Dermatomyositis and antisynthetase syndrome disease activity is associated with the expansion of peripheral GZMB+CD4+ cytotoxic T cells

Abstract

Background Dermatomyositis (DM) and antisynthetase syndrome (ASS) are heterogeneous subsets of idiopathic inflammatory myopathies with persistent unmet needs in disease activity assessment and stratification. Although CD4+ T cells are recognized as important contributors to disease pathogenesis, the role of CD4+ cytotoxic T lymphocytes (CTLs) remains insufficiently defined. Methods Peripheral blood samples were collected from patients with DM (n = 50), patients with ASS (n = 14), and healthy donors (HDs, n = 20). The frequency of CD4+ cytotoxic T lymphocytes with expression of cytotoxic protein granzyme B (GZMB+CD4+ CTLs) was analyzed by flow cytometry to quantify GZMB+CD4+ CTLs and characterize their phenotype. Disease activity and severity were evaluated using standard clinical indices. Multiplex immunohistochemistry was performed on skin biopsy specimens from patients with DM (n = 4) to assess tissue infiltration and endothelial injury. Results The proportion of circulating GZMB+CD4+ CTLs was significantly increased in both DM and ASS compared with HDs. In patients, this population showed phenotypic features consistent with enhanced cytotoxicity and tissue trafficking, including increased fibroblast growth factor binding protein 2 (FGFBP2) expression and reduced circulating fractions of cells positive for C-X3-C motif chemokine receptor 1 (CX3CR1) and C-X-C motif chemokine receptor 3 (CXCR3). GZMB+CD4+ CTL frequency was positively associated with global disease activity and cutaneous activity, and decreased after treatment independently of specific drug regimens. Receiver operating characteristic analysis showed that circulating GZMB+CD4+ CTLs effectively distinguished active from remitting disease in both DM and ASS. In DM skin lesions, GZMB+CD4+ CTLs were abundant and were accompanied by increased endothelial apoptosis and enhanced HLA-DR expression. Conclusions Peripheral GZMB+CD4+ CTLs are expanded in DM and ASS and are closely associated with disease activity. Their accumulation in lesional tissue and association with endothelial injury support a potential pathogenic role, while their diagnostic performance suggests that they may serve as a biomarker and potential therapeutic target in these diseases.