Dr Phill Hawkins, joint senior author of the paper commented, “This research is a nice example of how fundamental research into cell signalling pathways at the Babraham Institute provides the sort of detailed information that can help the pharmaceutical sector design drugs which can discriminate between pathology and normal physiology in the immune system.”
Neutrophils are a vital part of our front line defence against invading bacterial and fungal pathogens. They recognise pathogens using a number of specific strategies, including binding to antibodies (made by other immune cells called lymphocytes), which specifically bind to and coat the surface of the pathogen. Neutrophil recognition of these antibodies then triggers the release of toxic chemicals, involving the PI3K pathway, which help kill the pathogen. Unfortunately in auto-immune diseases the body makes mistakes, which lead to the production of antibodies against its own tissues; this results in inappropriate inflammation at the sites of ‘auto-antibody’ deposition as the body mounts an attack on its own tissues.
PI3Ks play a key role co-ordinating communication within cells, regulating a diverse range of activities including cell growth, metabolism, survival and movement. Once activated by receptors on the surface of cells, PI3K enzymes generate ‘signalling molecules’ to relay information from the receptors, triggered for example by the binding of antibodies, and generate an appropriate response by the cell. There are four different types of PI3Ks enzymes – PI3Ka, PI3Kβ, PI3Kg and PI3Kδ – enabling them to regulate a variety of cell functions and conferring distinct roles in maintaining health and in pathology. While the roles of PI3Ka, PI3Kg and PI3Kδ in the immune system are better characterised, the role of PI3Kβ has remained more elusive.
This study, in collaboration with academics in Germany, Hungary and the University of Cambridge, looked at the role of PI3Ks in the signalling pathways that link neutrophil recognition of antibodies to the release of toxic chemicals, including reactive oxygen species (ROS). They found that under circumstances where the neutrophil is stimulated by immobilised antibody-antigen immune complexes (which is analogous to those deposited in auto-immune disease) activation requires PI3Kβ and to a lesser extent PI3Kδ. Further, mice lacking PI3Kβ are significantly protected in models of auto-antibody driven inflammation. This research suggests that PI3Kβ may be a potential target to tackle auto-immune inflammatory diseases without compromising other essential aspects of the immune system.
The PI3K family is currently being targeted by the pharmaceutical industry in a range of therapeutic areas, including oncology and inflammation, thus it is hoped that this work will direct some of the existing interest in this area towards specifically targeting PI3Ks in auto-immune disease. Dr Hawkins explained, “We are currently exploring with Karus Therapeutics, a UK company based in Southampton, the potential of small molecule inhibitors of PI3Kβ/δ in the treatment of autoimmune diseases.”
Dr Stephen Shuttleworth, Chief Scientific Officer at Karus Therapeutics Ltd said, “The Babraham team’s research represents a critical development in both PI3K biology and translational research in immune-inflammatory diseases. At Karus, we have designed a novel, orally-active series of PI3Kβ/δ inhibitors, which have potential as a new class of personalised medicines; we are very excited about working with Dr Hawkins and Dr Stephens and to gaining further insight into the promise of these agents in the treatment of auto-immune inflammatory disorders.”
The Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC), is a centre for studying the basic biology of signalling inside and between cells, supporting BBSRC’s mission to drive advances in fundamental bioscience to underpin pharmaceuticals and for better health and wellbeing.
Professor Michael Wakelam, Director of the Babraham Institute said, “This work demonstrates the significant benefit of long-term funding by the BBSRC of research into the PI3K pathway and the benefits this can bring to understanding of both the normal and compromised state. With around 90 autoimmune diseases and the impact of ageing and medications on immune function, a greater understanding of how the immune system works is of direct relevance to promoting healthier lifespan. Our scientists seek to discover and characterise important pathways controlling healthy immune function, which may be targeted pharmaceutically to either boost or restrain aspects of the immune response. Results from these and other investigations may provide a rationale for the development of therapies to treat auto-immune diseases.”
Publication details:
PI3Kβ Plays a Critical Role in Neutrophil Activation by Immune Complexes
Science Signaling DOI: 10.1126/scisignal.2001104