Hyperactivation of PI3 kinase causes defects in human B-cell development and differentiation

Hyperactivation of PI3 kinase causes defects in human B-cell development and differentiation

Hyperactivation of PI3 kinase causes defects in human B-cell development and differentiation (#62)

Stuart Tangye ¹

Garvan Institute, Darlinghurst, NSW, Australia

Gain of function (GOF) mutations in PIK3CD, encoding the p110δ subunit of PI3-kinase, cause immune dysregulation characterized by recurrent respiratory infections, increased susceptibility to herpesvirus infection, lymphoma, organomegaly and autoimmunity. Affected individuals display dysgammaglobulinemia, typified by hyper-IgM and poor Ab responses to protein and polysaccharide Ags, suggesting defective humoral immune responses. To better understand humoral immune defects due to hyperactive PI3K, we analysed B cells in these individuals. In peripheral blood, transitional B cells were markedly increased while memory B cells were reduced. The phenotype of naïve B cells with PIK3CD GOF mutations resembled that of normal transitional B cells, indicating an aberrant arrest of developing B cells. Analysis of bone marrow revealed increased proportions of pro/pre-B cells and reduced recirculating mature B cells patients with PIK3CD GOF mutations. Within the memory B cell population there was a reduction in proportions of IgG⁺ and IgA⁺ cells, thereby revealing that hyper-active PI3 kinase signaling not only impedes the generation of memory B cells, but also blunts Ig class switching. Consistent with this, there was a selective impairment in IgG and IgA production by transitional or naive B cells following in vitro stimulation. Thus, the defects observed ex vivo likely result for intrinsic B-cell defects. Treatment of patients with the mTOR inhibitor rapamycin resulted in reductions in proportions of transitional B cells as well as increased proportions of memory B cells. Furthermore, in vitro treatment of B cell with specific inhibitors of PI3 kinase p110d led to improved secretion of IgG and IgA, establishing the possibility of therapies for affected individuals with inhibitors of the PI3 kinas pathway. Overall, our findings reveal key roles for balanced PI3 kinase signaling in immune regulation and long-lived humoral immunity.

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Authors contributing to this presentation.

Tangye, S

Dr Stuart Tangye is the Head of the Immunology Division at the Garvan Institute of Medical Research, Professor in the Faculty Medicine, University of NSW Australia, and an NHMRC Principal Research Fellow. He completed his PhD on B-cell leukemia at UTS in 1995 and undertook postdoctoral training at the DNAX Research Institute for Molecular and Cellular Biology (Palo Alto California, USA; 19996-1999). He returned to Australia in 2000 as a University of Sydney Research Fellow to work with Dr Phil Hodgkin at the Centenary Institute of Cancer Medicine and Cell Biology (University of Sydney). He established an independent research lab in 2002, and was recruited to the Garvan Institute in 2006. His research interests focus on human immunobiology in health and disease. This is achieved by studying lymphocyte development, signalling, differentiation and effector function in patients with diseases resulting from monogenic loss- or gain-of-function mutations in key regulators of immune responses, as well as in corresponding animal models of these human conditions. In the past few years, his lab has made significant contributions to elucidating how these mutations result in some of the clinical features associated with human primary immunodeficiencies. He has been funded by fellowships and project and program grants awarded by the NHMRC, Cancer Council NSW, XLP Research Trust and Association for International Cancer Research. Since 1995, he has published >140 peer-reviewed articles and invited reviews and in 2011 he received the Gottschalk Medal from the Australian Academy of Sciences, which recognises “outstanding research in the medical sciences by scientists no more than 40 years of age”. More recently he was awarded the Faculty of Science Alumni Excellence Award from the University of Technology Sydney (2013), and a Senior Scholarship from the US-Australian Fulbright Commission to undertake sabbatical study at Rockefeller University in New York (2015). He is on the senior editorial boards of J Exp Med, J Immunol and J Clin Immunol. When he is not at work, he enjoys surfing, cycling, swimming and most of all being a Dad to his three beautiful children!

Hyperactivation of PI3 kinase causes defects in human B-cell development and differentiation (#62)

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