Dual contribution of the spleen tyrosine kinase (SYK) to epidermolysis bullosa acquisita pathogenesis

Project: DFG ProjectsDFG Individual Projects

Project Details

Description

Epidermolysis bullosa acquisita (EBA) is a prototypical, organ-specific autoimmune disease caused by autoantibodies directed against type VII collagen (COL7). Over the past years, use of EBA animal models has significantly contributed to the understanding of the disease's pathogenesis. In contrast, the high medical need to develop novel treatments, has not been achieved so far. In the afferent phase of EBA pathogenesis, within a given genetic context, antigen-presenting cells induce a CD4-dependent B cell response, leading to the production of anti-COL7 autoantibodies. Recent evidence from our laboratory indicated that neutrophils and GM-CSF are also involved. The spleen tyrosine kinase (SYK) is central for both, B cell and neutrophil activation. Hence, SYK is a potential pharmaceutical target to modulate autoantibody production in experimental EBA (aim 1 of this proposal). The efferent phase is initiated by the binding of the autoantibodies to COL7, mainly located at the dermal-epidermal junction (DEJ) in the skin. This formation of immune-complexes (IC) at the DEJ establishes a pro-inflammatory milieu, resulting in the CD18-dependent recruitment of Gr-1 positive effector cells into the skin. In the skin, these effector leukocytes bind to the IC at the DEJ via specific, activating Fc gamma receptors (Fcgr). Through a signaling cascade involving PI3Kbeta, AKT, p38 and ERK1/2, reactive oxygen species (ROS) and proteases are released, ultimately causing subepidermal blistering. As SYK mediates Fcgr signaling, targeting SYK will most likely impair IC-induced activation of Gr-1 positive effector leukocytes in experimental EBA. These findings in the EBA mouse model will also be validated in a newly established mouse model of bullous pemphigoid. The potential therapeutic relevance will be evaluated in mice with already established (immunization-induced) EBA. As an exploratory aim, the contribution of other signaling molecules in experimental EBA pathogenesis will be tested both in vitro and in vivo. Ultimately, findings from mouse models will be (at least morphologically) validated in patient samples. To address these research questions, well-established models systems of EBA and BP will be used. In project-related preliminary work, we already established a key role of SYK for in vitro activation of neutrophils. Furthermore, pilot mouse experiments, using SYK-floxed and target cell-cre mice, indicate a cell type-specific contribution of SYK to blister formation in EBA. Given, our assumptions can be validated, SYK -and possibly additional signaling molecules- could emerge as potential new treatment options for patients with EBA, and possibly also BP.

Layman's description

Collectively we were able to demonstrate that: • Sykb is one of the major hub-genes expressed in the skin of mice with experimental EBA; • pharmacological SYK blockade dose-dependently and almost completely impairs induction of experimental EBA in mice induced by transfer of anti-COL7 IgG; • induction of anti-COL7 IgG-induced EBA requires SYK expression on cells of the myeloid, but not lymphoid linage; • SYK inhibition ablates signaling events downstream of SYK in immune complexactivated neutrophils; • Plaur and Fpr1 are involved in the SYK signaling pathway; • SYK is differentially expressed in skin with pemphigoid disease (BP and EBA) when compared to healthy control skin.

Key findings

Collectively we were able to demonstrate that: • Sykb is one of the major hub-genes expressed in the skin of mice with experimental EBA; • pharmacological SYK blockade dose-dependently and almost completely impairs induction of experimental EBA in mice induced by transfer of anti-COL7 IgG; • induction of anti-COL7 IgG-induced EBA requires SYK expression on cells of the myeloid, but not lymphoid linage; • SYK inhibition ablates signaling events downstream of SYK in immune complexactivated neutrophils; • Plaur and Fpr1 are involved in the SYK signaling pathway; • SYK is differentially expressed in skin with pemphigoid disease (BP and EBA) when compared to healthy control skin.

Statusfinished
Effective start/end date01.12.1430.11.19

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 205-19 Dermatology

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