May 2012

Danielle Molloy Wins EULAR Abstract Award

Wed, 9 May 12 09:00

Danielle Molloy, 4th year student of Biomedical Health and Life Sciences, has had two 1st author abstracts accepted to European League against Rheumatism Scientific Meeting. Danielle has also been selected as a finalist out of 3500 abstracts in the EULAR abstract awards 2012. The EULAR scientific meeting is the largest of its kind, bringing together more than 16,000 experts working in the field of rheumatology.

The award ceremony will take place during the opening plenary session of the congress on Wednesday, 6 June 2012 from 18.45-20.00. The Certificate will be presented by the EULAR President, Professor Maxime Dougados, France. Danielle, who was supervised by Dr Ursula Fearon and Dr Eamonn Molloy, composed the following summary of her work:

Danielle MolloyAs part of the Biomedical, Health and Life Science degree we all must undertake a research project in our final year. Towards the end of third year we choose our area of research based on research projects presented to us from scientists/clinicians from different disciplines. The reason I chose Giant cell arteritis (GCA) (apart from Dr. Ursula Fearon’s and Dr. Eamonn Molloy’s enthusiasm for the project!), was because the disease is a very interesting one that can give rise to serious complications and even stroke. GCA is characterised by vascular remodeling in response to inflammation, leading to intimal hyperplasia and lumen occlusion. Complications include visual loss, stroke, scalp and tongue necrosis. There are major deficits in the understanding of the pathogenesis of GCA and current treatment options are limited.

The aim of my study was to assess the vascular microenvironment and the potential pro-inflammatory triggers involved in regulating these processes in GCA. (1) Firstly we performed in situ histological analysis for markers of vascular dysfunction on tissue sections from patients with GCA and (2) at a functional level we established an ex-vivo temporal artery (TA) explant model to examine the potential upstream triggers (Acute serum amyloid A (A-SAA) and Toll-like receptor-2 (TLR2) involved in regulating these pathways.

At a histological level we demonstrated high expression of oxidative damage markers 8-oxo-dG, 4-HNE and angiogenic markers Ang2 and Tie-2 in the adventitial and intimal regions of temporal artery biopsies from patients with GCA. In parallel we demonstrated spontaneous release of many pro-inflammatory mediators Ang2, MMP-2, MMP-9, IL-6 and IL-8 from ex- vivo explants. Furthermore a significant number of the blood vessels were unstable, lacking pericyte recruitment. Oxidative damage, angiogenic markers and immature blood vessels were associated with higher disease activity, further supporting the concept that an unstable vascular microenvironment plays a critical role in the pathogenesis of GCA.

To examine the functional effect of potential upstream triggers we established a novel ex-vivo temporal artery explant model and a myofibroblast outgrowth model. These models maintain the architecture and cell-cell contact of the tissue and therefore more closely reflect the in-vivo environment. A-SAA and Pam3CSK4 (TLR2 agonist) induced expression of angiogenic growth factor Ang2, pro-inflammatory cytokines IL-8, IL-6 and MMP2, 9, all involved in blood vessel instability, cell migration and invasion. A-SAA and Pam3CSK4 also induced myofibroblast outgrowths from TA explants which was paralleled by an increase Ang2, MMP2/ 9 and pro-inflammatory cytokines.

In summary this is the first study directly demonstrating that the vascular microenvironment in GCA is unstable and associated with disease severity. Furthermore we demonstrated that A-SAA and TLR2 induce vascular instability and promoted migrational/invasive processes. TLR2 can mediate the effect of A-SAA, therefore these results suggest that this pathway may represent a potential therapeutic target for GCA.

Two abstracts have now been accepted for presentation at the 2012 EULAR meeting in Berlin.

ORAL Presentation (Awarded EULAR Abstract prize)

  • Abstract 1: ‘Angiogenesis and Blood Vessel Stability in GCA’                                          
  • Authors: Molloy D, Mc Cormick J, Connolly M, Haroon M, Veale D, Fearon U, Molloy E.

POSTER Presentation                                                                                                      

  • Abstract 2: Using ex vivo Temporal Artery Explant cultures we demonstrate that A-SAA and TLR2 activation induce pro-inflammatory mechanisms involved GCA pathogenesis.
  • Authors: Molloy D, Connolly M, McCormick J, Haroon M, Veale DJ, Murphy C, Molloy E, Fearon U.

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