February 2019 | Feabhra 2019

Understanding Tissue Damage in Rheumatoid Arthritis

Tue, 5 February 19 11:46

The UCD Centre for Arthritis Research have secured a rare chance to name an important gene which is associated with the development of several important autoimmune conditions.  This opportunity has arisen in recognition of their research in the functional significance of the gene, C5orf30 and its linkage to tissue damage.  Led by Prof Gerry Wilson (UCD Full Professor of Rheumatological Sciences at the UCD Conway Institute), the research group have examined genetic variants in C5orf30 which are associated with development of the autoimmune conditions, primary biliary cirrhosis and rheumatoid arthritis.

In rheumatoid arthritis, C5orf30 expression is cell-specific, with highest expression found in macrophages and synovial fibroblasts. C5orf30 is highly expressed in inflamed joints and is a negative regulator of tissue damage in a mouse model of inflammatory arthritis. Transcriptomic analysis from ultrasound-guided synovial biopsy of inflamed joints in a well characterized clinical cohort of newly diagnosed, disease-modifying antirheumatic drugs–naive rheumatoid arthritis patients was used to determine the clinical association of C5orf30 expression with disease activity.

A combined molecular and computational biology approach was used to elucidate C5orf30 function in macrophages both in vitro and in vivo. Synovial expression of C5orf30 is inversely correlated with both clinical measures of rheumatoid arthritis disease activity and with synovial TNF mRNA expression. C5orf30 plays a role in regulating macrophage phenotype and is differentially turned over in inflammatory and anti-inflammatory macrophages. Inhibition of C5orf30 reduces wound healing/repair–associated functions of macrophages, reduces signalling required for resolution of inflammation, and decreases secretion of anti-inflammatory mediators.

In an animal model of wound healing (zebrafish), C5orf30 inhibition increases the recruitment of macrophages to the wound site. Finally, the group demonstrate that C5orf30 skews macrophage immunometabolism, demonstrating a mechanism for C5orf30-mediated immune regulation.

The UCD Research Group have been invited by the Gene Nomenclature Committee of the Human Genome Organisation (HuGO) to propose a suitable name for the gene which complies with their naming conventions.  Prof Wilson’s team hope to consult with Irish patients affected by Rheumatoid Arthritis to select a name from a shortlist for the gene.

The Researchers authors wish to thank the patients that donated their samples to the Arthritis Research Coalition biobank in Ireland and to the Pathobiology Early Arthritis Cohort (PEAC) in the UK. Without their participation this work would not be possible.  This research work was conducted in conjunction with the University of Sheffield, Queen Mary University of London and Genetech.  It was funded by the Arthritis Ireland, the Health Research Board and by the Irish Research Council.

More Information

About the UCD Centre for Arthritis Research  http://www.ucd.ie/car/

Recent Publication

The Autoimmune Susceptibility Gene C5orf30 Regulates Macrophage-Mediated Resolution of Inflammation

Emma R. Dorris, Simon J. Tazzyman, John Moylett, Nandhini Ramamoorthi, Jason Hackney, Michael Townsend, Munitta Muthana, Myles J. Lewis, Costantino Pitzalis and Anthony G. Wilson

J Immunol January 18, 2019, ji1801155; DOI: https://doi.org/10.4049/jimmunol.1801155

Lay Summary of Work

The UCD Centre for Arthritis Research have produced a short lay summary of their investigations.

The immune system is often looked upon as a response to infection. While it has this function, it also does so much more, including being crucial for the normal growth and replenishment of the cells in the body. We looked at a type of immune cell, called a macrophage, that has a role in the inflammation stage but also in the growth and healing phase. These cells are like conductors of an orchestra: they tell the other immune cells when to fight infection but also when to turn off “fight” mode and to turn on “healing” mode. Therefore, when they stop working properly, the whole immune system can go out of tune.....  [more]