Thesis A thesis on immune differences in Chronic Fatigue Syndrome, Fibromyalgia and healthy controls, 2023, Groven

Source: Norwegian University of Science and Technology (NTNU) Date: January 2023 URL: https://ntnuopen.ntnu.no/ntnu-xmlui/handle/11250/3072207

https://ntnuopen.ntnu.no/ntnu-xmlui/bitstream/handle/11250/3072207/Nina Groven_PhD.pdf

A thesis on immune differences in Chronic Fatigue Syndrome, Fibromyalgia and healthy controls ------------------------------------------------------------------------
Nina Groven - Department of Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology

Abstract

Background Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are debilitating disorders that significantly affect the daily lives of those suffering from them, as well as their loved ones. Both conditions have overlapping clinical features that resemble inflammatory disorders, and overlapping symptoms, such as depression, suggest central nervous system (CNS) involvement. The role of the immune system’s soluble messengers in the pathogenesis of CFS and FM has been under investigation, but so far the results are inconclusive. In addition, there is growing evidence that the kynurenine pathway is involved in the pathology of diseases related to the CNS, yet the role of each metabolite is not clear. The relationship between kynurenine metabolism and CFS and FM has not been extensively explored. Few studies have simultaneously examined the immunological status in both CFS and FM, making this thesis the first to comprehensively evaluate the potential distinct immunological differences between the two disorders.

Objective The objective of this study was to compare the CFS and FM with healthy controls, regarding the levels of several soluble blood markers related to the immune system. The markers chosen were: * The inflammatory marker high-sensitive CRP (hsCRP) * The following cytokines and chemokines: Interferon (IFN)-gamma, Interleukin (IL)-1beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-17, Interferon gamma-induced protein (IP)-10, Monocyte Chemoattractant Protein (MCP)-1, Transforming Growth Factor (TGF)-beta1, TGF-beta2, TGF-beta3 and Tumour Necrosis Factor (TNF)-alpha * The metabolites and their ratios of the kynurenine pathway: Tryptophan (Try), kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykykynurenine (HK), anthranilic acid (AA), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA) and picolinic acid (Pic).

Method The population consisted of three groups: CFS patients (n=49), FM patients (n =58), and healthy controls (n=54). All participants were females aged 18–60. Patients were recruited from a specialised university hospital clinic and controls were recruited by advertisement among the staff and students at the hospital and university. Plasma levels of hsCRP were analysed at the hospital. The cytokines and chemokines IFN-gamma, IL-1beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-17, IP-10, MCP-1, TGF-beta1, TGF-beta2, TGF-beta3, and TNF-alpha were analysed by multiplex. Kynurenine metabolites were analysed by LC-MS/MS. Linear regression models of log-transformed data for hsCRP and the kynurenine metabolites were conducted for comparison of the three groups CFS, FM and controls. The Kruskal-Wallis test was used to analyse differences of cytokines between the three groups. Main findings were controlled for age, body mass index (BMI), and symptoms of anxiety and depression.

Results hsCRP levels were significantly higher for both the CFS and FM groups compared to healthy controls when adjusting for age and BMI (p=.006). There was no difference between the two patient groups. Level of hsCRP was affected by BMI (p<.001) but not age. MCP-1 was significantly increased in both patient groups compared to healthy controls (p<.001). IL-1beta, Il-4, IL-6, TNF-alpha, TGF-beta1, TGF-beta2, TGF-beta3 (all p<.001), IL-10 (p=.003) and IL17 (p=.002) all were significantly lower in the patient groups compared to healthy controls. IFN-gamma was significantly lower in the FM group (p<.001). For IL-8, IP-10 and IL- 1ra there were no significant difference.

QA differed between CFS and FM patients (p=.036) and was related to higher levels of BMI (p=.002). The KA/QA ratio was lower for CFS patients compared to healthy controls (p =.016). The KA/HK ratio was lower for FM patients compared to healthy controls, and this lower ratio was associated with increased symptoms of pain (p=.002). The kynurenine aminotransferase II (KAT II) enzymatic activity given by XA/HK was lower for FM patients compared to healthy controls (p=.013). In addition, BMI was negatively associated with enhanced KAT II enzymatic activity (p=.039).

Symptoms of anxiety and depression were not associated with any of the immune markers studied.

Conclusion In our material hsCRP and MCP-1 are increased in patients both with CFS and with FM, while several other cytokines are either similar or significantly lower in patients than controls. Our study also indicates associations between kynurenine metabolism and CFS and FM. Kynurenine also is associated with single symptoms such as fatigue and pain.

Forthcoming studies indicating interactions and causative effects, or restoration of the inflammatory status, may place cytokines and kynurenine metabolites as a target for treatment as well as prevention of these conditions in the future.

Has parts

Paper 1: Groven, Nina; Fors, Egil Andreas; Reitan, Solveig Merete Klæbo. Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls. Brain, Behavior, and Immunity 2019; Volum 81. s. 172-177. https://doi.org/10.1016/j.bbi.2019.06.010

Paper 2: Groven, Nina; Fors, Egil Andreas; Stunes, Astrid Kamilla; Reitan, Solveig Merete Klæbo. MCP-1 is increased in patients with CFS and FM, whilst several other immune markers are significantly lower than healthy controls. Brain, Behavior, and Immunity - Health (BBI - Health) 2020; Volum 4. https://doi.org/10.1016/j.bbih.2020.100067

Paper 3: Groven, Nina; Reitan, Solveig Merete Klæbo; Fors, Egil Andreas; Guzey, Ismail Cuneyt. Kynurenine metabolites and ratios differ between chronic fatigue syndrome, fibromyalgia, and healthy controls. Psychoneuroendocrinology 2021; Volum 131. https://doi.org/10.1016/j.psyneuen.2021.105287