Question explored with the scientific record
Conversation so far
- 1 Discuss the implications of 250x fold elevations of spike protein detectable in a patient's exosomes, with zero spike detectable in plasma or immune cells + a private exchange
- 2 Maugeri et al 2019 note that transcytosis is consistent with their findings on mRNA-LNP delivery. Is this transfection, rather than transcytosis? + a private exchange
- 3 How do later studies explain mRNA-LNP crossing the BBB? + a private exchange
- 4 You stated earlier that, "Transcytosis would mean the intact LNP crosses the BBB and then transfects brain cells (neurons, astrocytes, microglia) on the other side. Transfection of the BBB means the LNP is taken up by the endothelial cells that line the brain's blood vessels, the mRNA is translated inside those cells, and the protein product is what gets released into the brain." Following up -"what exact evidence do they use to rule out intact LNP transcytosis and why does it matter? + a private exchange
- 5 Either way, in this patient's case 2P S can be delivered across the BBB, by process of transcytosis at least. Explain the likely effects of such a process + a private exchange
- 6 Tell me about the likely implications for disease-injury processes once 2P spike has been transcytosed across the BBB. + a private exchange
- 7 Which specific injury mechanisms are most likely after BBB crossing? + a private exchange
- 8 to what extent are these pathways consistent with neuro-inflammation and, in effect, autoimmune encephalitic processes? + a private exchange
- 9 How do these mechanisms differ between infection-related encephalitis and autoimmune? + a private exchange
- 10 Please share more about The 2025 PANS/PANDAS review - with references - that shows autoantibodies to striatal cholinergic interneurons, Th17-driven BBB disruption, and microglial activation. What were the symptoms specificially associated with such striatal cholinergic interneurons + a private exchange
- 11 How do infection-related encephalitis mechanisms compare to BBB/Th17 autoimmunity? + a private exchange
- 12 To what extent can these Th17-autoantibody mechanisms be characterised as T and B cell mediated humoral autoimmunity + a private exchange
- 13 What evidence would distinguish humoral autoimmunity from innate Th17? + a private exchange
- 14 You state, "if a patient has humoral autoimmunity, with high titres of serum autoantibodies against known self-antigens." Such as what? + a private exchange
- 15 Hmm. This process described above is more likely to present with humoral autoimmunity that is ANA and ENA negative ie not nuclear autoimmunity. + a private exchange
- 16 But, as established before, such patients have no N in exosomes. It is not WT, but 2P spike in play. + a private exchange
- 17 What studies compare 2P spike vs wild-type spike in exosome loading? + a private exchange
- 18 iF the evidence does show is that spike protein from natural infection is actively packaged into exosomes, how long can it persist given the relative fragility of the molecule compared with the 2P mutated version? + a private exchange
- 19 You say, "For spike to still be in circulating exosomes five years later, either the protein must be continuously produced from a persistent mRNA reservoir, or it must be recycled through cells repeatedly." Recycled by transcytosis. My point entirely.
- 20 the mechanism would require continuous production or near-total recycling failure. Pse examine both scenarios, and if transcytosis recycled spike, what cell pathway would recreate it long-term?
Answered on this page ↓
the mechanism would require continuous production or near-total recycling failure. Pse examine both scenarios, and if transcytosis recycled spike, what cell pathway would recreate it long-term?
The short version: the continuous-production scenario fits what we know about mRNA persistence; the recycling-failure scenario is speculative and unsupported by evidence here.
The two scenarios are not equally plausible. Continuous production from a persistent mRNA reservoir is documented in principle. Self-amplifying mRNA (SAM) can produce antigen for at least 10 days, with a ten-fold increase over non-replicating mRNA and up to 8 days longer expression in one study [E5]. That is a designed feature for SAM vaccines, not the standard mRNA vaccines. But the standard mRNA platform also uses nucleoside modifications (1-methylpseudouridine) that reduce innate immune sensing and extend translation duration [E1], and purification of IVT mRNA to remove dsRNA contaminants can increase protein production 10-to-1000-fold in dendritic cells [E2]. These are features that could prolong spike output beyond the original few-week window, though the evidence here does not quantify how long.
The recycling-failure scenario has a problem from colloidal first principles. Exosomes are cleared with a half-life of hours, not years. For spike to remain elevated in circulating exosomes for five years without ongoing production, the exosomes themselves would need to be recycled back into circulation faster than they are cleared. The evidence here shows that exosomes can cross the blood-brain barrier via transcytosis [E3, E5] and that endothelial cells can take up exosomes and re-release them in a CD36- and caveolin-dependent process for fatty acid transfer [E2]. But that is a single-pass cycle measured in minutes to hours, not a sustained recycling loop. For spike to remain at 250-fold elevation for years, the recycling would need to recapture nearly all spike molecules before degradation, and the evidence for that simply does not exist.
The cell pathway that could recreate exosomal spike over years is the endosomal recycling compartment (ERC). Transcytosed exosomes are taken up by endothelial cells into early endosomes, then sorted either to lysosomes for degradation or to the ERC for re-release. The evidence here shows that this sorting is regulated by Rab proteins and ESCRT machinery [E1], and that exosomes can carry viral proteins like spike to neighboring cells [E1]. But none of this evidence measures the fraction that escapes degradation. If that fraction is small, the concentration decays fast. If it is high enough to sustain 250-fold elevation for years, the clearance pathway is essentially broken, and that is not a documented finding.
My call: continuous production from a persistent mRNA reservoir is the more parsimonious explanation for long-term spike in exosomes, but the evidence here does not prove either scenario and the 250-fold figure you cite is not measured in any study in this retrieval. Confidence: low for both, because the relevant study was never done.
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