Association of Increased Treg Cell Levels With Elevated Indoleamine 2,3‐Dioxygenase Activity and an Imbalanced Kynurenine Pathway in Interferon‐Positive Primary Sjögren's Syndrome

Abstract

Objective. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme that converts tryptophan to kynurenine, is driven in part by type I and type II interferons (IFNs). Naive T cells are polarized into FoxP31 Treg cells upon exposure to either IDO1 cells or kynurenine. Recent studies have suggested that the kynurenine pathway reflects a crucial interface between the immune and nervous system. The aims of the present study were to evaluate whether Treg cell levels are elevated, in conjunction with increased IDO activity, in patients with primary Sj€ ogren's syndrome (SS) who are positive for the IFN gene expression signature, and to investigate the downstream kynurenine pathway in these patients.Methods. Serum from 71 healthy controls, 58 IFNnegative patients with primary SS, and 66 IFN-positive patients with primary SS was analyzed using highperformance liquid chromatography to measure the levels of tryptophan and kynurenine. Expression levels of messenger RNA (mRNA) for IDO and downstream enzymes in the kynurenine pathway were assessed in CD141 monocytes using real-time quantitative polymerase chain reaction. CD41CD45RO1 T helper memory cell populations were analyzed by flow cytometry.Results. Significantly increased levels of IDO activity (assessed as the kynurenine:tryptophan ratio) (P 5 0.0054) and percentages of CD25 high FoxP31 Treg cells (P 5 0.039) were observed in the serum from IFN-positive patients with primary SS, and these parameters were significantly correlated with one another (r 5 0.511, P 5 0.002). In circulating monocytes from IFN-positive patients with primary SS, the expression of IDO1 mRNA was up-regulated (P < 0.0001), and this was correlated with the IFN gene expression score (r 5 0.816, P < 0.0001). Interestingly, the proapoptotic and neurotoxic downstream enzyme kynurenine 3-monooxygenase was up-regulated (P 5 0.0057), whereas kynurenine aminotransferase I (KATI) (P 5 0.0003), KATIII (P 5 0.016), and KATIV (P 5 0.04) were down-regulated in IFN-positive patients with primary SS compared to healthy controls.Conclusion. These findings demonstrate enhanced IDO activity in conjunction with increased percentages of CD25 high FoxP31 Treg cells in primary SS patients who carry the IFN signature. In addition, IFN-positive patients with primary SS exhibit an imbalanced kynurenine pathway, with evidence of a shift toward potentially more proapoptotic and neurotoxic metabolites. Intervening in these IFN-and IDO-induced immune system imbalances may

Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome

“…(II) Monocytes with high MDA5 protein expression showed clear nuclear expression of pIRF7, indicating TLR pathway activation combined with MDA5 expression in IFNpos patients with pSS. Although only a limited number of biopsies were studied here we observed TLR7, RIG-I and MDA5 expression, in concurrence with high MxA expression2 3 35 in SG infiltrates indicating that in addition to a possible role in systemic activation of IFN type I, these molecules could also contribute to local IFN activation in pSS SGs. (III) IFNpos pSS monocytes express the RLR-downstream signalling molecule TBK1 at an increased level compared with IFNneg patients.…”

“…This imbalanced profile possibly prevents IFN overactivation and its potential downstream consequences for autoantibody production and systemic manifestations, coinciding with a particular disease phenotype different from that of IFNpos pSS 46. A tightly regulated balance of these RNA-sensing receptor systems seems essential for tolerance preservation35 and preventing the onset of systemic autoimmunity.…”

Pathogenic role of endogenous TNF-α in the development of Sjögren's-like sialadenitis and secretory dysfunction in non-obese diabetic mice

“…Previous studies have shown an elevation in TNF-α levels in salivary glands and sera of SS patients 21–24 . We further showed in this study that salivary gland TNF-α expression increases with age in NOD mice accompanying the SS development, supporting a possible pathogenic role of this cytokine in SS, especially in the stage prior to the disease onset at 10 weeks of age.…”

“…TNF-α promotes the pathogenesis of these disorders by promoting production of pro-inflammatory cytokines, recruitment of immune and inflammatory cells to local tissues and destruction of organs 18, 20 . In SS patients, elevated TNF-α expression in both salivary gland and serum has been described compared to non-SS sicca patients 21–24 . TNF-α can be produced by many cell types, including salivary gland epithelium and salivary gland-infiltrating T helper 1 and T cytotoxic 1 cells 10, 22 .…”

T cells and their immunometabolism: A novel way to understanding sepsis immunopathogenesis and future therapeutics

“…Another study has shown an association between higher plasma kynurenine levels and immunosuppression due to loss of CD4 + and CD8 + T cells during sepsis (Darcy et al, 2011). An association between increased Tregs, elevated IDO activity, and imbalanced kynurenine pathway is observed in interferon-positive primary Sjögren's syndrome (PSS) (Maria et al, 2016). Thus it will be interesting to observe the impact of kynurenine levels on Tregs in sepsis and impact of IDO inhibition during sepsis.…”