Background/Purpose: Systemic sclerosis (SSc) is characterized by an initial inflammatory phase followed by fibrosis. Esophageal dysfunction in SSc is associated with Gastroesophageal Reflux Disease (GERD), which can lead to severe complications and contribute to fibrosis. SSc patients exhibit increased numbers of specific immune cells, such as CD14+ monocytes, fibrocytes, and tissue macrophages, which are correlated with disease severity and reduced survival. However, the role of macrophage populations in the esophagus and affected tissues remains poorly understood. This study aims to investigate the transcriptional heterogeneity of macrophages in the esophagus of SSc patients.

Methods: Esophageal biopsies were obtained from SSc patients, GERD patients without SSc, and healthy control patients. scRNA-Seq was performed on 20 samples and Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) was performed on 7 samples where CD45+ immune cells were isolated using fluorescence-activated cell sorting (FACS). Data were processed and analyzed using the 10X Genomics 3′ v3.0 pipeline and the Seurat package.

Results: Analysis of the integrated immune cell data identified 16 individual clusters from about 45,000 cells, including T cells, B cells, and various myeloid cell subsets. Within the myeloid subsets (18% of CD45+), 10 distinct clusters were identified, including multiple dendritic cell subsets (LAMP3⁺ ~5%) and macrophages. RNA expression analysis and protein expression confirmation revealed heterogeneity among macrophage subsets, characterized by differential expression of specific markers such as FABP4, CD11b, CD11c, and CCR2, and APOE as well as varying expression of HLA-antigens, indicating differences in antigen presentation capabilities. The number of macrophages was found to be increased up to 2-fold in SSc compared to GERD patients and healthy controls.

Conclusion: This is the first study to evaluate immune cells in the esophagus of SSc patients. We demonstrate the presence of diverse macrophage subsets within the esophagus of SSc patients, each potentially contributing to distinct functions and mechanisms in the pathogenesis of SSc. These findings underscore the importance of precisely identifying immune cell populations within affected organs and targeting specific subsets to effectively intervene in the inflammatory process of SSc. Future research will investigate the differential characteristics of these macrophage subsets compared to control and GERD patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigating-macrophage-heterogeneity-in-the-esophagus-of-ssc-patients/