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Severe ME patients have 1.7 broken copies of IDO2

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just wondering what this means really.

Broken IDO2 protects again some autoimmune diseases like RA, but produces more susceptibility to LPS toxicity by increasing cytokines and lowering stat3 expression.

IDO2 has very little affinity with tryptophan and is likely to metabolize some other natural substrate.

"Accumulating evidence indicates that IDO2 acts as a pro-inflammatory mediator of autoimmunity, with a functional phenotype distinct from IDO1. IDO2 is expressed in antigen-presenting cells, including B cells and dendritic cells, but affects inflammatory responses in the autoimmune context specifically by acting in B cells to modulate T cell help in multiple model systems. "

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119657/

"IDO1 is expressed in various tissues, whereas IDO2 is expressed in only a subset of these, namely, liver, kidney, and antigen-presenting cells (APCs) of the immune system, including dendritic cells (DCs) and B cells.3,4 Functionally, IDO1 is better able to catabolize Trp to its primary product, N-formylkynurenine, which is subsequently converted to kynurenine.
Enzymatic studies demonstrate that IDO2 is significantly less active, particularly human IDO2, though it remains to be seen if the proper substrate and/or enzymatic assay conditions have been correctly identified, as IDO2 activity toward l-Trp and various Trp derivatives is both highly pH and buffer dependent.57

Unlike IDO1, which efficiently catabolizes l-Trp, there are several Trp derivatives, particularly 5-methoxytryptophan, that are more efficiently catabolized by IDO2 than Trp itself.5
Underscoring the murky relationship between IDO2 and Trp catabolism, deletion of IDO2 in mouse models does not alter serum kynurenine levels, even under chronic inflammatory conditions.3,4
Given the nonenzymatic signaling functions defined for IDO1,812 it is also plausible that IDO2 has a nonenzymatic function yet to be elucidated, a possibility that must certainly be considered given the generally sluggish catalytic activity of IDO2."

"….Together, these data from SLE, RA, and CHS models provide strong evidence for IDO2 as a mediator of inflammatory autoimmunity in multiple systems."


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206095/

"Abstract
Indoleamine 2,3-dioxygenase 2 (Ido2) is a recently identified catalytic enzyme in the tryptophan-kynurenine pathway that is expressed primarily in monocytes and dendritic cells.

To elucidate the biological role of Ido2 in immune function, we introduced lipopolysaccharide (LPS) endotoxin shock to Ido2 knockout (Ido2 KO) mice, which led to higher mortality than that in the wild type (WT) mice.

LPS-treated Ido2 KO mice had increased production of inflammatory cytokines (including interleukin-6; IL-6) in serum and signal transducer and activator of transcription 3 (stat3) phosphorylation in the spleen.

Moreover, the peritoneal macrophages of LPS-treated Ido2 KO mice produced more cytokines than did the WT mice.

By contrast, the overexpression of Ido2 in the murine macrophage cell line (RAW) suppressed cytokine production and decreased stat3 expression.

Finally, RAW cells overexpressing Ido2 did not alter nuclear factor κB (NF-κB) or stat1 expression, but IL-6 and stat3 expression decreased relative to the control cell line. These results reveal that Ido2 modulates IL-6/stat3 signalling and is induced by LPS, providing novel options for the treatment of immune disorders."



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i'm late to see your comment, but believe you spotted the basis of me/cfs. Anytime ido2 is absent, the immune-endo system can be accelerated without inhibition so long as LPS is present. LPS is simply gram negative bacteria, such as ecoli in unpasteurized goat's milk. Any viral coinfection with a gram-negative infection can instigate a 'cytokine storm' without idol2 to inhibit the immune reaction, a damaging event that likely tilted us into the illness