Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis.

Lilian Cha,Scott N Byrne,Prue H Hart,William M Carroll,David R Booth,Robyn M Lucas,Allan G Kermode,Stephanie Trend,Marzena J Fabis‐Pedrini,Judith M Cole,Anderson P Jones

doi:10.1002/cti2.1037

Abstract

ObjectivesClinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS.MethodsAs immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l‐tryptophan‐ and l‐arginine‐catabolising enzymes, indoleamine 2,3‐dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS. As one measure of cell function, cytokine mRNA levels were analysed directly ex vivo and in cells after culture for 4 h in the absence of regulatory factors in autologous serum.ResultsWhen measured directly ex vivo, the expression of IDO and ARG was greater in cells from patients with CIS and MS than cells from healthy controls. Although not linked to IDO and ARG expression, PBMCs from the CIS patients were characterised by low IL‐10 and TGFB mRNA levels and not by greater expression of proinflammatory cytokines. When the cells were cultured for 4 h without autologous serum, pro‐ and anti‐inflammatory cytokine mRNA levels positively correlated with IDO1 expression, and TGFB mRNA levels correlated with ARG1 expression.ConclusionHigher IDO and ARG expression in CIS and MS provides one sustained homeostatic mechanism to control MS‐associated inflammation. However, potent extrinsic mediators in serum may regulate immune cell function in CIS and associations between IDO, ARG and cytokine expression.

Highlights

The survival and activity of immune cells are determined in large part by flux through metabolic pathways, including those providingATP interlinked with those providing the amino acids and nucleotides for protein and nucleic acid synthesis.[1]
Greater IL-6 mRNA levels were detected in peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) compared with Clinically isolated syndrome (CIS) patients; no significant differences were observed for TNF or IL1B expression between the healthy controls (HCs), CIS and MS groups (Figure 2)
The PBMCs of the MS patients studied had no adverse dampening of the expression of IDO and ARG; such a block may otherwise contribute to disease pathogenesis

Summary

Introduction

The survival and activity of immune cells are determined in large part by flux through metabolic pathways, including those providingATP interlinked with those providing the amino acids and nucleotides for protein and nucleic acid synthesis.[1]. Increased expression of the enzymes that catabolise amino acids such as L-tryptophan (Trp) and L-arginine (Arg) could limit the activity of inflammatory immune cells and restrict inappropriate autoimmune responses. Increased expression of these enzymes may reduce the supply of amino acids that limit immune cell survival, activation and expansion, but they would allow the production of multiple downstream metabolites such as the kynurenines and spermidine with proven immunomodulatory properties.[3,4,5].

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