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A transcriptional regulator controlling severity in experimental arthritis
Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Rydberglaboratoriet för tillämpad naturvetenskap (RLAS). Department of Drug Design and Pharmacology, Copenhagen University, Copenhagen, Denmark.ORCID-id: 0000-0003-4360-7710
Nordic Bioscience, Copenhagen, Denmark.
2019 (engelsk)Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, nr Suppl. 2, s. 667-667, artikkel-id FRI0011Artikkel i tidsskrift, Meeting abstract (Fagfellevurdert) Published
Abstract [en]

Background: 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, TBX3, is a candidate gene in Collagen Induced Arthritis (CIA), an experimental model for RA (2). TBX3 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). Objectives: The objective of this project is to understand the role for the transcriptional regulator TBX3 in development of RA. Methods: 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. Results: Studies of CIA development in mice with single nucleotide polymorphisms (SNPs) in the regulatory region of Tbx3 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 TBX3 gene is conserved between mouse and human, we are investigating whether similar genetic variations are found in the regulatory region of the human TBX3 gene and whether the putative genetic variation would lead to a distinct B-cell phenotype upon activation in vitro. Conclusion: 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.

sted, utgiver, år, opplag, sider
London, UK: BMJ Publishing Group Ltd, 2019. Vol. 78, nr Suppl. 2, s. 667-667, artikkel-id FRI0011
Emneord [en]
Rheumatoid Arthritis, Collagen-induced arthritis, TBX3, transcriptional regulator, biomarker
HSV kategori
Identifikatorer
URN: urn:nbn:se:hh:diva-39950DOI: 10.1136/annrheumdis-2019-eular.7057ISI: 000472207102055OAI: oai:DiVA.org:hh-39950DiVA, id: diva2:1328843
Konferanse
Annual European Congress of Rheumatology, EULAR 2019, Madrid, Spain, June 12-15, 2019
Tilgjengelig fra: 2019-06-23 Laget: 2019-06-23 Sist oppdatert: 2019-09-10bibliografisk kontrollert

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