Sickness Behaviour in Juvenile Idiopathic Arthritis. IDO + GTP-CH1 + BH4

[pattismith]

AB0887 Jia patients with high disease activity have increased activity of both the ido and gtp-ch1 pathway, but decreased bh4 efficacy: consequences for fatigue and well-being

2019


Abstract

Background Juvenile idiopathic arthritis (JIA) patients suffer from an inflammatory condition, resulting in painful joints. In addition, JIA patients often report symptoms of sickness behaviour, including depressive symptoms and fatigue. Recent animal studies suggest that proinflammatory cytokines produce sickness behaviour by increasing the activity of indoleamine-2,3-dioxygenase (IDO) and guanosinetriphosphate-cyclohydrolase-1 (GTP-CH1). Here it is hypothesised that inflammation in JIA patients affects the enzymatic activity of IDO and GTP-CH1 and the co-factor BH4. These compounds play a crucial role in the metabolism of the neurotransmitters serotonin and dopamine.

Objectives The aim of our study was to reveal whether inflammation affects BH4, IDO and GTP-CH1 (enzymatic) activity in JIA patients.

Methods Serum samples were collected of twenty-four JIA patients. In these samples, the concentrations of tryptophan, kynurenine, tyrosine, neopterin and phenylalanine were measured. An HPLC method with electrochemical detection was developed to quantify tryptophan, kynurenine and tyrosine. Neopterin and phenylalanine were quantified by ELISA. Kyn/trp ratio was measured as an index of IDO activity, while Phen/Tyr ratio was measured as an index of BH4 activity. Neopterin concentrations were used as an indirect measure of GTP-CH1 activity.

Results JIA patients with high disease activity showed higher levels of both neopterin and kynurenine, and a higher ratio of both Kyn/Trp and Phen/Tyr and lower tryptophan levels than clinically inactive patients.

Conclusions Altogether, these data support our hypothesis that inflammation increases the enzymatic activity of both IDO and GTP-CH1 and decreases the efficacy of the co-factor BH4. Further animal studies are needed to investigate whether inflammation-induced changes in these enzymatic pathways and co-factor lower the levels of the brain neurotransmitters dopamine and serotonin, and consequently produce sickness behaviour and fatigue.


Full text

https://www.mdpi.com/1424-8247/12/1/9/htm

 

[hixxy]

Has a study like this been done for ME before?

 

[pattismith]

figure from the study:

 

[pattismith]

other figure from the study:

 

[pattismith]

Has a study like this been done for ME before?

Kurup did some research in 2003:

https://forums.phoenixrising.me/ind...-chronic-fatigue-syndrome.61550/#post-1001019

I quote his finding:


"There were increased levels of tryptophan catabolites - nicotine, strychnine, quinolinic acid and serotonin - and decreased levels of tyrosine catabolites -dopamine, norepinephrine and morphine - in CFS. "

 

[Belbyr]

Hmmm. Most POTS/CFS people I know including myself have elevated norepinephrine. I had elevated dopamine as well from the same blood draw.

 

[hixxy]

I think pre-ME I had high norepinephrine and low dopmaine but during illness both are low. This is based mostly on symptoms but also when I had an OAT done the metabolites were always through the floor and I'm quite intolerant of anything that boosts or in any way tweaks serotonin.

 

[pattismith]

The serotonin 2B receptor is required in neonatal microglia to limit neuroinflammation and sickness behavior in adulthood

Catherine Béchade

Ivana D'Andrea

Fanny Etienne


First published: 23 October 2020

https://doi.org/10.1002/glia.23918


Abstract

Severe peripheral infections induce an adaptive sickness behavior and an innate immune reaction in various organs including the brain.

On the long term, persistent alteration of microglia, the brain innate immune cells, is associated with an increased risk of psychiatric disorders.

It is thus critical to identify genes and mechanisms controlling the intensity and duration of the neuroinflammation induced by peripheral immune challenges.

We tested the hypothesis that the 5‐HT2B receptor, the main serotonin receptor expressed by microglia, might represent a valuable candidate.

First, we observed that Htr2b−/− mice, knock‐out for the 5‐HT2B receptor gene, developed, when exposed to a peripheral lipopolysaccharide (LPS) challenge, a stronger weight loss compared to wild‐type mice; in addition, comparison of inflammatory markers in brain, 4 and 24 hr after LPS injection, showed that Htr2b deficiency leads to a prolonged neuroinflammation.

Second, to assess the specific contribution of the microglial 5‐HT2B receptor, we investigated the response to LPS of conditional knock‐out mice invalidated for Htr2b in microglia only.

We found that deletion of Htr2b in microglia since birth is sufficient to cause enhanced weight loss and increased neuroinflammatory response upon LPS injection at adult stage.

In contrast, mice deleted for microglial Htr2b in adulthood responded normally to LPS, revealing a neonatal developmental effect.

These results highlight the role of microglia in the response to a peripheral immune challenge and suggest the existence of a developmental, neonatal period, during which instruction of microglia through 5‐HT2B receptors is necessary to prevent microglia overreactivity in adulthood.