Recke, A. | bioRxiv Science

bioRxiv2025

ERK5 is required for neutrophil-mediated ROS release and essential in epidermolysis bullosa acquisita

Neutrophils are key effector cells in antibody-mediated autoimmune diseases, contributing to inflammation via the release of reactive oxygen species (ROS). Extracellular signal-regulated kinase 5 (ERK5), a member of the MAPK family, is expressed in neutrophils but its role in autoimmune disease pathogenesis remains unclear. We investigated the functional relevance of ERK5 in antibody-mediated autoimmune diseases by comparing neutrophil-dependent (epidermolysis bullosa acquisita, EBA; serum transfer arthritis, STA) and neutrophil-independent (immune thrombocytopenia, ITP) murine models using the small-molecule ERK5 inhibitor XMD8-92. In vitro, pharmacological ERK5 inhibition specifically reduced neutrophil ROS release and CD62L shedding without affecting adhesion, chemotaxis, or CD18 expression. No major effects on viability were observed. In vivo, ERK5 inhibition with XMD8-92 significantly ameliorated antibody transfer-induced EBA, supporting a critical role of neutrophil-derived ROS in disease pathogenesis. In STA and ITP, ERK5 inhibition did not affect clinical outcomes. Together, these findings highlight ERK5 as a regulator of neutrophil ROS release and a potential therapeutic target in ROS-driven autoimmune diseases such as EBA.

immunology↗

bioRxiv2025

CD19xCD3 bispecific T cell engager treatment induces remission in experimental pemphigoid disease

Pemphigoid diseases (PDs) are autoimmune disorders marked by autoantibodies (Aab) against skin and mucous membrane proteins, causing muco-cutaneous blistering in predominantly elderly patients. Since current therapeutics are often insufficient, PDs impose a significant morbidity and mortality burden. CD19xCD3 bispecific T cell engagers (TCEs) - originally developed for B cell malignancies - have shown promise in treatment-refractory autoimmune diseases like systemic sclerosis and rheumatoid arthritis. To explore their potential in PDs, we tested a murine CD19xCD3 TCE in a mouse model of epidermolysis bullosa acquisita (EBA), a prototypical PD. The TCE selectively depleted B cells in blood and bone marrow, but not spleen, of healthy mice. Mice with clinically manifest immunization-induced EBA were randomized to receive either the CD19xCD3 TCE or control treatment upon reaching a predefined disease severity. After 13 weeks, 45% of TCE-treated mice achieved remission, versus 23% of controls. This improvement correlated with reduced antigen-specific B cells, though total and antigen-specific IgG levels were unchanged. These findings suggest that CD19xCD3 TCE preferentially target autoreactive B cells and may be effective at lower doses than those used in oncology. Our data support the potential of CD19xCD3 bispecific T cell engagers as a therapeutic strategy for PDs. eTOC SynopsisGross, Jochimsen, Drager and colleagues demonstrate that CD19xCD3 bispecific T cell engagers, can selectively target autoreactive B cells and induce remission in a mouse model of pemphigoid disease, highlighting their potential as a novel therapeutic strategy for autoimmune blistering disorders.

immunology↗