The role of complement in mucous membrane pemphigoid

Project: DFG ProjectsDFG Individual Projects

Project Details

Description

Mucous membrane pemphigoid (MMP) is an immunobullous disease with autoantibodies against components of the dermal-epidermal junction (DEJ) and predominant mucosal involvement. While the identification of the target antigens on the molecular has improved the diagnosis of MMP, treatment of the disease remains challenging. More specifically, (i) only three controlled therapeutic trials have been conducted, (ii) clinical response to immunosuppression in patients with severe disease, in particular with ocular lesions, is poor, and (iii) conjunctival fibrosis is irreversible and, in contrast to other pemphigoid diseases, causes permanent damage when treatment is delayed or ineffective. Hence, there is a so far unmet high medical need for more specific and safer treatments for MMP. In order to develop novel treatment options, which are based on a detailed understanding of MMP pathogenesis, we recently developed a pre-clinical MMP model, in which the disease is induced by transfer of anti-laminin 332 (a well-defined autoantigen in MMP) antibodies into adult mice. In this model, major immunopathological and clinical characteristics of the human disease including lesions on the skin and in the oral and conjunctival mucosa are recapitulated. Herein, we noted that clinical MMP manifestation depends on activating Fc gamma receptors (FcR) and the C5aR1, indicating a crucial contribution of the C5a/C5aR1-axis. To better understand the contribution of the C5 to MMP pathogenesis, we here, will address the following open research questions employing the MMP mouse model: (i) the kinetics and cellular source(s) of C5a (ii) C5aR1 expression, (iii) how C5a/C5aR1 interaction drives MMP pathogenesis, (iv) which pathways lead to C5 cleavage, and (v) the impact of complement-targeting compounds on MMP. For this purpose, we will employ the newly developed MMP mouse model in several complement reporter- and deficient mice, as well use established pharmacological inhibitors to block specific pathways known to form a C5-convertase. Ultimately, we will gain detailed insights into the contribution of the C5a/C5aR1-axis in MMP, which will identify therapeutic targets that allow a relatively specific intervention in MMP.
Statusfinished
Effective start/end date01.01.1931.12.22

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)
  • Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

  • 205-19 Dermatology
  • 204-05 Immunology

Funding Institution

  • DFG: German Research Association

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.