Giant cell myocarditis lesions were characterized by increased CD4+ T cells and macrophages, with distinct spatial niches associated with disease progression.
Spatial proteomics and single-cell RNA sequencing reveal distinct immune niches and cellular interactions in giant cell myocarditis, providing novel insights into the molecular and spatial dynamics of inflammation.
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Abstract Background Giant cell myocarditis (GCM) is a rare and aggressive form of myocarditis characterized by extensive inflammation and multinucleated giant cells. The cellular heterogeneity and spatial organization within GCM lesions remain poorly understood, limiting advancements in therapeutic interventions. Objective This study aimed to characterize the immune cell composition, spatial organization, and interactions within GCM lesions and explore their associations with disease progression. Methods In this study, we applied spatial proteomics using the PhenoCycler-Fusion (PCF) platform to analyze cardiac tissue samples from four GCM patients and one healthy control. A panel of 31 antibodies was used to map the spatial distribution, cellular composition, neighborhood characteristics, and intercellular interactions within inflammatory niches of GCM. Cellular phenotyping and spatial clustering were performed, enabling the identification of distinct immune microenvironments. In addition, single-cell RNA sequencing (scRNA-seq) was performed to characterize the transcriptomic profiles of immune cells, providing complementary insights into the molecular features of GCM. Results Multiplexed imaging revealed heterogeneous spatial niches enriched in adaptive (CD4+ T cells, CD8+ T cells, B cells, Th1, and Treg) and innate immune cells (macrophages, neutrophils, dendritic cells, and monocytes) within GCM lesions. Compared to healthy controls, GCM tissues exhibited an increased abundance of macrophages and CD4+ T cells, with distinct spatial compartmentalization. Cellular neighborhood analysis identified three primary immune niches: (1) T cell-rich neighborhoods dominated by CD4+ and CD8+ T cells, (2) macrophage-enriched neighborhoods with dense infiltration of CD163+ and CD68+ macrophages, and (3) fibrosis-associated neighborhoods characterized by increased fibroblast and reduced immune cell presence. The proportions of these neighborhoods were associated with disease progression. Single-cell RNA sequencing revealed that CD4+ T cells exhibited pro-inflammatory Th1 characteristics. And macrophages displayed both inflammatory and tissue-repair signatures. Cross-modal integration of spatial and transcriptomic data highlighted spatial co-localization of pro-inflammatory T cells and macrophages in inflammatory niches, suggesting localized immune activation and tissue damage. Conclusions Our study provides a comprehensive spatial and transcriptomic map of immune cell heterogeneity and interactions within GCM lesions, revealing distinct immune niches and their associations with disease progression. The combination of PCF spatial proteomics and single-cell RNA sequencing offers novel insights into the molecular and spatial dynamics of inflammation and fibrosis in GCM, highlighting potential therapeutic targets for modulating immune responses in this disease.
Zhao et al. (Sat,) reported a other. Giant cell myocarditis lesions were characterized by increased CD4+ T cells and macrophages, with distinct spatial niches associated with disease progression.