FRI0011 A TRANSCRIPTIONAL REGULATOR CONTROLLING SEVERITY OF EXPERIMENTAL ARTHRITIS
Authors: Åsa Andersson, Samra Sardar
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Susceptibility to Rheumatoid Arthritis (RA) is dependent on complex interactions among genetic and environmental factors. Protein candidates and their role in pathways leading to chronic inflammation of the joints, in addition to their potential as drug targets, can be revealed with the help of experimental models for disease (1). From the results of functional genetic studies, we have recently shown that the T-box gene, <i>TBX3</i>, is a candidate gene in Collagen Induced Arthritis (CIA), an experimental model for RA (2). <i>TBX3</i> encodes a transcriptional regulator involved in differentiation of several organs, including bone, during embryonic development. It has, in addition, been demonstrated important in oncogenesis (3). Our studies suggest that TBX3 has a role in B-cell activation and is important for the severity of disease in the CIA model (2). <h3>Objectives:</h3> The objective of this project is to understand the role for the transcriptional regulator TBX3 in development of RA. <h3>Methods:</h3> Bioinformatics based comparative studies of mouse and human alleles in the regulatory region of TBX3. CRISPR/Cas9-introduced deletions and base modifications in human B-cell lines. Activation of genetically modified B-cells in vitro, followed by analyses of proliferative response and antibody production. <h3>Results:</h3> Studies of CIA development in mice with single nucleotide polymorphisms (SNPs) in the regulatory region of <i>Tbx3</i> revealed a significant difference in severity of arthritis. In line with this, the anti-collagen type II antibody titers were shown substantially higher in mice with more severe arthritis, even before onset of disease. In addition, preliminary data shows that the proliferative response to Type II collagen upon re-challenge of lymph node cells in vitro is higher in these mice, suggesting a more active response to the disease-inducing antigen. Because the <i>TBX3</i> gene is conserved between mouse and human, we are investigating whether similar genetic variations are found in the regulatory region of the human <i>TBX3</i> gene and whether the putative genetic variation would lead to a distinct B-cell phenotype upon activation in vitro. <h3>Conclusion:</h3> We suggest that the oncoprotein TBX3 is a novel candidate contributing to disease severity in experimental arthritis. Investigations of genetic variation in the TBX3 gene and its role in the activation of human B-cells will reveal whether this protein is a candidate for influencing also development of RA. <h3>References:</h3> [1] Sardar, S and Andersson, Å. Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development. Immunopharmacology and Immunotoxicology. 2016, 38:1. [2] Sardar, S, et al. The oncoprotein TBX3 is controlling severity in experimental arthritis. Arthritis Research and Therapy. 2019, 21:16. [3] Wilmer, T, et al. The T-Box transcription factor 3 in development and cancer. 2017, BioScience Trends. 24;11(3). <h3>Disclosure of Interests:</h3> Åsa Andersson: None declared, Samra Sardar Employee of: I am a full time employee at Nordic Bioscience