New immune pathway which results in immunodeficiency

Singapore doctors and scientists discover a novel mutation that impairs the immune system, using findings to devise treatment strategies

New immune pathway which results in immunodeficiency
Staining for the signalling protein NFκB (green) in skin cells from a healthy individual (left) and the patient (right) after immune stimulation. The patient’s novel NFKBIA variant impairs entry of NFκB into nucleus (blue). This defect led to changes in cytokine production, resulting in both immunodeficiency and multi-organ damage. (Copyright: A*STAR’s Institute of Molecular and Cell Biology)

Singapore, 27 October 2020 - Scientists from A*STAR’s Institute of Molecular and Cell Biology (IMCB), in collaboration with doctors from KK Women’s and Children’s Hospital (KKH), have discovered a new immune pathway based on an investigation of severe immunodeficiency caused by a novel mutation in the NFKBIA gene. The findings were published in The Journal of Clinical Investigation.

The immune system has to strike a delicate balance. While we need it to combat infections, over-activation at the wrong times can lead to damage to our own cells. Primary immunodeficiencies are rare diseases where this balance is disturbed, and can cause recurrent severe infections as well as the inability of the immune system to mount an appropriate response to the inflammation.

When doctors at the KK Women’s and Children’s Hospital (KKH) admitted a week-old baby with recurrent infections alongside lung, skin and liver damage, they roped in the help of A*STAR scientists to investigate the cause of this unprecedented disease and devise a treatment strategy. The research team found out that they were dealing with a rare primary immunodeficiency when they identified a new genetic variant in NFKBIA that changed the levels of soluble proteins called cytokines, produced by white blood cells to drive inflammation. Abnormally high production of one cytokine, IL-1β, was identified as the key derangement. Crucially, the clinical team was able suppress the patient’s disease by rational administration of the IL-1β-blocking drug, Anakinra, based on these scientific results.

The research team, comprising scientists from A*STAR’s IMCB, Singapore Immunology Network (SIgN) and Institute of Medical Biology (IMB), as well as doctors from KKH, discovered a previously unknown pathway, which controls IL-1β production. By replicating the mutation in pre-clinical and cellular models, experimental results conclusively showed that the patient’s genetic variant was the cause of IL-1β hyper-production, and hence the disease. These findings have implications for the development of treatments against liver disease and cancer that target this novel pathway.

“While other mutations in NFKBIA have been reported before to cause disease, this mutation has never before been identified. It is the only mutation in which hyper-production of IL-1β, severe liver cholestasis and systemic inflammation were documented. The research team believes the mutation limits immune responses via the suppression of many pro-inflammatory cytokines. Yet at the same time, it causes over-production of IL-1β, leading to liver damage and inflammation. Using this bedside-to-bench approach of identifying the underlying genetic causes of immunodeficiency diseases, previously unknown pathways which control immune responses can be revealed. These then serve as targets for personalised treatment strategies," said Dr John Connolly, a Research Director at IMCB and co-corresponding author of the study.

“Diagnosis and management of primary immunodeficiency diseases (PIDs) is both extremely challenging and rewarding. These rare diseases provide a window to better understand the complex immunity pathways,” said Dr Liew Woei Kang, Visiting Consultant and Paediatric Immunologist, KKH. “New PIDs are still being discovered and many do not have treatment protocols we can follow. It is thus great that we have research collaboration with A*STAR to work out the functional immunology pathways, and provide the best care to our patients.”

The research team will further examine which new mediators are responsible for controlling IL-1β production by this genetic variant, given that this regulatory association between the protein encoded in NFKBIA and IL-1β was not observed previously. As this novel pathway has also been a popular target for cancer drugs that failed trials due to inflammatory side effects, the team will investigate whether these new mediators are responsible for the failure of these drugs, and determine if the side effects can be circumvented.

About A*STAR’s Institute of Molecular and Cell Biology (IMCB)

The vision of Institute of Molecular and Cell Biology (IMCB) is to be a premier cell and molecular biology institute which addresses the mechanistic basis of human diseases and its mission is to conduct cutting-edge discovery research in disease pathways; to groom early career researchers to be future leaders in research; and to collaborate with medical and industry communities for research impact. IMCB plays an important role training and recruiting scientific talents, and has contributed to the development of other research entities in Singapore. Its success in fostering a biomedical research culture in Singapore has catalysed Singapore’s transformation into an international hub for biomedical research, development and innovation.

Funded by A*STAR, IMCB’s Discovery research comprises 5 major programmes: Cancer Cell Signalling, Multi-Modal Molecular (M3) Biology, Epigenetics and Diseases, iPS cell and Regenerative Medicine, and Technology and Translation. IMCB’s technologies and platforms focus on Genome-wide RNAi, Humanised Mouse Models, Proteomics and Protein Engineering, Gene Therapy and Gene Editing, and Molecular Histopathology.

For more information about IMCB, please visit www.a-star.edu.sg/imcb.

About the Agency for Science, Technology and Research (A*STAR)

The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector R&D agency. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit the economy and society. As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by improving societal outcomes in healthcare, urban living, and sustainability. A*STAR plays a key role in nurturing scientific talent and leaders for the wider research community and industry. A*STAR’s R&D activities span biomedical sciences to physical sciences and engineering, with research entities primarily located in Biopolis and Fusionopolis. For ongoing news, visit www.a-star.edu.sg.