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The following is a summary of “Granzyme K– and amphiregulin-expressing cytotoxic T cells and activated extrafollicular B cells are potential drivers of IgG4-related disease,” published in the April 2024 issue of Allergy & Immunology by Koga, et al.
IgG4-related disease (IgG4-RD) represents a type I immune disease characterized by dysregulated resolution of inflammation and wound healing, leading to immune-mediated fibrotic disorders. However, specific autoantibodies associated with IgG4-RD remain unidentified. For a study, researchers sought to gain an unbiased understanding of tissue-infiltrating T and B cells in IgG4-RD through single-cell RNA sequencing, as well as T-cell receptor and B-cell receptor sequencing.
Unbiased single-cell RNA sequencing analysis was performed on sorted CD3+ T and CD19+ B cells from affected tissues of patients with IgG4-RD. Additionally, T-cell receptor sequencing and B-cell receptor sequencing were conducted. Quantitative analyses of T-cell and B-cell subsets were performed in patients with IgG4-RD and compared to patients with Sjögren syndrome.
The study revealed that clonally expanded T cells in affected tissues were primarily Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells or GZMK+CD8+ T cells. These cytotoxic T cells co-expressed amphiregulin and TGF-β but lacked expression of immune checkpoints. Phenotypically heterogeneous tissue-infiltrating CD8+ T cells were also identified. Clonally expanded MKI67+ B cells and IgD−CD27−CD11c−CXCR5− double-negative 3 B cells were observed infiltrating affected tissue lesions. Notably, GZMK+CD4+ cytotoxic T cells were found to colocalize with MKI67+ B cells in the extrafollicular area of affected tissues.
The study suggested that these identified cells may participate in T-B collaborative events, indicating potential targets for therapy. Validation through orthogonal approaches, such as multicolor immunofluorescence and comparison with other disease groups, supported the central role of GZMK-expressing cytotoxic CD4+ and CD8+ T cells in the pathogenesis of inflammatory, fibrotic disorders.
Reference: sciencedirect.com/science/article/abs/pii/S0091674923024120