New tools to analyse the complement system
The complement system is an important part of the body’s defence against pathogens, and malfunctions can leave people more susceptible to disease. The SciFiMed project team are developing new tools to analyse the FH family of proteins and build a deeper picture of diseases associated with dysregulation of the complement system, as Professor Diana Pauly explains.
The complement system forms an important part of the body’s defence against pathogens, reacting rapidly to the presence of foreign material, while also identifying and tagging cellular debris for removal by phagocytes. When this system is dysregulated or out of balance, it can leave individuals more susceptible to diseases. “A malfunctioning complement system can heighten susceptibility to infections, such as meningococcal infections. Conversely, an overactive complement system can lead to autoimmune diseases, where the body attacks itself,” explains Professor Diana Pauly, group leader of the experimental ophthalmology lab at Philipps University Marburg in Germany. While the complement system has been intensively studied over the years, some of the regulatory mechanisms are still not fully understood, a topic at the heart of the EU-backed SciFiMed project. “We are investigating the role of complement factor H (FH) and FH-related proteins (FHRs), which are key regulators of the complement system. FH is one of the most important inhibitors, while FHR proteins share structural domains with FH,” says Professor Pauly, the project’s Principal Investigator.
FHR proteins
flow assays using these new antibodies, opens up wider possibilities. Researchers can now conduct clinical studies across a variety of biomaterials for different diseases, where previously only genetic associations with these proteins had been established. “This allows us and other researchers to explore a wide range of diseases. Initially, our partners tested healthy individuals to establish baseline values, and we have conducted preliminary studies in patients with age-related macular degeneration, delirium, and stroke, showing promising trends that merit further exploration,” says Professor Pauly. The complement system is known to be involved in a broad spectrum of autoimmune diseases, and Professor Pauly says functional assays can help researchers build a fuller picture. “We know a fair amount about the complement system’s role in infections, but less about autoimmune diseases. These assays could help researchers find out how the complement system is involved in autoimmune diseases,” she outlines.
longer have to be sent to central laboratories, with a waiting time of a week or more for the results,” says Professor Pauly. “With lateral flow assays, doctors or medical technicians can check the FHR status directly on-site, allowing for immediate adjustments to potential therapies.”
A significant degree of progress has been made in this respect, and work is ongoing to improve the lateral flow assays, with the aim of moving towards commercialisation in the future. Currently the project’s lateral flow assay is capable of detecting three proteins - FHR-2, FHR-3, and FHR-4 - within the FH family in 15 minutes, while other assays are at different stages of development. “The quantitative assays and the antibodies have been commercialised and are available for researchers, while we are also developing at least two functional assays for the whole protein family,” outlines Professor Pauly.
The overarching goal in this research is to help improve the treatment of diseases associated
SciFiMed
Screening of inFlammation to enable personalized Medicine
Project Objectives
The function of the FH-related (FHR) proteins, important components of the complement system, is unclear, a topic at the heart of the SciFiMed project. The project consortium, bringing together eight partners from across Europe, are working together to develop tools to analyse these proteins, which will ultimately help researchers develop more effective therapies against a wide variety of diseases.
Project Funding
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 899163.
Project Partners
SciFiMed brings together an excellent multidisciplinary team of Engineers, Chemists, Geneticists, Immunologists, and Physicians from both academia and industry from four different countries.
https://www.scifimed.eu/our-team
Contact Details
Project Coordinator,
Professor Diana Pauly, Ph.D
Exp. Ophthalmologie, Augenheilkunde
AG Pauly
AWT-Nummer: 3911
Baldingerstraße
35043 Marburg
Germany
T: +49 170 2738864
E: diana.pauly@uni-marburg.de
W: https://www.scifimed.eu/ W: www.paulylab.de
There are generally considered to be five main FHR proteins. Researchers in the project aim to investigate their functions and gain a deeper understanding of their roles in disease development and progression. The FHRs share some structural similarities with FH, but Professor Pauly says there are also some clear differences. “The FH protein has some regulatory domains which are not present in the FHRs, while some of the FHRs have dimerization domains which are not present in the others,” she outlines. The project team is working to build a fuller picture of the impact of FHR proteins on disease, looking beyond genetic associations. “We know that changes in FHRs are associated with the development of specific diseases – or protection against others – especially in the eye and the kidney. But we only know that on a DNA basis,” explains Professor Pauly. “We have developed a variety of new tools to analyse each of the individual proteins in this FH family and get an idea of their function. We have commercialised new ELISAs (Enzyme-Linked Immunosorbent Assays) to detect FHR proteins.”
This allows researchers to identify cases where the concentration of these proteins is particularly high or low, and then investigate the impact on disease. Specific antibodies have also been generated through project partner, Sanquin, allowing researchers to distinguish between each of the proteins, which Professor Pauly says is an important development. “These tools, which are now available commercially through our partner Hycult, will be instrumental in advancing research,” she says. These antibodies are already proving invaluable for investigating the function of FHR proteins, while other tools are also under development in the project. “We have used these antibodies to stain FHR proteins in specific tissues for example, and to isolate them from tissue extracts for interaction studies. This helps us to identify the regulatory processes in which they are involved,” explains Professor Pauly. “We believe that this research will extend beyond SciFiMed, paving the way for many new discoveries.” The development of ELISA, as well as lateral
“A malfunctioning complement system can heighten susceptibility to infections, such as meningococcal infections. Conversely, an overactive complement system can lead to autoimmune diseases, where the body attacks itself.”
Personalised medicine
This research represents a step towards the goal of providing personalised care that more closely reflects the specific circumstances of individual patients. Clinical studies (although not on a personalised basis) are planned, which it is hoped will lead to the identification of biomarkers for disease development and treatment effectiveness. “This will help doctors provide more personalised treatment,” continues Professor Pauly. Researchers are also working to develop lateral flow assays capable of rapidly providing information to clinicians on the levels of FH and FHR proteins, which can then guide treatment. “We can imagine a scenario where blood samples, urine, or other samples that need FHR concentration measurements no
with dysregulation of the complement system. The tools developed in the project will help researchers build a deeper understanding of these diseases, believes Professor Pauly. “With the ELISA and the antibodies, we hope that researchers will push the science forward, conducting studies and uncovering the role of these proteins in infections and autoimmune diseases,” she says. This will ultimately contribute to the development of new, more effective therapies against a variety of different diseases. “The importance of the complement system is increasingly recognised, especially with the growing number of complement-targeting drugs that have been approved. This represents a significant opportunity for combating various diseases,” says Professor Pauly.
