Laboratory Head
A/Professor Margaret Hibbs
Phone: (03) 99030921
Email: margaret.hibbs@monash.edu
Department of Immunology
Monash University
Level 2, AMREP Building
89 Commercial Road
Melbourne Victoria 3004
AUSTRALIA
Staff Research Fellows
Dr Anne Kong
Dr Mhairi Maxwell
Dr Evelyn Tsantikos
PhD Students
Maverick Lau
Geraldine Cheng
Erika Duan
Hons Student
Timothy Gottschalk
Leukocyte Signalling Laboratory
The Leukocyte Signaling Laboratory is studying signaling pathways that play a role in immune system development and function. We are primarily interested in what regulates the development of immunity and we are trying to understand the processes that are perturbed when autoimmunity and inflammatory diseases develop. We are also interested in understanding what regulates haematopoiesis or blood cell development, and believe that this will give us a greater understanding of the signals that go awry in the development of blood cell cancers. The lab also has a major interest in understanding the mechanisms underlying chronic inflammatory lung disease and we aim to identifying key pathways or targets for therapeutic intervention.
We have been concentrating our studies on Src-family protein tyrosine kinases, enzymes that are found inside cells that play very important roles in transmitting information from the cell surface to the nucleus to initiate a cellular response. Deregulation of the function of Src-family kinases has been linked with cancer, and also to immune system disorders such as autoimmune disease, immunodeficiency, osteopetrosis, and compromised host defence. The Lyn tyrosine kinase is a unique member of the Src-family whose predominant role is to regulate signals through inhibitory receptors, and to promote signal termination.Animal models of Lyn deficiency and constitutive Lyn activity have been developed in the laboratory and are the major focus of our studies. Our studies have demonstrated the importance of Lyn for B lymphocyte development and function, and have identified Lyn as a potential tumour suppressor. We have also recently shown that Lyn can control macrophage activation and susceptibility to inflammatory lung disease.Our research employs a variety of powerful techniques such as mouse models, mutagenesis, multi-colour flow cytometry, RNA interference, real-time PCR, proteomics and micro-array based RNA expression analysis.
Projects
- Understanding the mechanisms behind autoimmune disease development using animal models of lupus. Our previous studies have shown that Lyn-deficient mice develop antibody-mediated autoimmune disease that resembles lupus. We have recently shown a requirement for both inflammatory factors and B cells in switching the disease to a pathogenic state. Currently we are trying to define the relationship between inflammation and lymphocyte activation in the development and progression of autoimmune disease.
- Identifying Lyn-regulated proteins and genes. We are attempting to identify Lyn regulated proteins and genes using proteomics and microarray technologies. For these studies we are making use of cells from mice expressing a gain of function mutation in Lyn, as they show numerous tyrosine phosphorylated proteins that are likely to be bone fide Lyn substrates.
- Determining how Lyn regulates haematopoiesis and progenitor cell number. Our previous studies have shown that Lyn deficiency leads to deregulation of haematopoiesis and increases in progenitor cell numbers. We are actively investigating the basis for these phenotypes.
- Defining the role of Lyn in inflammatory lung disease and cancer. We have previously shown that Lyn functions as a negative regulator of lung inflammation. However, we have also found that Lyn can be a positive regulator of signaling: mice expressing a gain of function mutation in Lyn develop destructive lung inflammation. We are now trying to understand how Lyn activation contributes to macrophage deregulation and chronic obstructive pulmonary disease, and whether mutation of Lyn alters susceptibility to lung adenocarcinoma.
Publications
- Hibbs ML, Tarlinton DM, Armes J, Grail D, Hodgson G, Maglitto R, Stacker SA and Dunn AR. Multiple defects in the immune system of lyn-deficient mice, culminating in autoimmune disease. Cell. 83: 301-311, 1995.
- Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, Quilici C, Grail D, Hodgson GS, Dunn AR, and Hibbs ML. Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage. Immunity. 15: 603-615, 2001.
- Hibbs ML, Harder, KW, Armes J, Kountouri N, Quilici C, Casagranda F, Dunn AR, and Tarlinton DM. Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity. J. Exp. Med. 196: 1593-1604, 2002.
- Harder KW, Quilici C, Naik E, Inglese M, Kountouri N, Turner A, Zlatic K, Tarlinton DM and Hibbs ML. Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1. Blood, 104: 3901-3910, 2004.
- Beavitt S-JE, Harder KW, Kemp JM, Jones J, Quilici C, Casagranda F, Lam E, Turner D, Brennan S, Sly PD, Tarlinton DM, Anderson GP and Hibbs ML. Lyn-deficient mice develop severe, persistent asthma: a critical role for Lyn as a negative regulator of Th2 immunity. J. Immunol. 175: 1867-1875, 2005.
- Xu Y, Harder KW, Huntington ND, Hibbs ML and Tarlinton DM. Lyn tyrosine kinase; accentuating the positive and the negative. Immunity, 22: 9-18, 2005.
- Hibbs ML and Harder KW. The duplicitous nature of the Lyn tyrosine kinase in growth factor signaling. Growth Factors 24: 137-149, 2006.
- Hibbs ML, Quilici C, Kountouri N, Seymour JF, Armes JE, Burgess AW and Dunn AR. Mice lacking three myeloid colony-stimulating factors (G-CSF, GM-CSF and M-CSF) still produce macrophages and granulocytes, and mount an inflammatory response in a sterile model of peritonitis. J. Immunol. 178: 6435-6443, 2007.
- Tsantikos E, Quilici C, Harder KW, Wang B, Zhu HJ, Anderson GP, Tarlinton DM and Hibbs ML. Perturbation of the CD4 T cell compartment and expansion of regulatory T cells in autoimmune-prone Lyn-deficient mice. J. Immunol. 183: 2484-2494, 2009.
- Tsantikos E, Oracki SA, Quilici C, Anderson GP, Tarlinton DM and Hibbs ML. Autoimmune disease in Lyn-deficient mice is dependent on an inflammatory environment established by interleukin-6. J. Immunol. 184: 1348-1360, 2010.
- Mackay F, Figgett W, Saulep D, Lepage M and Hibbs ML. B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor. Immunol. Rev. 237: 205-225, 2010.
- Maxwell MJ, Duan M, Armes JE, Anderson GP, Tarlinton DM and Hibbs ML. Genetic segregation of inflammatory lung disease and autoimmune disease severity in SHIP-1-/- mice. J Immunol 186: 7164-7175, 2011.
