Secondary lymphoid organs are specialized regions in the body where immune cells multiply and develop to respond to new pathogens like viruses and bacteria. An international team led by Kaan Boztug, CeMM Adjunct PI, Scientific Director of the CCRI and Professor at the Medical University of Vienna, has identified a completely new form of a rare disease that affects these organs, shedding light on the significance of these structures for the human immune system. A genetic defect – discovered by the researchers – 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 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 CeMM and the Medical University of Vienna (MedUni Vienna).

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. 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.

The Study “LTβR deficiency causes lymph node aplasia and impaired B cell differentiation” was published in Science Immunology on November 22, 2024. DOI: 10.1126/sciimmunol.adq8796

Funding: This work was supported by the European Research Council (ERC), the Austrian Research Promotion Agency (FFG), the P.T. Engelhorn Foundation, the Austrian Academy of Sciences, the Austrian Science Fund (FWF), the Scientific and Technological Research Council of Turkey and Alex’s Lemonade Stand Foundation for Childhood Cancer.