Role of TL1A in the Pathogenesis of Rheumatoid Arthritis

Abstract

TNF-like ligand 1A (TL1A), a member of the TNF superfamily, is the ligand of DR3 and DcR3. Several types of cells, such as endothelial cells, monocytes/macrophages, dendritic cells, and CD4 and CD8 T cells, are capable of producing this cytokine. In present study, we demonstrated that TL1A aggravated collagen-induced arthritis in mice. It increased collagen-induced arthritis penetrance and clinical scores as well as the severity of the pathological findings. TL1A administration led to the occurrence of multiple enlarged germinal centers in the spleen, and it boosted serum anti-collagen Ab titers in vivo. In vitro, TL1A augmented TNF-α production by T cells upon TCR ligation, and it greatly enhanced Th17 differentiation and IL-17 production. We further showed that human rheumatoid arthritis (RA) synovial fluids had elevated TL1A titers, and human chrondrocytes and synovial fibroblasts were capable of secreting TL1A upon TNF-α or IL-1β stimulation. Taken together, these data suggest that TL1A secretion in lymphoid organs might contribute to RA initiation by promoting autoantibody production, and TL1A secretion stimulated by inflammatory cytokines in RA joints might be a part of a vicious circle that aggravates RA pathogenesis.

TNF-like Ligand 1A (TL1A) Gene Knockout Leads to Ameliorated Collagen-Induced Arthritis in Mice: Implication of TL1A in Humoral Immune Responses

“…The presence of TL1A in diseased tissues, fluids, and sera from patients of chronic colitis and rheumatoid arthritis (RA) corroborates the findings in animal models (2,5,(17)(18)(19). In vivo studies of different animal models have provided direct evidence supporting the role of TL1A in autoimmune diseases.…”

“…In vivo studies of different animal models have provided direct evidence supporting the role of TL1A in autoimmune diseases. We have demonstrated that the administration of recombinant TL1A to mice with collagen-induced arthritis (CIA) aggravates the disease (5). Furthermore, overexpression of TL1A in transgenic mice results in spontaneous inflammatory bowel disease as well as increased number of Th cells (9,20,21).…”

“…It was identified during homology searches in an endothelial cell cDNA library. It is produced by the endothelial cells (1), monocytes, dendritic cells (DC), T cells, NKT cells, synovial fibroblasts and chondrocytes, either upon stimulation or in situ in inflammatory sites (2)(3)(4)(5)(6). Like other TNF superfamily members, TL1A can either be membrane-bound or soluble after being cleaved from the cell surface, but the cleavage happens on DC and not on T cells (1,7).…”

DcR3-TL1A signalling inhibits cytokine-induced proliferation of rheumatoid synovial fibroblasts

“…these results suggest a robust association of dcr3 with tl1a. a number of recent studies have illustrated the functions of TL1A in autoimmune diseases, including inflammatory bowel diseases (iBd) and ra (14,(31)(32)(33)(34)(35)(36). consistent with the role of tnf in inducing the release of tl1a, serum tl1a levels have been shown to substantially decrease in ra patients treated with adalimumab, an anti-tnf monoclonal ab (31), indicating that tl1a has a role in the progression rather than induction of the disease (36).…”

Efnb1 and Efnb2 Proteins Regulate Thymocyte Development, Peripheral T Cell Differentiation, and Antiviral Immune Responses and Are Essential for Interleukin-6 (IL-6) Signaling

“…Purity of the naive CD4 ϩ cells was routinely greater than 95%. Purified naive T cells (0.25 ϫ 10 6 cells/well) were mixed with T cell-depleted irradiated (3000 rads) C57BL/6 feeder splenocytes (1.25 ϫ 10 6 cells/well) and cultured in 96-well plates under Th1, Th2, Th17, or Treg polarization conditions, as described in our earlier publication (31), and then analyzed by flow cytometry.…”