Background/Purpose: A role for indoleamine-2,3-dioxygenase (IDO) in suppression of effector T-cell function and promotion of regulatory T-cell (Treg) differentiation has been described. IDO – the rate-limiting enzyme in tryptophan (TRP) catabolism – is driven in part by type I and type II IFNs. Systemic overactivation of IFN-signaling is evident in Primary Sjögrens syndrome (pSS), and could shift the delicate regulatory balance towards a more auto-reactive state in these patients. Interestingly aberrant systemic TRP catabolism, resulting in a shift from neuroprotective towards neurotoxic downstream metabolites, has been associated with mood disturbances as well as neurophsychiatric consequences, and possibly contributes to symptoms of fatigue and depression in pSS. Here we investigate the role of IDO and downstream TRP catabolism in pSS and hypothesize an increase in Tregs, in concordance with increased IDO-activity in IFNpositive pSS patients.
Methods: In a Cohort of 20 Healthy controls (HC), 18 IFNnegative and 21 IFNpositive pSS patients, diagnosed according to the 2002 American-European criteria, CD4+CD45RO+ T helper (Th) memory cell populations defined by chemokine receptor expression: CD25hiFoxP3+ Tregs, CCR6+CCR4+CXCR3–CCR10– Th17, CCR6+CCR4+CXCR3‑CCR10+ Th22, CCR6-CXCR3+CCR4- Th1 and CCR6–CXCR3‑CCR4+ Th2-cells were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMCs). Analysis of TRP and Kynurenine (KYN) were performed simultaneously in serum using HPLC. CD14+ monocyte mRNA-expression of IDO1and downstream enzymes was assessed using real-time quantitative PCR, to investigate the direction of downstream TRP catabolism in pSS.
Results: Activity of IDO (p=0.0054) – as determined by measuring levels of the KYN/TRP-ratio in sera – and CD25hiFoxP3+ Tregs (p=0.039) were significantly increased in IFNpositive pSS patients. In addition, CD25hiFoxP3+ Tregs significantly correlated with the KYN/TRP-ratio (p=0.002;r=0.509) as well as the IFNscore (p=0.011;r=0.375). Peripheral monocytes showed an upregulation of IDO-expression (p<0.0001) in IFNpositive pSS, also highly correlating with the IFNscore (p<0.0001;r=0.816). Interestingly the neuroprotective downstream enzymes KAT1 (p=0.0003), KAT3 (p=0.016) and KAT4 (p=0.04) were downregulated, whereas the neurotoxic enzymes KMO (p=0.0057) and KYNU (p=0.0001) – which convert KYN into the neutoxic metabolite Quinolinic acid – were upregulated in these patients, suggesting a skew towards neurotoxicity.
Conclusion: Here we find enhanced IDO activity in coherence with increased CD25hiFoxP3+ Tregs, and evidence for a shift towards production of more neurotoxic metabolites – previously associated with “sickness behavior” – in IFNpositive pSS. This imbalance towards neurodegenerative effects might contribute to increased fatigue and depressive symptoms in these patients. However, whether this shift in Tregs reflects an immune rescue-mechanism or increases “tolerance to self” remains unknown. Intervening in these IFN and IDO-induced imbalances offers new possibilities for therapeutic interventions.
Disclosure:
N. I. Maria,
None;
C. G. van Helden-Meeuwsen,
None;
Z. Brkic,
None;
S. M. J. Paulissen,
None;
V. A. Dalm,
None;
P. L. V. Daele,
None;
P. M. van Hagen,
None;
S. M. Gibney,
None;
A. Harkin,
None;
H. A. Drexhage,
None;
E. Lubberts,
None;
M. A. Versnel,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-indoleamine-23-dioxygenase-ido-activity-and-kynurinene-3-monooxygenase-kmo-expression-in-interferon-positive-primary-sjogrens-syndrome-patients-is-associated-with-increased-cd25hifoxp3/