Research at the Babraham Institute, investigating how white blood cells known as B cells develop, has revealed that genes from the Phosphatidylinositol 3-kinase (PI3Ks) family of enzymes are critical in enabling the B cells to produce antibodies in the spleen and lymph nodes. PI3Ks are involved in a diverse range of activities inside cells, generating signalling molecules to control cell growth, proliferation, motility, survival and intracellular trafficking. Faults in these processes can lead to the development of cancer; consequently the PI3Ks are currently among the most hotly pursued drug targets in the pharmaceutical industry.
The PI3K enzymes are made up of two parts, a regulatory subunit and a catalytic subunit known as p110, of which there are four types (isoforms) -- p110 alpha, p110 beta, p110 gamma and p110 delta. Mutations in p110 alpha are seen in many cancers including breast and colon cancer and drugs inhibiting the activity of all four of these isoforms are being trialled as anti-cancer drugs. Published online in the journal Science Signaling, this is the first description of p110 alpha in immune cells. The findings suggest that drugs targetting p110 alpha specifically may retain significant anti-cancer effect without compromising immunity.
B cells start to develop in the bone marrow, before they mature and populate the spleen and lymph nodes, where they make antibodies to eliminate viruses and bacteria from the body. Previous studies suggested a non-essential role for the PI3K family in early B cell development. However, this research at the Babraham Institute, an institute of BBSRC, has shown that if both p110 alpha and p110 delta are inhibited, no B cells develop. The spleen and lymph nodes of mice lacking both p110 alpha and p110 delta genes were devoid of B cells and virtually no antibodies could be found in the blood. Hence, blocking these enzymes together would have a dramatic effect on the immune system.
The p110 gamma and p110 delta isoforms are produced in cells of the immune system but are not found in other organs and tissues. They are therefore potential therapeutic targets for autoimmune diseases and inflammation. However, it was unclear whether p110 alpha was also important in immune cells.
Dr Klaus Okkenhaug leading the research explained, "Blocking p110 alpha alone had no effect on B cells, nor did the inhibition of p110 beta or p110 gamma. However, if 110 delta was blocked, B cells continued to develop but made fewer antibodies, thus potentially dampening unwanted immune responses.
"It is possible to develop drugs that will inhibit one of these isoforms selectively. For instance, p110 alpha, but neither of the other three isoforms, is frequently mutated and hyper-active in tumour cells and is therefore an obvious target in cancer therapy. Although drugs that target p110 delta selectively could be useful to treat autoimmune and inflammatory diseases, anti-cancer drugs might be less toxic to the immune system if they are designed to inhibit p110 alpha, but not p110 delta," he added. However, as pointed out by Jose Limon and David Fruman (UC Irvine) in a perspective on the article, inhibition of both p110 alpha and p110 delta may be required to treat B cell malignancies.
The Babraham Institute is a centre for studying the basic biology of signalling inside and between cells, supporting BBSRC's mission to drive advances in fundamental bioscience for better health and improved quality of life. With around 90 autoimmune diseases, 100 inherited immune deficiencies as well as the impact of ageing, malnutrition or the use of medications on immune function, a greater understanding of immunity and how the immune system is established is of direct relevance to promoting healthier lifespan. The Babraham researchers seek to discover and characterise important pathways controlling healthy immune function, which may be targeted pharmaceutically to either boost or curtail aspects of the immune response. Results from these investigations may provide rationale for the use of PI3K inhibitors in therapeutic settings.
This work was a BBSRC-funded collaboration between the groups of Klaus Okkenhaug (Laboratory of Lymphocyte Signalling & Development, Anne Corcoran (Laboratory of Chromatin & Gene Expression, both at the Babraham Institute, and Bart Vanhaesebroeck, (Barts & The London School of Medicine).
- F. Ramadani, D. J. Bolland, F. Garcon, J. L. Emery, B. Vanhaesebroeck, A. E. Corcoran, K. Okkenhaug. The PI3K isoforms p110a and p110d are essential for pre%u2013B cell receptor signaling and B cell development. Science Signaling, 2010; DOI: 10.1126/scisignal.2001104
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