Periodic Reporting for period 1 - IgG4-TREAT (Systematic study of IgG4-autoimmune diseases to develop new treatment strategies)
Reporting period: 2023-09-01 to 2025-08-31
Autoimmune diseases are the result when the immune system targets its own organs and tissues. We recently described a specific group of autoimmune diseases, termed "IgG4-mediated autoimmune diseases" (IgG4-AID), which are caused by a specific antibody type, IgG4. These diseases can affect different organs, including the brain, nerves, and muscles, and while each is rare, together they impact an estimated half a million people across the European Union. Patients often experience delayed diagnosis, limited treatment options, and relapses despite therapy, leading to long-term health problems and reduced quality of life.
The IgG4 subclass has unique biological properties that distinguish it from other antibodies. Instead of activating the immune system, IgG4 interferes with cellular communication and tissue integrity, representing a new paradigm in autoimmunity. It is unclear why the immune system produces harmful IgG4 antibodies, and current treatments rely on non-specific immunosuppression or plasma exchange, which are not equally effective for all patients and may cause serious side effects.
The IgG4-TREAT addressees knowledge gaps by combining scientific excellence and interdisciplinary training within a EU research network. Experts in neuroimmunology, molecular biology, and clinical sciences collaborate to uncover the cellular, molecular, and genetic mechanisms driving pathogenic IgG4 antibodies. By analysing patient samples and advanced molecular profiling, the consortium aims to identify disease drivers and biomarkers that can guide the development of new, targeted therapies. Further, IgG4-TREAT aims to develop a new disease model and an innovative therapeutic approach capable of selectively removing harmful IgG4 antibodies without affecting beneficial ones.
Beyond its scientific objectives, IgG4-TREAT is dedicated to train the next generation of scientists by offering an innovative training programme. The project fosters responsible and inclusive research practices, including sustainable laboratory work, gender equality, resilience in academia, and open science. By integrating advanced research with high-quality training, IgG4-TREAT contributes to improved understanding and treatment of rare autoimmune diseases, enhances diagnostic precision, and strengthens EU leadership in biomedical innovation. The long-term impact is expected to include better patient outcomes, improved healthcare, and new opportunities for biomedical innovation across Europe.
The IgG4 subclass has unique biological properties that distinguish it from other antibodies. Instead of activating the immune system, IgG4 interferes with cellular communication and tissue integrity, representing a new paradigm in autoimmunity. It is unclear why the immune system produces harmful IgG4 antibodies, and current treatments rely on non-specific immunosuppression or plasma exchange, which are not equally effective for all patients and may cause serious side effects.
The IgG4-TREAT addressees knowledge gaps by combining scientific excellence and interdisciplinary training within a EU research network. Experts in neuroimmunology, molecular biology, and clinical sciences collaborate to uncover the cellular, molecular, and genetic mechanisms driving pathogenic IgG4 antibodies. By analysing patient samples and advanced molecular profiling, the consortium aims to identify disease drivers and biomarkers that can guide the development of new, targeted therapies. Further, IgG4-TREAT aims to develop a new disease model and an innovative therapeutic approach capable of selectively removing harmful IgG4 antibodies without affecting beneficial ones.
Beyond its scientific objectives, IgG4-TREAT is dedicated to train the next generation of scientists by offering an innovative training programme. The project fosters responsible and inclusive research practices, including sustainable laboratory work, gender equality, resilience in academia, and open science. By integrating advanced research with high-quality training, IgG4-TREAT contributes to improved understanding and treatment of rare autoimmune diseases, enhances diagnostic precision, and strengthens EU leadership in biomedical innovation. The long-term impact is expected to include better patient outcomes, improved healthcare, and new opportunities for biomedical innovation across Europe.
IgG4-TREAT brings together a pan-European consortium to advance understanding and treatment of IgG4-AID. Early in the project, a European biobank for IgG4-AID biosamples was established. It now contains more than 750 carefully characterized biological samples. This resource enables comparative analyses across different IgG4 diseases, identification of shared mechanisms, and discovery of biomarkers. It represents a unique and lasting infrastructure for future research.
A major focus of the project has been to uncover why and how the immune system starts producing pathogenic IgG4 antibodies. Using genetic and molecular profiling, researchers have identified regions of the genome that increase susceptibility to specific IgG4 autoimmune diseases and have discovered molecules in patient blood that vary with disease activity. These findings provide valuable clues for diagnostic and therapeutic development.
The project also investigates what makes IgG4 antibodies harmful at the molecular level. IgG4 molecules can undergo structural changes that influence their interactions with tissues and other immune components. Using advanced methods such as mass spectrometry and protein engineering, researchers are studying how these structural variations affect disease mechanisms and immune regulation. Newly cloned antibodies from patients are being analyzed to understand how they disrupt normal cellular communication and contribute to tissue dysfunction.
At the translational level, the consortium is developing a new disease model and a new therapeutic strategy designed to selectively eliminate pathogenic IgG4 antibodies. This work paves the way for more precise and personalized therapies for patients affected by these rare diseases.
A major focus of the project has been to uncover why and how the immune system starts producing pathogenic IgG4 antibodies. Using genetic and molecular profiling, researchers have identified regions of the genome that increase susceptibility to specific IgG4 autoimmune diseases and have discovered molecules in patient blood that vary with disease activity. These findings provide valuable clues for diagnostic and therapeutic development.
The project also investigates what makes IgG4 antibodies harmful at the molecular level. IgG4 molecules can undergo structural changes that influence their interactions with tissues and other immune components. Using advanced methods such as mass spectrometry and protein engineering, researchers are studying how these structural variations affect disease mechanisms and immune regulation. Newly cloned antibodies from patients are being analyzed to understand how they disrupt normal cellular communication and contribute to tissue dysfunction.
At the translational level, the consortium is developing a new disease model and a new therapeutic strategy designed to selectively eliminate pathogenic IgG4 antibodies. This work paves the way for more precise and personalized therapies for patients affected by these rare diseases.
IgG4-TREAT has created the first transnational and multidisciplinary research network focused on the comparative study of IgG4-AID. Its biobank constitutes the first EU infrastructure combining clinical, molecular, and biological information, which will allow future collaborative research on IgG4-AID. IgG4-TREAT is advancing knowledge on how IgG4 antibodies are produced and cause disease. Through the integration of state-of the art methodology such as single-cell technologies, multi-omics profiling, and comparative genomics, the consortium has already identified new genetic and molecular factors that can affect the production of IgG4 autoantibodies. These discoveries constitute the basis for research into more targeted therapeutic approaches.
On the technological level, the project’s work on new disease models and innovative therapies aimed at the reduction of IgG4 autoantibodies will offer an innovative alternative to current plasma exchange treatments. This selective removal of harmful antibodies has strong potential for clinical translation, offering improved safety and efficacy.
Beyond scientific and technological progress, IgG4-TREAT contributes to long-term societal and strategic goals. Its structured training programme will equip the next generation of scientists with interdisciplinary expertise in translational medicine, but also on sustainability, gender inclusion, open science, and responsible research.
To ensure continued progress and uptake, further research funding will be needed to validate newly discovered biomarkers and therapeutic targets. Partnerships with clinical centres, biotech companies, and patient organisations will support this translation and ensure that innovations reach those in need.
On the technological level, the project’s work on new disease models and innovative therapies aimed at the reduction of IgG4 autoantibodies will offer an innovative alternative to current plasma exchange treatments. This selective removal of harmful antibodies has strong potential for clinical translation, offering improved safety and efficacy.
Beyond scientific and technological progress, IgG4-TREAT contributes to long-term societal and strategic goals. Its structured training programme will equip the next generation of scientists with interdisciplinary expertise in translational medicine, but also on sustainability, gender inclusion, open science, and responsible research.
To ensure continued progress and uptake, further research funding will be needed to validate newly discovered biomarkers and therapeutic targets. Partnerships with clinical centres, biotech companies, and patient organisations will support this translation and ensure that innovations reach those in need.