Neopterin

Hutan · May 30, 2025 at 8:16 AM

Petrichor noted here
A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff
that some papers have reported elevated levels of neopterin in ME/CFS. That's interesting because macrophages produce neopterin when stimulated with gamma interferon.

Wikipedia said:

Neopterin belongs to the chemical group known as pteridines. It is synthesised by human macrophages upon stimulation with the cytokine interferon-gammaand is indicative of a pro-inflammatory immune status. Neopterin serves as a marker of cellular immune system activation.[1] In humans neopterin follows a circadian (daily) and circaseptan (weekly) rhythm.[2]
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I thought it was worth checking out the evidence supporting the claim of elevated neopterin.

Neopterin serves as a marker of cellular immune activation and can be measured in various bodily fluids like blood, urine, and cerebrospinal fluid.
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Hutan · May 30, 2025 at 1:20 PM

https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-11-205
Morris and Maes, 2013
Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics

That paper references five papers reporting elevated levels of neopterin:

127 - Maes M, Twisk FNM, Kubera M, Ringel K: Evidence for inflammation and activation of cell-mediated immunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin CAS PubMed Google Scholar paywall
see post #3

141 - Buchwald D, Wener MH, Pearlman T, Kith P: Markers of inflammation and immune activation in chronic fatigue and chronic fatigue syndrome. J Rheumatol. 1997, 24: 372-376. CAS PubMed Google Scholar paywall

142 - Matsuda J, Gohchi K, Gotch N: Serum concentrations of 2′,5′-oligoadenylate synthetase, neopterin, and beta-glucan in patients with chronic fatigue syndrome and in patients with major depression. J Neurol Neurosurg Psychiatry. 1994, 57: 1015-1016. CAS PubMed PubMed Central Google Scholar
see post #4

143 - Chao CC, Gallagher M, Phair J, Peterson PK: Serum neopterin and interleukin-6 levels in chronic fatigue syndrome. J Infect Dis. 1990, 162: 1412-1413. CAS PubMed Google Scholar

144 - Chao CC, Janoff EN, Hu SX, Thomas K, Gallagher M, Tsang M, Peterson PK: Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine. 1991, 3: 292-298. CAS PubMed Google Scholar
This has a paywall. The abstract doesn't mention neopterin.

Hutan · May 30, 2025 at 8:11 AM

127 - Maes M, Twisk FNM, Kubera M, Ringel K: Evidence for inflammation and activation of cell-mediated immunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin Google Scholar Paywall

In this study we therefore measured plasma interleukin-(IL)1, tumor necrosis factor (TNF)α, and PMN-elastase, and serum neopterin and lysozyme in 107 patients with ME/CFS, 37 patients with chronic fatigue (CF), and 20 normal controls.
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Patients with “fatigue” as a result of chronic Epstein–Barr infection show activation of IFNγ-induced pathways, as measured by means of serum neopterin and plasma tryptophan (Bellmann-Weiler et al., 2008). In CFS, some authors detected increased serum neopterin (Buchwald et al., 1997, Chao et al., 1990, Matsuda et al., 1994).
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Serum IL-1, TNFα, neopterin and lysozyme are significantly higher in patients with ME/CFS than in controls and CF patients. ... Increased IL-1 and TNFα are significantly correlated with fatigue, sadness, autonomic symptoms, and a flu-like malaise; neopterin is correlated with fatigue, autonomic symptoms, and a flu-like malaise; and increased PMN-elastase is correlated with concentration difficulties, failing memory and a subjective experience of infection.
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Hutan · May 30, 2025 at 8:31 AM

142 - Matsuda J, Gohchi K, Gotch N: Serum concentrations of 2′,5′-oligoadenylate synthetase, neopterin, and beta-glucan in patients with chronic fatigue syndrome and in patients with major depression.
https://pmc.ncbi.nlm.nih.gov/articles/PMC1073106/pdf/jnnpsyc00038-0135b.pdf
Letter to the editor

We conducted this study to clarify whether or not 2',5'-oligoadenylate synthetase (2,5-AS), neopterin, adenosine deaminase, endotoxin, or ,B-glucan participate in the pathogenesis of chronic fatigue syndrome.

The subjects were 63 patients who fulfilled the criteria of the working definition for chronic fatigue syndrome.' The controls were 67 age and sex matched patients who fulfilled DSM-III-R criteria for major depression (depressive disorders). All patients with major depression and 40 healthy volunteers (recruited from hospital and laboratory staff) as normal controls completed the 30 item general health questionnaire, a screening test for psychiatric morbidity.
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We found that mean (SD) serum concentrations of 2,5-AS, neopterin, and fi-glucan were significantly higher in patients with chronic fatigue syndrome (110 (10) pmol/dl, 5.8 (3.7) nmol/l, 9.5 (6.3) pg/ml, respectively) than in the normal controls (43 (13) pmol/dl, 4.1 (1.0) nmol/l, 6.1 (1.5) pg/ml respectively) (p < 0-01; Student's t test). Concentrations of 2,5-AS (78 (15) pmol/dl), neopterin (5 4 (2 5) nmol/l), and f,-glucan (12-0 (6 4) pg/ml) were also higher in patients with major depression than in the controls (all p < 0 01).
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The mechanism(s) for this increase is unclear at present, but the possibility of latent and prolonged infection by micro-organisms(s) that are difficult to detect by ordinary laboratory tests cannot be ruled out. The raised fl-glucan in the patients with chronic fatigue syndrome may have stimulated their lymphocytes to induce pro-duction of 2,5-AS and neopterin.2 3
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It is well documented that treatment with interferon can be associated with fatigue and neuropsychiatric symptoms including depression. Consequently, it is conceivable that interferon induced by the mechanisms discussed may substantially contribute to the pathogenesis of chronic fatigue syndrome as well as to major depression. This abnormal cytokine production may induce mainly physiological symptoms, depending on the underlying psychiatric and immunological state of each patient. Equally the mood disorder in both patient groups may induce these abnormalities of immunity.
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mariovitali · May 30, 2025 at 10:16 AM

Thanks @Hutan

I found an association of neopterin with IDO1 (indoleamine)

https://www.degruyterbrill.com/docu...C9s8Y_k9TDgWWzal-tQXPpda0XrdEKLQTQSCUo2biQDBg

Nightsong · May 30, 2025 at 5:14 PM

Two other Maes papers assessing neopterin: (a) this one [link] - "[p]atients with ME/CFS showed significantly higher values for IL-1, TNFα, neopterin and elastase than those with CF"; (b) also, this one [link] (J. Affect. Disord, 2013), which seems quite confused in places.

Two other papers from the psychosomatic literature found that neopterin was elevated in "somatisation" - this one [link] and this one [link]. Haven't read them but perhaps some misdiagnosed pwME amongst these groups.

There was also a negative result: Linde et al (link) found that "markers for T lymphocyte activation (soluble IL-2 and CDS) and for monocyte activation (neopterin) were significantly elevated during acute infectious mononucleosis but not in patients with chronic fatigue syndrome".

144 - Chao CC, Janoff EN, Hu SX, Thomas K, Gallagher M, Tsang M, Peterson PK: Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine. 1991, 3: 292-298. CAS PubMed Google Scholar

This has a paywall. The abstract doesn't mention neopterin.
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The only mention of neopterin in this is a reference to the 1990 Chao study.

Perhaps quantification of neopterin should be attempted in a well-characterised ME/CFS cohort.

Jonathan Edwards · May 30, 2025 at 5:04 PM

In the past there was a lot of talk about methylation and folate and genetic variants that got forgotten. But tetrahydrobiopterin and adenine derivative metabolism did seem to come up on the Zhang study if I remember rightly and maybe, for whatever reason, there is something relevant in here in terms of signalling thresholds? It is above my pay grade though.

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