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Granzyme K- and amphiregulin-expressing cytotoxic T cells and activated extrafollicular B cells are potential drivers of IgG4-related disease
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| Abstract | Background: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound hea...ling. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. Objective: We sought to perform single-cell RNA sequencing and T-cell receptor and B-cell receptor sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T and B cells. Methods: We performed unbiased single-cell RNA-sequencing analysis for the transcriptome and T-cell receptor sequencing and B-cell receptor sequencing on sorted CD3^+ T or CD19^+ B cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3^+ T-cell and CD19^+ B-cell subsets in 68 patients with IgG4-RD and 30 patients with Sjögren syndrome. Results: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4^+ cytotoxic T cells or GZMK^+CD8^+ T cells. These GZMK-expressing cytotoxic T cells also expressed amphiregulin and TGF-b but did not express immune checkpoints, and the tissue-infiltrating CD8^+ T cells were phenotypically heterogeneous. MKI67^+ B cells and IgD^-CD27^-CD11c^-CXCR5^- double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK^+CD4^+ cytotoxic T cells colocalized with MKI67^+ B cells in the extrafollicular area from affected tissue sites. Conclusions: The above-mentioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4^+ and CD8^+ T cells expressing GZMK, amphiregulin, and TGF-b in the pathogenesis of inflammatory fibrotic disorders.show more |
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| Created Date | 2024.04.04 |
| Modified Date | 2024.04.17 |