Mackay (F) laboratory: B lymphocytes, BAFF, autoimmunity and cancer
Professor Mackay's laboratory has an interest in autoimmune diseases and mechanisms leading to loss of immune tolerance, in particular that of B-lymphocytes. Prof Mackay has spent years studying a cytokine from the TNF superfamily named BAFF/BLyS and demonstrated the role of this factor in B cell survival. Excess BAFF leads to autoimmunity in mice and is associated with human autoimmunity, in particular Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome. Inhibitors of BAFF have met the primary endpoints in a phase III clinical trial with SLE patients, validating in human patients the critical role of the BAFF system in SLE. Belimumab, a therapeutic antibody blocking BAFF has been approved for use in the clinic in March 2011. This clinical outcome validates over ten years of professor Fabienne Mackay's work on BAFF.
Figure 1: Strongly self-reactive immature transitional type 1 (T1) B cells are killed after binding to self antigen before expressing sufficient B cell activating factor receptor (BAFFR) on their cell surface and therefore cannot be rescued from deletion by BAFF. By contrast, self-reactive B cells with low affinity for self antigen are positively selected, acquire expression of BAFFR on their cell surface, proliferate in response to increased levels of BAFF and mostly accumulate in the marginal zone compartment of the spleen. Low-affinity self-reactive B cells expressing a DNA-specific or RNA-specific B cell receptor (BCR), in particular marginal zone B cells, are highly responsive to Toll-like receptor (TLR)-mediated activation. B cells expressing rheumatoid factor can also bind DNA indirectly. After internalization of the antibody-DNA complex, DNA can activate TLR9. DNA-specific and RNA-specific self-reactive B cells could therefore be activated directly through TLR9 and TLR7, respectively. Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI; also known as TNFRSF13B) activation upregulates TLR expression, and TLR activation increases TACI expression. After TLR activation, and in the presence of high levels of BAFF, self-reactive B cells produce pro-inflammatory autoantibodies (in particular, IgG2b and IgG2c), which deposit in the kidney and promote complement activation and tissue destruction. Mackay F. and Schneider P. Nature Reviews in Immunology 2009; 9: 491-502.
Autoimmunity: BAFF drives autoimmunity independently of T cells but this process requires the function of Toll-like receptors (TLR) and as such drives an unusual form of autoimmunity. BAFF signals through three receptors BAFF-R, TACI and BCMA. BAFF-R triggers survival but is also express on activated T cells and regulatory T cells on which the role of BAFF-R is still obscure. TACI is expressed on a subset of B cells, monocytes and dendritic cells, and its expression is regulated by TLR activation. TACI is required for T-independent antibody responses but also negatively regulate B cells. Its role as a negative regulator of B cells remains unclear. TACI appears to be activated by oligomeric forms of BAFF and APRIL crosslinked by Heparan Sulfate Proteoglycans (HSPG) but not by trimeric ligands. Oligomeric BAFF may be involved in disease progression. BCMA is expressed on plasma cells and is required for cell survival. The function of APRIL another ligand for TACI and BCMA versus BAFF is also not fully understood. APRIL is highly expressed by cancer cells and it may drive TACI-dependent immune mechanisms in tumors. All these issues are currently addressed in Prof Mackay's laboratory.
We have demonstrated that TACI-mediated production of autoantibodies is key to drive BAFF-mediated autoimmunity. Our laboratory is developing anti-TACI blocking antibodies. Blocking TACI rather than BAFF has the advantage of stopping autoimmunity without affecting B cell survival or T cell-dependent immune responses. Therefore, blocking TACI is a safer approach than broad B cell depletion induced by BAFF inhibitors.
Autoimmunity and Microbiota: We study the influence of the diet on the development of SLE and with expert microbiologists at the Peter Doherty Institute, we are dissecting microbial communities that are harmful or beneficial. We are trying to understand the physiology of modified microbial communities and how it has an impact on disease symptoms.
Tissue fibrosis: Prof Mackay's lab also works on the chemokine receptor CXCR7, which is important for heart formation and tissue remodelling. CXCR7 appears to be a critical receptor driving tissue fibrosis and a key therapeutic target. CXCR7 deficiency delays some autoimmune conditions in mouse models and its role in T cells will be addressed. CXCR7 is highly expressed on a subset of B cells called Marginal Zone B cells.
Cancer: The laboratory also focuses on blood cancers, in particular Chronic Lymphocytic Leukemia (CLL) and in particular looks at the defect in the immune system that could be corrected to restore anti-tumor immune-competency. We have identified new immune checkpoints that can be targeted to repair vital immunity in cancer patients.
Prof Chris Goodnow, Garvan Institute, Sydney
Prof Carola Vinuesa, John Curtins School, ANU, Canberra
Dr Stuart Tangye, Garvan Institute, Sydney
Dr Robert Brink, Garvan Institute, Sydney
Dr Matthew Cook, John Curtins School, ANU, Canberra
Dr Ansem Enders, John Curtins School, ANU, Canberra
Dr Jon Sprent, Garvan Institute, Sydney
Prof Eric Morand, Monash University, Clayton
Prof David Tarlinton, Monash University, Clayton
Prof Stephen Nutt, Walter Eliza Hall Institute, Melbourne
Prof Paul Hertzog, The Hudson Institute, Clayton
Dr Andrew Wei, Monash University, Clayton
Dr Constantine Tam, Peter MacCallum Institute, Melbourne
Prof David Huang, Walter Eliza Hall Institute, Parkville
Prof Carlo Croce, Ohio State University College of Medicine
Prof David Curtis, Monash University, Clayton
Prof Pascal Schneider, University of Lausanne, Switzerland
Prof Xavier Mariette, Bicetre Hospital, Paris, France
Prof Charles Mackay, CSO Pfizer, Boston, USA
NHMRC Senior Research Fellowship
NHMRC Program Grant
NHMRC Project Grant
Worldwide Cancer Research Grant
Please click here for a list of Professor Fabienne Mackay's Publications
- Restoring immunocompetency in Chronic Lymphocytic Leukemia
- Developing new therapies for Systemic Lupus Erythematosus
- The Role of CXCR7 in Tissue Fibrosis
- Elucidating the beneficial and harmful elements of the BAFF/APRIL system in multiple sclerosis
- A new function of the cytokine BAFF in dendritic cell maturation: Implications for immunity and cancers
- Regulation of telomerase activity in B cells
Faculty Research Themes
School Research Themes
For further information about this research, please contact Professor Fabienne Mackay