Periodic Reporting for period 5 - iDysChart (Charting key molecules and mechanisms of human immune Dysregulation)
Berichtszeitraum: 2024-12-01 bis 2025-05-31
Inherited defects of the immune system (so-termed “inborn errors of immunity”, IEI, also known as primary immunodeficiencies) represent unique models to dissect essential nodes of the immune system. Many IEIs are characterized by autoinflammation or autoimmunity, which is the failure of the immune system to distinguish invading pathogens from self-resulting in inappropriate immune attacks on organs and tissues. Also, many common diseases are characterized by a multitude of autoimmune phenomena, however, the molecular mechanisms are often poorly understood.
Humans are constantly challenged by exposure to different pathogens, which has prompted evolution to develop sophisticated defenses, leading to the formation of the human immune system as we know it today. The main challenge for the immune system therefore is to recognize self and distinguish it from foreign (in form of pathogens or other antigens), to neutralize the latter. From an evolutionary point of view, high efficiency of immune responses enabling elimination of microbial threats is arguably more important than avoiding overreactive immune responses against self, and not surprisingly a vast number of human diseases are the result of misguided immune reactions leading to autoimmunity and/or autoinflammation.
We successfully achieved the following aims of the iDysChart project:
i.) identify novel etiologies of monogenic autoimmune/autoinflammatory diseases
ii.) dissect the molecular pathomechanisms involved in such diseases.
iii.) identify targets for a potential therapy
Humans are constantly challenged by exposure to different pathogens, which has prompted evolution to develop sophisticated defenses, leading to the formation of the human immune system as we know it today. The main challenge for the immune system therefore is to recognize self and distinguish it from foreign (in form of pathogens or other antigens), to neutralize the latter. From an evolutionary point of view, high efficiency of immune responses enabling elimination of microbial threats is arguably more important than avoiding overreactive immune responses against self, and not surprisingly a vast number of human diseases are the result of misguided immune reactions leading to autoimmunity and/or autoinflammation.
We successfully achieved the following aims of the iDysChart project:
i.) identify novel etiologies of monogenic autoimmune/autoinflammatory diseases
ii.) dissect the molecular pathomechanisms involved in such diseases.
iii.) identify targets for a potential therapy
We have made substantial progress in identifying and characterizing novel inborn errors of immunity (IEIs). Our work has led to the discovery of multiple new disease mechanisms, the development of diagnostic tools, and the identification of potential therapeutic targets. These findings have been disseminated through various publications in prestigious scientific journals, as well as presentations at different (international) conferences (oral and poster presentations).
Selected Key Scientific Results
We characterized CD137 deficiency as a newly discovered inborn error of immunity marked by lymphocyte abnormalities and early-onset EBV-associated lymphoma, revealing CD137’s crucial role in maintaining immune balance and antitumor defense (Blood, 2019).
By studying a previously unrecognized inborn error of immunity, we identified HEM1 as a critical regulator of B cell signaling intensity, essential for proper development and immune system balance (Science Immunology, 2020).
Mutations in the SYK (spleen tyrosine kinase) gene cause a newly identified immune disorder marked by constant SYK activation, leading to severe inflammation in the gut, skin, and nervous system, increased lymphoma risk, and potential for personalized treatment (Nature Genetics, 2021).
We contributed to the expansion of the Human Phenotype Ontology (HPO), improving rare disease diagnostics through machine learning and expert curation (Journal of Allergy & Clinical Immunology, 2021).
In a patient with HLH (hemophagocytic lymphohistiocytosis) symptoms and severely impaired CTL and NK cell function, biallelic mutations in RhoG revealed it as a key regulator of human lymphocyte cytotoxicity and the cause of a previously unrecognized genetic form of HLH (Blood, 2021).
We have identified a previously unknown germline inborn error of immunity involving a Helios-dependent epigenetic defect that disrupts T cell homeostasis. The study highlights Helios’s role in transcriptional regulation through its protein interactions, advancing our understanding of Ikaros family functions in immune balance. (Science Immunology, 2021). In a follow-up study, five different monoallelic Helios mutations were found in six patients with immune dysregulation, presenting with HLH, immune thrombocytopenia, or systemic lupus erythematosus. All cases showed disrupted interaction between Helios and the NuRD complex, leading to abnormal gene transcription and immune dysfunction. (Blood Advances, 2021).
The “AutoCore” study presents a network-based map of 186 inborn errors of immunity linked to autoimmunity and autoinflammation, identifying key molecular hubs and shared disease markers. By grouping these into 19 distinct endotypes, it offers a new framework for classifying immune dysregulation and guiding targeted therapies (Science Advances, 2023).
Together with our collaboration partners in Turkey, we have discovered that mutations in the NFATC1 gene cause an immune disorder by disrupting T cell metabolism. Notably, this metabolic defect could be partially corrected in vitro using anti-diabetic drugs like metformin or rosiglitazone. (Blood, 2023).
We have identified DOCK11 mutations as the cause of a previously unknown disease marked by systemic inflammation, infection susceptibility, anemia, and developmental delay. The study also revealed how DOCK11 regulates actin dynamics and inflammasome activation, linking cytoskeletal function to immune regulation. (New England Journal of Medicine, 2023).
In collaboration with partners from Turkey, we have identified a rare immune disorder caused by mutations in the LTBR gene, which disrupts the development of secondary lymphoid organs. This defect leads to severe immune deficiencies in children and highlights the critical role of these organs in protecting against life-threatening infections (Science Immunology, 2024).
Exploitation of Results
Several findings have direct clinical implications, such as the recommendation for early stem cell transplantation in CD27/CD70 deficiencies and the repurposing of metformin for NFATC1-related immune dysfunction.
The expanded HPO terms are integrated into diagnostic platforms, improving genomic interpretation in rare disease clinics.
Identified therapeutic targets (e.g. SYK, HEM1, Helios) are being explored in preclinical models and drug screening pipelines.
Dissemination Activities
Results have been published in top-tier journals including Blood, Nature Genetics, Science Immunology, Science Advances, and The New England Journal of Medicine.
Findings were presented at international conferences, such as the ESID Meetings 2022 and 2024, and the International Conference on Rare and Undiagnosed Diseases in Vienna in 2022.
Selected Key Scientific Results
We characterized CD137 deficiency as a newly discovered inborn error of immunity marked by lymphocyte abnormalities and early-onset EBV-associated lymphoma, revealing CD137’s crucial role in maintaining immune balance and antitumor defense (Blood, 2019).
By studying a previously unrecognized inborn error of immunity, we identified HEM1 as a critical regulator of B cell signaling intensity, essential for proper development and immune system balance (Science Immunology, 2020).
Mutations in the SYK (spleen tyrosine kinase) gene cause a newly identified immune disorder marked by constant SYK activation, leading to severe inflammation in the gut, skin, and nervous system, increased lymphoma risk, and potential for personalized treatment (Nature Genetics, 2021).
We contributed to the expansion of the Human Phenotype Ontology (HPO), improving rare disease diagnostics through machine learning and expert curation (Journal of Allergy & Clinical Immunology, 2021).
In a patient with HLH (hemophagocytic lymphohistiocytosis) symptoms and severely impaired CTL and NK cell function, biallelic mutations in RhoG revealed it as a key regulator of human lymphocyte cytotoxicity and the cause of a previously unrecognized genetic form of HLH (Blood, 2021).
We have identified a previously unknown germline inborn error of immunity involving a Helios-dependent epigenetic defect that disrupts T cell homeostasis. The study highlights Helios’s role in transcriptional regulation through its protein interactions, advancing our understanding of Ikaros family functions in immune balance. (Science Immunology, 2021). In a follow-up study, five different monoallelic Helios mutations were found in six patients with immune dysregulation, presenting with HLH, immune thrombocytopenia, or systemic lupus erythematosus. All cases showed disrupted interaction between Helios and the NuRD complex, leading to abnormal gene transcription and immune dysfunction. (Blood Advances, 2021).
The “AutoCore” study presents a network-based map of 186 inborn errors of immunity linked to autoimmunity and autoinflammation, identifying key molecular hubs and shared disease markers. By grouping these into 19 distinct endotypes, it offers a new framework for classifying immune dysregulation and guiding targeted therapies (Science Advances, 2023).
Together with our collaboration partners in Turkey, we have discovered that mutations in the NFATC1 gene cause an immune disorder by disrupting T cell metabolism. Notably, this metabolic defect could be partially corrected in vitro using anti-diabetic drugs like metformin or rosiglitazone. (Blood, 2023).
We have identified DOCK11 mutations as the cause of a previously unknown disease marked by systemic inflammation, infection susceptibility, anemia, and developmental delay. The study also revealed how DOCK11 regulates actin dynamics and inflammasome activation, linking cytoskeletal function to immune regulation. (New England Journal of Medicine, 2023).
In collaboration with partners from Turkey, we have identified a rare immune disorder caused by mutations in the LTBR gene, which disrupts the development of secondary lymphoid organs. This defect leads to severe immune deficiencies in children and highlights the critical role of these organs in protecting against life-threatening infections (Science Immunology, 2024).
Exploitation of Results
Several findings have direct clinical implications, such as the recommendation for early stem cell transplantation in CD27/CD70 deficiencies and the repurposing of metformin for NFATC1-related immune dysfunction.
The expanded HPO terms are integrated into diagnostic platforms, improving genomic interpretation in rare disease clinics.
Identified therapeutic targets (e.g. SYK, HEM1, Helios) are being explored in preclinical models and drug screening pipelines.
Dissemination Activities
Results have been published in top-tier journals including Blood, Nature Genetics, Science Immunology, Science Advances, and The New England Journal of Medicine.
Findings were presented at international conferences, such as the ESID Meetings 2022 and 2024, and the International Conference on Rare and Undiagnosed Diseases in Vienna in 2022.
We identified and published several previously unknown inborn errors of immunity, including forms of combined immunodeficiency. These discoveries advance the current state of the art and reveal potential targets for personalized therapies
We uncovered previously unknown genetic causes of immune dysregulation, including mutations in CD137, HEM1, SYK, RhoG, Helios, LTBR, NFATC1, and DOCK11. These discoveries have redefined our understanding of immune surveillance, inflammation, and cancer predisposition in children.
Our work has established new disease mechanisms, such as the role of RhoG in cytotoxic exocytosis and SYK in inflammasome activation, offering novel insights into immune cell biology.
We developed AutoCore, a pioneering network-based framework that organizes 186 IEIs into 19 molecular and clinical endotypes, providing a new classification system for immune disorders and guiding precision medicine approaches.
By contributing to the expansion of the Human Phenotype Ontology (HPO), we have improved the diagnostic accuracy of rare immune diseases, integrating machine learning with expert clinical knowledge.
We uncovered previously unknown genetic causes of immune dysregulation, including mutations in CD137, HEM1, SYK, RhoG, Helios, LTBR, NFATC1, and DOCK11. These discoveries have redefined our understanding of immune surveillance, inflammation, and cancer predisposition in children.
Our work has established new disease mechanisms, such as the role of RhoG in cytotoxic exocytosis and SYK in inflammasome activation, offering novel insights into immune cell biology.
We developed AutoCore, a pioneering network-based framework that organizes 186 IEIs into 19 molecular and clinical endotypes, providing a new classification system for immune disorders and guiding precision medicine approaches.
By contributing to the expansion of the Human Phenotype Ontology (HPO), we have improved the diagnostic accuracy of rare immune diseases, integrating machine learning with expert clinical knowledge.