Dysregulation of the cytotoxic-humoral axis and expansion of regulatory T cells in anti-TIF1γ- positive dermatomyositis

Abstract

Introduction Dermatomyositis (DM), particularly the anti-TIF1γ‑positive subtype, is associated with a substantially elevated risk of malignancy. However, the peripheral immune landscape of this autoantibody-defined subset, especially in patients without concurrent cancer, remains incompletely understood. Methods We performed single‑cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from five patients with anti‑TIF1γ‑positive DM (the subtype with the highest malignancy risk) and compared their profiles with those of two other DM subtypes: anti‑MDA5‑positive DM (intermediate malignancy risk) and anti‑synthetase syndrome (ASyS, low malignancy risk). Results All three subtypes exhibited profound immune remodeling, characterized by reduced frequencies of cytotoxic lineage cells. Anti‑TIF1γ‑positive DM showed a compensatory shift toward humoral immunity, with increased B‑lineage cells, whereas classical monocyte elevation was specific to the anti‑MDA5‑positive DM and ASyS subtypes. Notably, anti‑TIF1γ‑positive DM was uniquely distinguished by an increased frequency of immunosuppressive regulatory T (Treg) cells, a finding validated by immunohistochemistry in patient skin tissue. Conclusion These results delineate a peripheral immunological signature of anti‑TIF1γ‑positive DM, marked by compromised cytotoxic surveillance, aberrant humoral responses, and selective Treg enrichment. We hypothesize that this Treg elevation may contribute to an immunosuppressive milieu that favors malignancy, although this mechanism remains speculative and requires functional validation in prospective cohorts.