Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF

Abstract

Background: The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. Methods: We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. Results: Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. Conclusions: TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.

TL1A/DR3 Axis, A Key Target of TNF-a, Augments the Epithelial–Mesenchymal Transformation of Epithelial Cells in OVA-Induced Asthma

“…Therefore, a positive feedback loop is present between the two cytokines. Previous study results in the RA patient serum have revealed the inhibition of TL1A production via anti-TNF-a ( 28 ). The results of the present study supports these findings, in which the inhalation of TNF-a induce TL1A/DR3 expression in mice, and the reduction of TL1A/DR3 in asthmatic mice is induced by OVA after anti-TNF-a treatment.…”

Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) agonists in islet transplantation: Endogenous in vivo regulatory T cell expansion promotes prolonged allograft survival

“…Activation of the TNFRSF25 signaling pathway by its cognate ligand, tumor necrosis factor‐like cytokine 1A (TL1A), which is mainly expressed by antigen‐presenting and endothelial cells, 21 promotes cytokine production 22 . These interactions serve as co‐stimulatory signals and have been linked to exacerbations of inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, and skin psoriasis 23–27 . Additionally, agonistic stimulation of TNFRSF25 leads to antigen‐specific T cell proliferation, a feature that has been explored in the areas of vaccinology, 28 infectious diseases, 29 and oncology 30 …”

“…22 These interactions serve as co-stimulatory signals and have been linked to exacerbations of inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, and skin psoriasis. [23][24][25][26][27] Additionally, agonistic stimulation of TNFRSF25 leads to antigen-specific T cell proliferation, a feature that has been explored in the areas of vaccinology, 28 infectious diseases, 29 and oncology. 30 True to its co-stimulatory role, TNFRSF25 signaling, beyond the need for TL1A, requires T-cell receptor (TCR) engagement by cognate antigens and the presence of IL-2.…”

Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review

“…CIA is a model of human RA with similar histopathological and clinical features ( 62 ). After treatment with anti-TL1A antibody, total joint score was decreased and clinical inflammation of CIA mice was effectively alleviated, which was mediated by blocking the TL1A/DR3 signaling pathways ( 63 ). Similarly, compared to WT mice, TL1A gene knockout mice had improved clinical profiles for CIA (improved synovial hyperplasia and cartilage erosion) through reduction of inflammatory cells infiltration and reduced production of pathogenic antigens ( 58 ).…”

“…TL1A levels in serum and synovial fluid were higher in RA patients when compared to that in healthy controls and correlated with expression of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), as well as disease activity ( Table 1 ) ( 63 , 68 , 69 ). RF and anti-CCP antibodies are promising disease markers for early diagnosis and prognosis of RA ( 63 ).…”