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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 December 2023 issue of Allergy and Immunology by Koga et al.

IgG4-related disease (IgG4-RD) represents a fibrotic disorder within the spectrum of type I immune diseases characterized by a disturbed balance in inflammation resolution and wound healing. However, distinctive autoantibodies exclusive to IgG4-RD have not yet been pinpointed, prompting a thorough investigation into tissue-infiltrating T- and B-cell populations. Employing single-cell RNA sequencing (scRNA-seq), T-cell receptor (TCR) sequencing, and B-cell receptor (BCR) sequencing, the study group scrutinized sorted CD3⁺ T-cells and CD19⁺ B-cells derived from affected tissues of IgG4-RD patients. The results unveiled predominant clonally expanded Granzyme K (GZMK)-expressing CD4⁺ cytotoxic T cells (CTLs) or GZMK⁺CD8⁺ T cells within the tissue lesions. These CTLs exhibited amphiregulin and TGFβ expression but notably lacked immune checkpoint markers, showcasing their distinct phenotypic traits.

Moreover, tissue-infiltrating CD8⁺ T cells displayed substantial phenotypic diversity. The study also identified MKI67⁺ B cells and IgD-CD27-CD11c-CXCR5- double-negative 3 B cells exhibiting clonal expansion and tissue infiltration in the affected areas. Importantly, in the extrafollicular zones, GZMK⁺CD4⁺ CTLs were found to co-localize with MKI67⁺ B cells, indicating potential collaborative interactions between these cell populations. These findings suggest promising prospects for targeted therapeutic interventions that could potentially harness the T-B cell interplay observed in IgG4-RD pathogenesis. The validation of these results through multiple methodologies, including multicolor immunofluorescence and comparison with other disease cohorts, strengthens the crucial role of GZMK-expressing cytotoxic CD4⁺ and CD8⁺ T cells, along with amphiregulin and TGFβ, in the development of inflammatory, fibrotic disorders associated with IgG4-RD.

Source: sciencedirect.com/science/article/abs/pii/S0091674923024120