Project

SciFiMed, European Horizon 2020 Research Consortium on the Factor H protein family

Goal: Inflammation is a common denominator of diseases. The complement system, an intrinsic part of the innate immune system, is a key driver of inflammation in numerous disorders. Recently, a family of proteins has been suggested to be of vital importance in conditions characterized by complement deregulation: the human Factor H protein family. This group of proteins consists of Factor H, Factor H-like protein 1, and the five Factor H-related proteins. This protein family has been linked to infectious, vascular, eye, kidney, and autoimmune diseases. In contrast to Factor H, the functions of the other highly homologous proteins are largely unknown and, hence, their role in the different disease-specific pathogenic mechanisms remains elusive.

Using a biosensor approach, we aim to develop a novel analytic tool for the complete Factor H protein family. We will utilize various molecular approaches to investigate the structural and functional differences of these (at least) seven highly similar family members. Subsequently, this knowledge will allow us to, not only quantify levels but also assess functional activity in various samples. The development of a point-of-care biosensor for the detection of the Factor H protein family will then enable the scientific and clinical community to advance our understanding of the Factor H protein family in infectious, vascular, eye, kidney, and autoimmune diseases. These disorders can be difficult to treat and some are even incurable. Correspondingly, the vision of this consortium is to improve quantification and functional discrimination of all Factor H protein family members to enable the identification and validation of new therapeutic targets.

SCIFIMED: Our consortium consists of eight partners from four different countries and our project “Screening of inFlammation to enable personalized Medicine” (SciFiMed) has received significant funding from the European Union. SciFiMed promotes young scientists, gender balance and has a female coordinator. Our consortium consists of an excellent multidisciplinary team of engineers, chemists, geneticists, immunologists, and physicians while being advised by an interdisciplinary, international scientific board.

Through our project, we hope to propel immunological research in Europe, enable new product development of bioanalytical companies, modernize the EU-diagnostic market and provide new perspectives for patients, which in turn will pave the way for novel approaches for drug development.

More info: https://www.scifimed.eu/
Twitter: @SciFiMed

SciFiMed is funded by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No 899163.

Date: 30 December 2020 - 30 December 2024

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Project log

Mihály Józsi
added a research item
Components of the extracellular matrix (ECM), when exposed to body fluids may promote local complement activation and inflammation. Pathologic complement activation at the glomerular basement membrane and at the Bruch’s membrane is implicated in renal and eye diseases, respectively. Binding of soluble complement inhibitors to the ECM, including factor H (FH), is important to prevent excessive complement activation. Since the FH-related (FHR) proteins FHR1 and FHR5 are also implicated in these diseases, our aim was to study whether these FHRs can also bind to ECM components and affect local FH activity and complement activation. Both FH and the FHRs showed variable binding to ECM components. We identified laminin, fibromodulin, osteoadherin and PRELP as ligands of FHR1 and FHR5, and found that FHR1 bound to these ECM components through its C-terminal complement control protein (CCP) domains 4-5, whereas FHR5 bound via its middle region, CCPs 3-7. Aggrecan, biglycan and decorin did not bind FH, FHR1 and FHR5. FHR5 also bound to immobilized C3b, a model of surface-deposited C3b, via CCPs 3-7. By contrast, soluble C3, C3(H2O), and the C3 fragments C3b, iC3b and C3d bound to CCPs 8-9 of FHR5. Properdin, which was previously described to bind via CCPs 1-2 to FHR5, did not bind in its physiologically occurring serum forms in our assays. FHR1 and FHR5 inhibited the binding of FH to the identified ECM proteins in a dose-dependent manner, which resulted in reduced FH cofactor activity. Moreover, both FHR1 and FHR5 enhanced alternative complement pathway activation on immobilized ECM proteins when exposed to human serum, resulting in the increased deposition of C3-fragments, factor B and C5b-9. Thus, our results identify novel ECM ligands of FH family proteins and indicate that FHR1 and FHR5 are competitive inhibitors of FH on ECM and, when bound to these ligands, they may enhance local complement activation and promote inflammation under pathological conditions.
Mihály Józsi
added a research item
Besides being a key effector arm of innate immunity, a plethora of non-canonical functions of complement has recently been emerging. Factor H (FH), the main regulator of the alternative pathway of complement activation, has been reported to bind to various immune cells and regulate their functions, beyond its role in modulating complement activation. In this study we investigated the effect of FH, its alternative splice product FH-like protein 1 (FHL-1), the FH-related (FHR) proteins FHR-1 and FHR-5, and the recently developed artificial complement inhibitor mini-FH, on two key innate immune cells, monocytes and neutrophilic granulocytes. We found that, similar to FH, the other factor H family proteins FHL-1, FHR-1 and FHR-5, as well as the recombinant mini-FH, are able to bind to both monocytes and neutrophils. As a functional outcome, immobilized FH and FHR-1 inhibited PMA-induced NET formation, but increased the adherence and IL-8 production of neutrophils. FHL-1 increased only the adherence of the cells, while FHR-5 was ineffective in altering these functions. The adherence of monocytes was increased on FH, recombinant mini-FH and FHL-1 covered surfaces and, except for FHL-1, the same molecules also enhanced secretion of the inflammatory cytokines IL-1β and TNFα. When monocytes were stimulated with LPS in the presence of immobilized FH family proteins, FH, FHL-1 and mini-FH enhanced whereas FHR-1 and FHR-5 decreased the secretion of TNFα; FHL-1 and mini-FH also enhanced IL-10 release compared to the effect of LPS alone. Our results reveal heterogeneous effects of FH and FH family members on monocytes and neutrophils, altering key features involved in pathogen killing, and also demonstrate that FH-based complement inhibitors, such as mini-FH, may have effects beyond their function of inhibiting complement activation. Thus, our data provide new insight into the non-canonical functions of FH, FHL-1, FHR-1 and FHR-5 that might be exploited during protection against infections and in vaccine development.
Diana Pauly
added a research item
Complement Factor H-Related 3 (FHR-3) is a major regulator of the complement system, which is associated with different diseases, such as age-related macular degeneration (AMD). However, the non-canonical local, cellular functions of FHR-3 remained poorly understood. Here, we report that FHR-3 bound to oxidative stress epitopes and competed with FH for interaction. Furthermore, FHR-3 was internalized by viable RPE cells and modulated time-dependently complement component (C3, FB) and receptor (C3aR, CR3) expression of human RPE cells. Independently of any external blood-derived proteins, complement activation products were detected. Anaphylatoxin C3a was visualized in treated cells and showed a translocation from the cytoplasm to the cell membrane after FHR-3 exposure. Subsequently, FHR-3 induced a RPE cell dependent pro-inflammatory microenvironment. Inflammasome NLRP3 activation and pro-inflammatory cytokine secretion of IL-1ß, IL-18, IL-6 and TNF-α were induced after FHR-3-RPE interaction. Our previously published monoclonal anti-FHR-3 antibody, which was chimerized to reduce immunogenicity, RETC-2-ximab, ameliorated the effect of FHR-3 on ARPE-19 cells. Our studies suggest FHR-3 as an exogenous trigger molecule for the RPE cell “complosome” and as a putative target for a therapeutic approach for associated degenerative diseases.
Felix Poppelaars
added a research item
Primary IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and kidney failure for which there is no disease-specific treatment. However, this could change, since novel therapeutic approaches are currently being assessed in clinical trials, including complement-targeting therapies. An improved understanding of the role of the lectin and the alternative pathway of complement in the pathophysiology of IgAN has led to the development of these treatment strategies. Recently, in a phase 2 trial, treatment with a blocking antibody against mannose-binding protein-associated serine protease 2 (MASP-2, a crucial enzyme of the lectin pathway) was suggested to have a potential benefit for IgAN. Now in a phase 3 study, this MASP-2 inhibitor for the treatment of IgAN could mark the start of a new era of complement therapeutics where common diseases can be treated with these drugs. The clinical development of complement inhibitors requires a better understanding by physicians of the biology of complement, the pathogenic role of complement in IgAN, and complement-targeted therapies. The purpose of this review is to provide an overview of the role of complement in IgAN, including the recent discovery of new mechanisms of complement activation and opportunities for complement inhibitors as the treatment of IgAN.
Veronika Ehinger
added an update
We shot a short movie to introduce us, the project and the science behind it.
Head over to our youtube channel and have a look!
Let us know, what you think and if you learned something :-)
 
Felix Poppelaars
added a research item
Inflammation is a common denominator of diseases. The complement system, an intrinsic part of the innate immune system, is a key driver of inflammation in numerous disorders. Recently, a family of proteins has been suggested to be of vital importance in conditions characterized by complement dysregulation: the human Factor H (FH) family. This group of proteins consists of FH, Factor H-like protein 1 and five Factor H-related proteins. The FH family has been linked to infectious, vascular, eye, kidney and autoimmune diseases. In contrast to FH, the functions of the other highly homologous proteins are largely unknown and, hence, their role in the different disease-specific pathogenic mechanisms remains elusive. In this perspective review, we address the major challenges ahead in this emerging area, including 1) the controversies about the functional roles of the FH protein family, 2) the discrepancies in quantification of the FH protein family, 3) the unmet needs for validated tools and 4) limitations of animal models. Next, we also discuss the opportunities that exist for the immunology community. A strong multidisciplinary approach is required to solve these obstacles and is only possible through interdisciplinary collaboration between biologists, chemists, geneticists and physicians. We position this review in light of our own perspective, as principal investigators of the SciFiMed Consortium, a consortium aiming to create a comprehensive analytical system for the quantitative and functional assessment of the entire FH protein family.
Veronika Ehinger
added an update
Have an overview over SciFiMed on our fact sheet!
Different versions and languages are also available on our homepage in the downloads section.
 
Veronika Ehinger
added an update
SciFiMed has officially started and we are more than excited! Can't wait to start the research and to fulfill our vision of next level diagnostics by screening of inflammation to enable personalized medicine!
Find the press release and more information on the project and the team on our homepage:
 
Diana Pauly
added a project goal
Inflammation is a common denominator of diseases. The complement system, an intrinsic part of the innate immune system, is a key driver of inflammation in numerous disorders. Recently, a family of proteins has been suggested to be of vital importance in conditions characterized by complement deregulation: the human Factor H protein family. This group of proteins consists of Factor H, Factor H-like protein 1, and the five Factor H-related proteins. This protein family has been linked to infectious, vascular, eye, kidney, and autoimmune diseases. In contrast to Factor H, the functions of the other highly homologous proteins are largely unknown and, hence, their role in the different disease-specific pathogenic mechanisms remains elusive.
Using a biosensor approach, we aim to develop a novel analytic tool for the complete Factor H protein family. We will utilize various molecular approaches to investigate the structural and functional differences of these (at least) seven highly similar family members. Subsequently, this knowledge will allow us to, not only quantify levels but also assess functional activity in various samples. The development of a point-of-care biosensor for the detection of the Factor H protein family will then enable the scientific and clinical community to advance our understanding of the Factor H protein family in infectious, vascular, eye, kidney, and autoimmune diseases. These disorders can be difficult to treat and some are even incurable. Correspondingly, the vision of this consortium is to improve quantification and functional discrimination of all Factor H protein family members to enable the identification and validation of new therapeutic targets.
SCIFIMED: Our consortium consists of eight partners from four different countries and our project “Screening of inFlammation to enable personalized Medicine” (SciFiMed) has received significant funding from the European Union. SciFiMed promotes young scientists, gender balance and has a female coordinator. Our consortium consists of an excellent multidisciplinary team of engineers, chemists, geneticists, immunologists, and physicians while being advised by an interdisciplinary, international scientific board.
Through our project, we hope to propel immunological research in Europe, enable new product development of bioanalytical companies, modernize the EU-diagnostic market and provide new perspectives for patients, which in turn will pave the way for novel approaches for drug development.
Twitter: @SciFiMed
SciFiMed is funded by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No 899163.