TI-3: The Complement Network as a Novel target in CIBD

Coordinators: J. Köhl (UzL), C. Kemper (UzL), E. Schmidt (UzL)

The immune system and the networks that regulate it determine the origin and the development of chronic inflammatory barrier diseases (CIBD). The so-called complement system is part of the innate immune system, and thus an integral part of these regulatory networks. A goal of TI-3 is to uncover the underlying mechanisms behind the complex activation and regulation of the complement system in pemphigoid diseases as prototypical inflammatory diseases. Pemphigoid diseases are autoimmune diseases of the skin, in which blisters and erosions form on the skin and mucous membranes close to the surface. The findings from TI-3 should pave the way for new, individualized diagnostic and therapeutic approaches to these inflammatory diseases.

What does this research area’s work build on?

The complement system consists of soluble and cell-bound molecules which network with other humoral and cellular components of the innate immune system. Members of TI-3 have recently demonstrated that the complement system is not only a serum system, but that many immune cells can produce complement proteins locally in tissue, divide them and activate them within the cell by specific proteases. In order to better understand these new functions of the system, the TI-3 researchers have developed unique tools that provide detailed insights into the regulation of the system. These are important for understanding the immune mechanisms which underlie chronic inflammatory diseases. Thus, autoreactive IgG antibodies often cause massive local and/or systemic complement activation in patients with pemphigoid diseases, but this varies considerably between individual patients.

 

What are the main research objectives?

An important goal is the characterization of the systemic and local complement activation, and the expression of complement receptors in experimental and human autoimmune diseases of the skin. This knowledge should be used to identify the patient groups where the complement activation drives the auto-antibody-mediated skin inflammation. Furthermore, the effects of local complement production and activation on the activation and regulation of immunological networks should be determined in the context of pemphigoid diseases. In addition, in TI-3 the bilateral relationship between local complement production and activation and the composition and diversity of the skin microbiome should be defined, since the microbiome interacts extensively with the innate and acquired immune system.

 

What makes this research area special?

With the complement system, this research area focuses on a part of the innate immune system which - in the context of chronic inflammatory diseases - has previously only been insufficiently researched and understood. By using new reporter systems for the detection and differential activation of the complement system, this research area offers new approaches to individual diagnostics and treatment of chronic inflammatory diseases. This is being investigated experimentally and clinically in different groups of patients with pemphigoid disorders.

 

What does the research area contribute to precision medicine in chronic inflammation?

The results from TI-3 should lead to a new classification of patients with pemphigoid diseases which is based on the patterns of their local canonical and non-canonical complement activation. Detailed mechanistic insights into the activation of complement-mediated signaling pathways should be used in order to develop new therapeutic approaches which block the defined complement signaling pathways and/or receptors. A specific complement inhibitor developed in the Köhl laboratory is available for this purpose. In addition, the bilateral relationship between the local complement activation and the composition and diversity of the microbiome should be decoded, with the aim of specifically modulating this interaction.

 

Cooperation with other research areas in the cluster

TI-3 works closely with RTFs I, III and IV, from which it receives the data that details the individual genomic, metagenomic and immunophenotypic differences between the patients. For the microbiome analysis of the skin in experimental pemphigoid models, as well as from pemphigoid patients, TI-3 collaborates closely with TI-1, CD-5 and the CCIMs.