The role of NF-kB in the development of autoimmunity and cancer in FasL-Fas mutant mice

Project type

Honours and/or PhD

Supervisor(s)	Division	Email
Dr Lorraine O'Reilly (Primary)	Molecular Genetics of Cancer	.(JavaScript must be enabled to view this email address)
Professor Andreas Strasser (Co-supervisor)	Molecular Genetics of Cancer	.(JavaScript must be enabled to view this email address)

Details of project

The death receptor Fas and its ligand, FasL, are guardians against autoimmune disease and lymphadenopathy.

Membrane-bound FasL (mFasL) can be processed leading to the shedding of secreted FasL (sFasL). Mice expressing sFasL only (ΔmFasL) rapidly develop glomerulonephritis and SLE-like autoimmunity or histiocytic sarcoma because membrane-bound FasL is essential for Fas-induced apoptosis.

With increasing age, the ΔmFasL mice accumulate abnormally increased cytokine levels and activated (nuclear) NF-κB in inflammatory infiltrates. This is manifest before overt disease, indicating that abnormally increased NF-κB activation with consequent increase in certain pro-inflammatory cytokines may be critical for the development of autoimmunity and tumourigenesis in mice in which Fas-induced apoptosis is impaired.

We are currently assessing the role of NF-κB in the development of autoimmunity and cancer in the FasLΔm/Δm and lpr mice (mutation in Fas) by crossing them with gene-targeted mice lacking individual NF-κB components (nfκb1-/-, nfκb2-/- and c-rel-/-). These unique mouse strains are now available for analysis and are showing exciting autoimmunity and unexpected cancer phenotypes or protection from disease.

The prospective student will be analysing these mice using whole animal biology, histology, pathology, confocal analysis, flow cytometry/cell sorting, tumour analysis in vivo and in vitro, cytokine analysis by muliplex, western blotting and tissue culture and will have at their disposal use of the new imaging and flow cytometry facilities available at WEHI. The project will be tailored to suit honours or PhD time frames.

<p>Confocal images of kidney from sick FasL mutant mouse stained with antibodies to IgM or IgG (green) and the C1q complement component (red) to show co-localisation of IgG and IgM with C1q in kidney disease. Nuclei stained with DAPI (blue).
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Project references

O’ Reilly LA, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, Haynes NM, Tarlinton DM, Zhang J-G, Belz GT, Smyth MJ, Bouillet P, Robb L, Strasser A. Membrane-bound Fas Ligand Only is Essential for Fas-Induced Apoptosis. Nature. 2009 461:659-665.
Bouillet P and O’Reilly LA. CD95 Bim and T cell homeostasis. Nature Reviews Immunology. 2009 9(7):514-9.
Peter ME, et al. The CD95 receptor: apoptosis revisited. Cell. 2007 129:447-450.
Gerondakis S, et al. Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models. Oncogene. 2006 25:6781-6799.

Research interests

Our broad area of research is to determine the role of regulators of the apoptotic process in the development of diseases such as cancer and autoimmunity using mouse models. We are interested in the TNF-R family, in particular the FasL-Fas signaling pathway and its interaction with NF-κB in the development of disease.

Autoimmunity due to the breakdown of immunological tolerance results in an aberrant immune system that attacks “self”, and can precipitate a plethora of pathologies. The “death receptor” Fas and its ligand FasL play an important role in the removal of potentially dangerous immune cells by apoptosis. Mutations in the genes encoding FasL or Fas result in a lupus (SLE)-like multi-organ autoimmune disease in mice and humans.

Our unique approach to cross FasL mutant and Fas mice to mice lacking individual or multiple NF-κB family members should shed light on which pathway and which NF-κB component/s are required for the development of autoimmunity and cancer. This has the potential to identify novel therapeutic strategies for these diseases.

Selected publications

Strasser A, Jost PJ and Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009 30:180-192.
O’Reilly LA, Kruse EA, Puthalakath P, Kelly PN, Kaufmann T, Huang DC, Strasser A. MEK/ERK-mediated phosphorylation of Bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation. Journal of Immunolology. 2009 183(1):261-9.
Strasser A, Puthalakath H, O'Reilly LA, et al. What do we know about the mechanisms of elimination of autoreactive T and B cells and what challenges remain. Immunol Cell Biol. 2008 86:57-66.

Research theme

Chronic inflammatory diseases

Scientific discipline

Autoimmunity
Cell Biology
Genetics
Immunology
Molecular Biology

Keywords

apoptosis, cancer, FasL/Fas, NF-KB, pathology

The Walter and Eliza Hall Institute of Medical Research