Biology subjects

Schneider, A.-K.

Publications and source records attributed to Schneider, A.-K..

4 recordsLinked to original sources

bioRxiv2026

Targeting neutrophil signaling networks in immune complex-mediated autoimmune disease

Fragment crystallizable gamma receptor (Fc{gamma}R)-induced signaling is a crucial process that determines the cellular response to immune complexes (IC) in autoimmune diseases. In several diseases including pemphigoid diseases (PD), such as epidermolysis bullosa acquisita (EBA), or rheumatoid arthritis (RA), neutrophils are prominently involved as effector cells, while others such as immune thrombocytopenia (ITP) are independent of neutrophils. At the same time, most diseases are commonly treated by broad-range immunosuppression accompanied by severe risk for adverse effects. Signal transduction inhibitors (STIs) have been successfully applied in cancer therapy. However, their use in autoimmune diseases is an emerging, but so far understudied potential treatment avenue. Therefore, we screened a target-selective compound library consisting of 155 STIs in a neutrophil-based assay and conducted a multiplex kinase activity profiling with IC-stimulated neutrophils. Thus, we found novel potential therapeutic targets that were validated both in vitro in functional neutrophil assays and in vivo in murine models of EBA Here, we demonstrate that both systemic and topical treatment with several individual STIs is effective in a prophylactic approach in these models. Furthermore, therapeutic treatment with the BTK inhibitor ibrutinib in the immunization-induced EBA model reduced disease severity by approximately 85 % and showed efficacy in additional experimental models of EBA, arthritis, and ITP. Together, the present study contributes to the elucidation of Fc{gamma}R-dependent signaling in neutrophils and identifies multiple novel promising treatment options including inhibition of PLC, PDK-1, PKC, p38, DNA-PK, KSP, c-Met, TBK-1 and BTK for IC-mediated autoimmune diseases.

immunology↗

bioRxiv2026

A human immune system mouse model for preclinical evaluation of therapies in pemphigoid disease

Pemphigoid diseases (PD) including Epidermolysis bullosa acquisita (EBA) are rare immunoglobulin G (IgG)-driven autoimmune skin blistering diseases with limited therapeutic options. Mechanistically, chronic inflammation in the skin leads to disruption of the dermal-epidermal junction (DEJ) with a crucial contribution of Fc{gamma}R-mediated activation of myeloid immune cells such as neutrophils. Thus, targeting of kinases involved in Fc{gamma}R-dependent activation of myeloid immune cells holds great promise as a therapeutic strategy. In this study, we employ human immune system (HIS) mice featuring all major human leukocytes which allows to investigate the impact of therapeutics on human immune cells in vivo. In a passive transfer approach, repetitive application of collagen VII (COL7c) specific IgG was associated with skin inflammation including infiltration of activated human immune cells and thickening of the epidermis. While application of recombinant human G-CSF boosted myeloid cell maturation and thus disease severity, treatment with Fc{gamma}R-blocking antibodies impaired disease development confirming the crucial role of human cells. Finally, small molecule PDK1 inhibitor BX-795 abrogated development of skin inflammation associated with reduced leukocyte infiltration and activation supporting the role of PDK1 in Fc{gamma}R-driven immune cell activation. This study establishes the first in vivo model of EBA in HIS mice and reveals its suitability for pre-clinical screening and evaluation of therapeutic agents. Importantly, it highlights the potential of kinase inhibition for treatment of EBA.

immunology↗

bioRxiv2025

CDK7, CDK9, or CDK11 Inhibition Reduces Neutrophil-Driven Inflammation and Tissue Damage in Experimental Autoimmune Models

BackgroundCyclin-dependent kinases (CDKs) are involved in basic cellular processes like regulation of cell-cycle progression and transcription. However, recent data also indicate a specific role in terminally differentiated neutrophils by promoting reactive oxygen species (ROS) release, degranulation, neutrophil extracellular trap formation, or apoptosis. Since these mechanisms are implicated in multiple autoimmune diseases, we aimed to delineate the role of CDKs in IC-mediated autoimmune diseases both in vitro and in vivo. MethodsWe analyzed CDK gene expression in unstimulated and immune complex (IC)-stimulated neutrophils. Subsequently, we investigated the effect of pharmacological CDK inhibition on IC-activated neutrophil functions. To analyze the inhibitors in a more translational approach, we proceeded with the systemic and topical application of the effective inhibitors in a murine antibody transfer-induced local epidermolysis bullosa acquisita (EBA) model. The most efficient inhibitor, MC180295, was validated in two other IC-mediated models of autoimmune disease: Serum-transfer arthritis (STA), which also, but not exclusively, depends on neutrophils and immune thrombocytopenia (ITP), which is considered less neutrophil-dependent. ResultsWe found 14 CDKs expressed in unstimulated cells, while the IC-stimulation showed an upregulation of CDK2 and CDK4 expression. Inhibitors selectively targeting CDK1, CDK2, CDK4/6, CDK7, CDK9, CDK11, and CDK12 showed effects on different neutrophil functions (surface activation marker expression, ROS release, adhesion, apoptosis) in vitro. In the predominantly neutrophil-driven EBA model, we observed a reduction of disease severity upon treatment with CDK7, CDK9, or CDK11 inhibitors. Inhibiting these CDKs with topical THZ2, MC180295, or OTS964, respectively, also improved the clinical phenotype. In line with our hypothesis, MC180295 impaired the development of STA, but not ITP. ConclusionsCDK7, CDK11, and especially CDK9 inhibition show therapeutic potential in IC-driven neutrophil-mediated diseases such as rheumatoid arthritis and EBA.

immunology↗

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↗