis: clinical observations and transcriptomic insights from peripheral blood

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月10日

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  • Yuzo Ikari,
  • Chenyang Lu,
  • Alyssa Rosek,
  • Alexander Cai,
  • Neha Khanna,
  • James St Clair,
  • Anna Webber,
  • Caroline Foster,
  • Yi-Chen Chen,
  • Ramadan A. Ali,
  • Dinesh Khanna,
  • David A. Fox,
  • Pei-Suen Tsou

摘要

Background

Soluble CD13 (sCD13), generated through cleavage of membrane-bound CD13 by matrix metalloproteinase-14 (MMP14), exhibits proinflammatory, angiogenic, and arthritogenic properties. Its known receptors include bradykinin receptor B1 (B1R) and protease-activated receptor 4 (PAR4). Building on our previous findings that the sCD13-B1R axis contributes to fibrosis in systemic sclerosis (SSc), we investigated whether plasma sCD13 levels and gene expression by peripheral blood cells are associated with clinical features of SSc.

Methods

Plasma sCD13 levels were quantified by ELISA in SSc patients and healthy controls enrolled at the University of Michigan Scleroderma Program. Three independent patient cohorts were analyzed to assess associations with disease subtype, vascular complications, and early-stage disease. Public transcriptomic datasets were used to evaluate the expression of CD13-related genes in peripheral blood cells. Statistical analyses included t-tests, one-way ANOVA, chi-square tests, and correlation analyses, with significance defined as p < 0.05.

Results

Plasma sCD13 levels were significantly elevated in SSc patients compared to healthy controls but showed no association with vascular complications or baseline severity of skin disease as shown by mRSS, interstitial lung disease, pulmonary function, and autoantibody profiles. In early-stage SSc, higher baseline sCD13 predicted greater improvement in skin fibrosis over one year (r = -0.42, p = 0.001), and longitudinal decline in sCD13 corelated with changes in DLCO% (r = 0.53, p = 0.04). Transcriptomic analysis revealed upregulation of ANPEP (CD13), MMP14, and F2RL3 (PAR4) in SSc blood, with strong positive correlations between ANPEP and both MMP14 and F2RL3. In addition, ANPEP and MMP14 expression correlated with TGFB1 and IL6, key cytokines in SSc pathogenesis. Single-cell data further localized ANPEP and MMP14 expression to myeloid cells, particularly CD14⁺ and CD16⁺ monocytes and dendritic cells.

Conclusions

Our results demonstrate that circulating sCD13 reflects dynamic disease activity rather than static severity in SSc. Its expression in myeloid cells and linkage to fibrotic cytokines suggest an active role in disease pathogenesis. While systemic sCD13 alone may have limited biomarker utility, longitudinal monitoring and integration with tissue-level markers could enhance prediction of disease trajectory and therapeutic response.