Genetic Defect in Secondary Immune Organs Causes Life-Threatening Infections in Children
(Vienna, November 22, 2024) An international team led by Kaan Boztug, MD has identified a new form of a rare disease that affects secondary lymphoid organs, shedding light on the significance of these structures for the human immune system. The discovered genetic defect leads to either the absence or significant dysfunction of these organs in several children. As a result, affected children suffer from recurring, life-threatening infections. The findings, published in Science Immunology, could significantly improve treatment options for patients with similar diseases.
Over the past years, the research group led by Univ.-Prof. Dr. Kaan Boztug has identified several rare genetic immune system disorders, characterizing the functions of key components of the immune system. Their work has also provided substantial new insights into the connection between immune deficiencies and the susceptibility to developing childhood tumors. Boztug, an expert in rare diseases, is the scientific director of the St. Anna Children’s Cancer Research Institute (CCRI), and conducts research at the Medical University of Vienna (MedUni Vienna) and CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences.
A New Type of Disease
The current study, conducted in collaboration with leading centers in Istanbul and Ankara, describes a novel rare disease that is remarkable in multiple ways. “In the DNA of the affected individuals, we identified mutations in the LTβR gene, which encodes the lymphotoxin-beta receptor (LTβR),” explains Dr. Bernhard Ransmayr, the study’s first author and a PhD student in Kaan Boztug’s laboratory. The patients lack all lymph nodes, including tonsils, and have a non-functional spleen. However, these secondary lymphoid organs are essential for activating the immune system and facilitating the differentiation, proliferation, and maturation of specialized immune cells. Consequently, these patients are unable to produce a sufficient quantity of protective antibodies.
Artificial Environment provides insights
Interestingly, the immune cells themselves are not directly affected by the genetic defect but are instead indirectly impaired due to the absence of the supportive environment provided by the secondary lymphoid organs. This was demonstrated by the team through laboratory experiments that mimicked the structure and function of lymph nodes. In this artificial environment, cells from the patients could develop normally into antibody-producing immune cells (B cells). This finding highlights the fundamental importance of interactions between surrounding cells (stromal cells) and immune cells for establishing an effective immune defense.
From Immune Genetics to Precision Medicine
Boztug emphasizes, “The discovery of the LTβR defect marks a significant advancement in our understanding of the architecture of immune organs and their role in human health. It illustrates how basic research can directly contribute to improving the lives of patients with rare diseases. Patients with LTβR mutations benefit from specialized care at immunodeficiency centers and corresponding medical support for their immune defense. A key insight from this research is that bone marrow transplantation—an established treatment for other immune deficiencies—would not succeed here, as the defect lies not within the immune cells themselves but in the structural components of lymphoid organs.” Future research aims to further decode the molecular mechanisms of LTβR within the human immune system and to develop potential therapeutic options.
Publication
LTβR deficiency causes lymph node aplasia and impaired B-cell differentiation Bernhard Ransmayr M.D., Sevgi Köstel Bal, M.D., Ph.D., Marini Thian, Ph.D., Michael Svaton, M.D., Ph.D., Cheryl van de Wetering, Ph.D., Christoph Hafemeister, Ph.D., Anna Segarra-Roca, M.Sc., Jana Block, Ph.D., Alexandra Frohne, M.Sc., Ana Krolo, Ph.D., Melek Yorgun Altunbas, M.D., Sevgi Bilgic Eltan M.D., Ayca Kıykım, M.D., Omer Aydiner, M.D., Selin Kesim, M.D., Sabahat Inanir M.D., Elif Karakoc-Aydiner, M.D., Ahmet Ozen M.D., Ümran AbaM.Sc., Aylin Çomak M.D., Gökçen Dilşa Tuğcu, M.D., Robert Pazdzior, Ph.D., Bettina Huber, Ph.D., Matthias Farlik, Ph.D., Stefan Kubicek, Ph.D., Horst von BernuthM.D., Ph.D., Ingrid Simonitsch-Klupp., Marta Rizzi, M.D., Ph.D., Florian Halbritter, Ph.D., Alexei V. Tumanov, M.D., Ph.D., Michael J Kraakman Ph.D., Ayşe Metin, M.D., Ph.D., Irinka Castanon Ph.D., Baran Erman Ph.D., Safa Baris, M.D., Kaan Boztug.D.