• PhD in Medical Science - University of Birmingham, 2006
• MSc in Immunology – Distinction, University of Birmingham, 2002
• BSc (Hons) in Biochemistry - First Class, University of Lancaster, 2001

Helen graduated from the University of Lancaster in 2001 with a BSc (Hons) in Biochemistry, during this course she spent a year studying aboard at Oregon State University, USA. She obtained a MSc. in Immunology from the University of Birmingham in 2002, undertaking a research project looking at neutrophil apoptosis (cell death) with Janet Lord and Dagmar Scheel-Toellner in the School of Immunity and Infection. She subsequently joined Gerard Nash’s Cardiovascular Rheology Group in the School of Clinical and Experimental Medicine, where she completed her PhD in Medical Sciences in 2006.

Helen has continued to work in Birmingham investigating the processes controlling leukocyte recruitment and fate both in health and disease, focusing on the role of the tissue microenvironment. She was appointed as a University Fellow in Inflammation Biology within the System Science for Health multidisciplinary translational research consortium at Birmingham in 2011.

In 2012, Helen was awarded an Arthritis Research Career Development Fellowship to explore the role of synovial fibroblasts in regulating leukocyte accumulation during the development of persistent arthritis.

Helen co-organised the 24th UK Adhesion Society Meeting in September 2011, which attracted ~ 50 academic attendees from the UK and Europe. She also co-organises a monthly seminar series for the Vascular, Thrombosis, Inflammation and Angiogenesis (VITA) arm of the Centre for Cardiovascular Sciences.

• MRes Maths & Computing in Biology & Medicine
• MBChB – Year 2; Integrated problems

Helen’s research concentrates on the concept that the state of the local tissue (stromal) microenvironment defines the responsiveness of endothelial cells, and also the subsequent fate of recruited leukocytes. This has involved the development and validation of novel in vitro, multi-cellular, multi-layered static and flow-based culture systems. Her goal is to develop a more complete understanding of the molecular circuitry regulating tissue migration and egress during acute and chronic inflammation reactions, with a view to developing anti-inflammatory, pro-resolution therapeutic strategies. A novel approach that we areinvestigating is to manipulate the local stroma to instruct recruited cells to leave chronically inflamed tissue, in effect to “switch on” resolution, or alternatively to stop leukocytes entering the inflamed site by “turning off” recruitment.

RESEARCH THEMES
Leukocyte recruitment, migration and fate
Endothelial-fibroblast interactions and leukocyte recruitment to the synovium
Vascular-lymphatic endothelial cell crosstalk and leukocyte exit from tissue

RESEARCH ACTIVITY

Leukocyte recruitment, migration and fate
Inflammation requires the recruitment of leukocytes by the vascular endothelium and their subsequent migration into the tissue. The mechanisms regulating the migration phase are poorly understood. Migrated lymphocytes tend to remain in close vicinity to the endothelium and were unable to move into an underlying collagen gel matrix, with a proportion continuously migrating back and forth in a ‘frustrated’ manner. In contrast, neutrophils rapidly move into the gel. Addition of extracellular matrix protein (fibronectin) or chemokine (CXCL10) to the gel induced a modest increase in lymphocyte penetration of the matrix. Thus it appears a separate signal is required to allow lymphocytes to move into the tissue, adding an additional level of regulation which may allow the tissue to select which cells enter.

Endothelial-fibroblast interactions and leukocyte recruitment to the synovium
Access to unique clinical samples from healthy and diseased synovium has allowed the simultaneous comparison of physiological and pathological responses. Rheumatoid synovial fibroblasts continuously activated adjacent endothelial cells inducing unwanted leukocyte infiltration. Conversely, healthy dermal fibroblasts demonstrated a regulatory capacity, reducing lymphocyte recruitment in vascular constructs exposed to inflammatory cytokines. Fibroblasts (dermal, synovial and bone marrow) also have the ability to retain/trap endothelially recruited cells. Extending this work further, Arthritis Research are funding a Career Development Fellowship to examine the hypothesis that as non-resolving disease develops, a fibroblast phenotype is acquired that perpetuates leukocyte infiltration, and that in resolving arthritis this phenotype is never established. Results of this work will be important in the development of novel therapies for Rheumatoid Arthritis.

Vascular-lymphatic endothelial cell crosstalk and leukocyte exit from tissue
The key step in leaving tissue is for leukocytes (namely T-cells) to migrate through endothelial cells lining the lymphatic vessels. Leukocytes obtain messages as they migrate into tissue though vascular endothelium, which change their subsequent behaviour and ability to migrate through lymphatic endothelium. In addition, vascular endothelial cells communicate with neighbouring cells, including lymphatic cells, to regulate migration. This project investigates how lymphatic endothelial cells 'talk' to vascular endothelial cells and leukocytes, to modulate (i) entry, (ii) transit through and (iii) exit of T-cells from inflamed tissue.

H.M. McGettrick, L.M. Butler, C.D. Buckley and G.E. Rainger and G.B. Nash. (2012). Stromal tissue as a regulator of leukocyte recruitment in inflammation. Journal of Leukocyte Biology, (Epub Jan 2012)

E. Hidalgo, S. Essex, L. Yeo, S.J. Curnow, A. Filer, M. Cooper, A.M. Thomas, H.M. McGettrick, M. Salmon, C.D. Buckley, K. Raza and D. Scheel-Toellner (2011). The response of T cells to IL-6 is differentially regulated by the microenvironment of the rheumatoid synovial fluid and tissue. Arthritis and Rheumatism, 63:3284-3293

H.M. McGettrick, S.R. Ahmed, C.D. Buckley, M. Ratcliffe, G.B. Nash, and G.E. Rainger. (2011). Prostaglandin-D2 regulates the traffic of CD4+ memory T cells across blood vascular endothelial cells and primes the same cells for clearance across lymphatic endothelium. Journal of Immunology, 187:1432-1439

M. Mura, X. Zhuang, H. Vorschmitt, R.K. Swain, S. Durant, J.F.J. Beesley, J.M.J. Herbert, H. Sheldon, M. Andre, S. Sanderson, G. Reynolds, K. Glen, N-T. Luu, H.M. McGettrick, P. Antczak, F. Falciani, G.B. Nash, Z. Nagy and R. Bicknell (2011). Low shear stress induces the novel tumour endothelial marker CLEC14A that mediates filopodia formation, cell migration and vascular development. Oncogene, doi: 10.1038/onc.2011.233 (Epub June 2011)

V.J. Burton, L.M. Butler, H.M. McGettrick, P.C. Stone, C.O. Savage, G.E Rainger and G.B. Nash. (2011) Delay of migrating leukocytes by the basement membrane deposited by endothelial cells in long-term culture. Experimental Cell Research, 317:276-292

H.M. McGettrick, C.D. Buckley, G.E. Rainger and G.B. Nash. (2010). Stromal cells differentially regulate neutrophil and lymphocyte migration through the endothelium. Immunology, 131:357-370

H.M. McGettrick, E. Smith, A. Filer, S. Kissane, M. Salmon, C.D. Buckley, G.E. Rainger and G.B. Nash. (2009). Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells. European Journal of Immunology, 39:113-125

H.M. McGettrick, K. Hunter, P. Moss, C.D. Buckley and G.B. Nash. (2009). Direct observations of the kinetics of migrating T-cells suggest active retention by endothelial cells with continual bidirectional migration. Journal of Leukocyte Biology, 85:98-107 (Epub Oct 2008)