08.22 The role of transmembrane rather than soluble tnf in spondyloarthritis

Background TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). Here we aimed to investigate how TNF can lead to completely different disease phenotypes such as destructive peripheral polysynovitis in RA versus axial and peripheral remodelling arthritis in SpA. Materials and methods We assessed expression of TNF, TNF-R, and TACE (ADAM17) in synovial fluid, synovial tissue, and synovial fibroblasts from SpA and RA. tmTNFtg mice (TgA86) 1 were clinically scored for development of peripheral and axial disease, and sacrificed at the end of the experiments for radiologic and histologic assessment. Mechanistic studies included bone marrow chimaera experiments and crossing with TNF-R1 or TNF-R2 knock-out animals. Results Arthritis was characterised by lower levels of sTNF and higher levels of tmTNF in SpA versus RA. This misbalance was related to decreased TACE activity in SpA versus RA FLS, as further confirmed by lower levels of other soluble molecules cleaved by TACE (including sTNF-RI, sTNF-RII, and sCD163) in the inflamed SpA joint. Assessing whether tmTNF has a functional role in SpA pathology, mice selectively over-expressing the transmembrane form of TNF spontaneously developed a deforming arthritis and spondylitis, starting at 4 weeks of age and reaching a 100% incidence. Histology revealed peripheral and axial synovitis, enthesitis, and osteitis, as well as inflammation of the connective tissue located at the junction of the annulus fibrosus with the vertebral bone. tmTNFtg mice did not develop extra-articular inflammation. Structural phenotyping by histology and radiology revealed mild destructive features in combination with foci of hypertrophic chondrocytes and axial and peripheral new bone formation leading to bridging of tail vertebra over time. Mechanistic experiments revealed that this SpA-like phenotype was mediated by tmTNF expression on stromal cells but not on hematopoietic cells and required the expression of TNF-R1. Conclusions Collectively, these data suggest that tmTNF expressed by stromal cells is responsible for the key pathological features of SpA. References 1.Alexopoulou L, et al . Eur J Immunol 1997;27(10):2588–92.