Genetics: Chromosome 20: ARFGEF2, CSE1L, STAU1

[jnmaciuch]

Perhaps during EBV infection and other significant fever states there is an acceleration of immigration of 'adult' precursors into brain parenchyma. Maybe this is the sort of thing @jnmaciuch has been trying to persuade me of!

I'm thinking it's even simpler than that. Since we had a hint of endothelial cell relevance, I went back to some of the papers about ARFGEF2's function. Turns out that's what that TNFa link was about.

In an endothelial cell-line, knocking down ARFGEF2 [correction: makes cells package less TNF receptors into exosomes, which may alter TNF responsiveness of these cells or nearby genes]. But it also does something else very interesting:
ARFGEF2 Knockdown Enhances TNF-α Induced Endothelial Expression of the Cell Adhesion Molecules VCAM1 and ICAM1

Under cytokine stimulation, VCAM-1 and ICAM-1 expression normally increase in endothelial cells. Knocking down ARFGEF2 makes those adhesion molecules ramp up even more, up to 50 fold more than baseline.

And if we're thinking about EBV and its effects on the brain, guess what role those adhesion molecules play?
Adhesion of Epstein–Barr virus-positive natural killer cell lines to cultured endothelial cells stimulated with inflammatory cytokines

Chronic active Epstein–Barr virus (EBV) infection (CAEBV) is characterized by chronic recurrent infectious mononucleosis-like symptoms. Approximately one-fourth of CAEBV patients develop vascular lesions with infiltration of EBV-positive lymphoid cells. Furthermore, EBV-positive natural killer (NK)/T cell lymphomas often exhibit angiocentric or angiodestructive lesions. These suggest an affinity of EBV-positive NK/T cells to vascular components. In this study, we evaluated the expression of adhesion molecules and cytokines in EBV-positive NK lymphoma cell lines, SNK1 and SNK6, and examined the role of cytokines in the interaction between NK cell lines and endothelial cells. SNKs expressed intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) at much higher levels than those in EBV-negative T cell lines. SNKs produced the larger amount of tumour necrosis factor (TNF)-α, which caused increased expression of ICAM-1 and VCAM-1 in cultured human endothelial cells, than that from EBV-negative T cell lines. Furthermore, SNKs exhibited increased adhesion to cultured endothelial cells stimulated with TNF-α or interleukin (IL)-1β, and the pretreatment of cytokine-stimulated endothelial cells with anti-VCAM-1-antibodies reduced cell adhesion. These indicate that the up-regulated expression of VCAM-1 on cytokine-stimulated endothelial cells would be important for the adhesion of EBV-positive NK cells and might initiate the vascular lesions.

Epstein–Barr virus induces aberrant B cell migration and diapedesis via FAK-dependent chemotaxis pathways

Infection with the Epstein-Barr virus (EBV) is a major risk factor for the development of cancer and autoimmune disorders. The virus enters the body in the pharynx, but EBV causes disease in distant organs, including the gut and the brain. Here we show, using in vitro culture and mouse infection models, that EBV-infected B cells display features of homing cells. Infected B cells undergo migration following paracrine CCL4 release and CCR1 induction, while CCR1 deficiency inhibits migration and, unexpectedly, proliferation of infected B cells. Furthermore, migrating EBV-infected B cells undergo CCL4-dependent diapedesis, induce ICAM-1 on endothelial cells, and disrupt the integrity of endothelial barriers. Both migration and diapedesis are regulated by FAK, with FAK inhibition blocking growth and survival of EBV-transformed B cells, as well as their spreading to spleen and brain in an animal model in vivo. Moreover, IL-10 secreted by EBV-infected B cells attracts and facilitates diapedesis of EBV-negative CD52highCD11c+ B cells, which have reported autoimmune properties. Our results thus provide mechanistic insight on EBV-induced B cell dysregulation, and also hint curbing migration as a potential target for reducing the pathogenicity of EBV-infected B cells.

So if ME/CFS patients with that variant have less constitutive ARFGEF2 activity in brain endothelial cells, that would increase ICAM-1 and VCAM-1 locally during anything that induces that cytokine signaling. Which, as it happens, would make the brain endothelium a perfect little niche to house latently infected circulating cells.

 

[jnmaciuch]

When we're thinking of age of onset I think we do have to keep the overlap with MS in mind. I don't think people have looked to see if there is a clear resolution of two distinct peaks in MS, but general age of onset covers the same range: ~20-50, with a peak around 35. Is it possible that this age range might have to do with EBV-related biology? The earlier age range would definitely correspond to a spike in young-adult-onset mononucleosis frequency. I remember from McGrath et al. that neither peak in ME/CFS was associated with infectious onset, but in the case of MS, the disease usually doesn't start immediately after EBV infection. So people who recover from EBV and get ME/CFS two years later wouldn't necessarily count themselves as infectious-onset unless they had something like a SARS-CoV-2 infection that, unbeknownst to them, reactivated EBV. Residual spike protein taken up into endothelial cells could also feed into the same problem by inducing the cytokine signaling locally in those cases.

So let's theorize that both MS and ME/CFS are diseases enabled by latent EBV hanging out in brain vessels: the former because it increases the changes of an autoreactive B cell making it into the CNS, the latter perhaps due to some interplay between brain activity and signaling from a nearby latently infected B cell. It would also be another interesting way of making sense of cognitive activity inducing symptoms. I wonder how a niche of latently infected lymphocytes somewhere in the brain vasculature might react if local blood flow increases substantially during cognitive activity. Would a set of common variants that affect synapses and increase neuron excitability also enhance that aberrant B cell signaling in response to cognitive activity?

 

[SugarSquared]

When talking about age of onset, we also can’t forget about migraine. Different papers show different things according to different types of migraines and different sexes, but a bimodal age of onset similar to ours is likely, at least in migraine with aura.

Migraine prevalence by age and sex in the United States: a life-span study, 2010, Victor et al

 

[jnmaciuch]

When talking about age of onset, we also can’t forget about migraine. Different papers show different things according to different types of migraines and different sexes, but a bimodal age of onset similar to ours is likely, at least in migraine with aura.

Migraine prevalence by age and sex in the United States: a life-span study, 2010, Victor et al

Certainly would be interesting if migraine was also an EBV-related, or at least a neural vasculature related problem. The latter makes a lot of sense

 

[Jonathan Edwards]

I'm thinking it's even simpler than that.

OK, but what you put there looks much more complicated. I agree that the effect on VCAM-1 and ICAM-1 looks good, butI doubt any fancy EBV-infected cells are needed. (And it would not work for all the other infections.) All I think one needs to postulate is facilitation of mononuclear cell ingress.

But the more ideas the merrier.

 

[V.R.T.]

Under cytokine stimulation, VCAM-1 and ICAM-1 expression normally increase in endothelial cells. Knocking down ARFGEF2 makes those adhesion molecules ramp up even more, up to 50 fold more than baseline.

Would that cause something like what was seen here?

Finally, exposure of endothelial cells to serum from long COVID patients induced increases in ICAM-1, VCAM-1 and TNF irrespective of neurological sequelae.

Two other studies that mention VCAM-1:

Furthermore, PC2 was associated with higher levels of VCAM-1 and triglycerides, and lower serotonin concentrations (all p < 0.05).

Sleep and circadian rhythm alterations in myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID fatigue syndrome and its association with cardiovascular risk factors: A prospective cohort study

Abstract
This study aimed to investigate circadian rhythm manifestations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients (including a subpopulation of long-COVID patients) and matched healthy controls while also exploring their association with cardiovascular health variables. Thirty-one ME/CFS patients (75% females), 23 individuals diagnosed with post-COVID ME/CFS (56% females) and 31 matched healthy controls (68% females) were enrolled in this study. Demographic and clinical characteristics were assessed using validated self-reported outcome measures. Actigraphy data, collected over one week, were used to analyze the 24-h profiles of wrist temperature, motor activity, and sleep circadian variables in the study participants. Associations between lipid profile with endothelial dysfunction biomarkers (such as endothelin-1, ICAM-1 and VCAM-1) and with sleep and circadian variables were also studied. No differences were found in these variables between the two group of patients. Patients showed lower activity and worse sleep quality than matched healthy controls, together with a worse lipid profile than controls, that was associated with disturbances in the circadian temperature rhythm. ICAM-1 levels were associated with plasma lipids in healthy controls, but not in patients, who showed higher levels of endothelin-1 and VCAM-1. These findings suggest that lipid profiles in ME/CFS are linked to disrupted circadian rhythms and sleep patterns, likely due to endothelial dysfunction. Furthermore, they highlight the intricate relationship between sleep, circadian rhythms, and cardiovascular health in this condition.

Chronobiology International - https://www.tandfonline.com/doi/full/10.1080/07420528.2024.2380020

 

[Jonathan Edwards]

When we're thinking of age of onset I think we do have to keep the overlap with MS in mind. I don't think people have looked to see if there is a clear resolution of two distinct peaks in MS, but general age of onset covers the same range: ~20-50, with a peak around 35. Is it possible that this age range might have to do with EBV-related biology?

I have looked through a lot of diseases in discussions with Simon and Audrey and I am pretty sure that there is no extra peak for MS and the profile is distinctly later. Audrey was keen on the idea that EBV explained the early peak in ME/CFS and there is no doubt that they found a high proportion of early onset cases reporting and EBV related onset (maybe 60%? I forget). Nevertheless, the peak looks too early to me. So although something at that age may facilitate and EBV often takes advantage I ended up being pretty sure that we still have to postulate some other early facilitation.

 

[Jonathan Edwards]

So let's theorize that both MS and ME/CFS are diseases enabled by latent EBV hanging out in brain vessels: the former because it increases the changes of an autoreactive B cell making it into the CNS, the latter perhaps due to some interplay between brain activity and signaling from a nearby latently infected B cell. It would also be another interesting way of making sense of cognitive activity inducing symptoms. I wonder how a niche of latently infected lymphocytes somewhere in the brain vasculature might react if local blood flow increases substantially during cognitive activity. Would a set of common variants that affect synapses and increase neuron excitability also enhance that aberrant B cell signaling in response to cognitive activity?

I like the enthusiasm but my understanding of the histological architecture, going back to Margaret Esiri's original observations of B lineage cells next to demyelination in MS, is that there really isn't much niche room for anything less than an MS plaque that would upset local brain function. Moreover, brain dysfunction in ME/CFS seems to affect a certain core set of functions rather than being spotted around doing different things in different people.

And, as mentioned, the ME/CFS is too early for peak EBV, not a bit late.

I do like the adhesion molecules though.

 

[SugarSquared]

Certainly would be interesting if migraine was also an EBV-related, or at least a neural vasculature related problem. The latter makes a lot of sense

Is this the kind of neural vasculature you’re talking about?

Neurovascular mechanisms of migraine and cluster headache

Migraine is frequently talked about as a neurovascular disorder. This recent GWAS paper says:

The genetic association of migraine has shown a general enrichment in genes highly expressed in vascular and central nervous system-related tissues

The two sources for that statement are:

• Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles
• Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

 

[jnmaciuch]

I agree that the effect on VCAM-1 and ICAM-1 looks good, butI doubt any fancy EBV-infected cells are needed. (And it would not work for all the other infections.)

EBV drives homing to the brain and is known to use those adhesion molecules to establish niches in the endothelium, plus it provides a mechanism for long-term alteration of the function of latently infected cells (as I've said before, "latent" is a bit of a misnomer). It might not be strictly necessary in all cases but, as seems likely in MS, pushes the lever on several things that might make falling into a particular feedback loop more likely.

Without EBV we have to posit some other unknown mechanism by which long lived or otherwise continuously replenished populations of circulating cells specifically make a home in the brain endothelium and behave unusually. Which might also exist, but it would be silly to ignore something which checks all those boxes being handed to us on a silver platter when we're thinking about testable hypotheses.

Second point would already be addressed in what I mentioned about post-COVID onset.

 

[Jonathan Edwards]

In an endothelial cell-line, knocking down ARFGEF2 makes cells less TNF responsive by reducing surface expression of the receptor. But it also does something else very interesting:


Under cytokine stimulation, VCAM-1 and ICAM-1 expression normally increase in endothelial cells. Knocking down ARFGEF2 makes those adhesion molecules ramp up even more, up to 50 fold more than baseline.

This seems a bit paradoxical. Is this due to increased responsiveness to other cytokines?

 

[Jonathan Edwards]

Is this the kind of neural vasculature you’re talking about?

Probably not. Migraine involves arterial or arteriolar calibre change I think. We are talking about events at the capillary and venule surface. Stimulation of very small vessel nerves might produce reflexes active on arterioles but i think this is probably off target.

 

[jnmaciuch]

I like the enthusiasm but my understanding of the histological architecture, going back to Margaret Esiri's original observations of B lineage cells next to demyelination in MS, is that there really isn't much niche room for anything less than an MS plaque that would upset local brain function. Moreover, brain dysfunction in ME/CFS seems to affect a certain core set of functions rather than being spotted around doing different things in different people.

That's reading too much into what I was proposing. The idea is just that the random occurence of an auto-reactive B cell making its way past the blood brain barrier to trigger MS becomes a lot more likely if you have a bunch of long lived latently infected B cells already embedding themselves into the endothelium. Doesn't have to be a big niche. A sprinkling will do.

And I've already brought up this paper multiple times:

Thread 'Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment, 2016, Blank +'

Oct 24, 2025

Link

Spoiler: Authors

Thomas Blank 1 ∙ Claudia N. Detje 2 ∙ Alena Spieß 1 ∙ Nora Hagemeyer 1 ∙ Stefanie M. Brendecke 1 ∙ Jakob Wolfart 3 ∙ Ori Staszewski 1 ∙ Tanja Zöller 1 ∙ Ismini Papageorgiou 4 ∙ Justus Schneider 4 ∙ Ricardo Paricio-Montesinos 1 ∙ Ulrich L.M. Eisel 5∙ Denise Manahan-Vaughan 6 ∙ Stephan Jansen 6 ∙ Stefan Lienenklaus 2, 7 ∙ Bao Lu 8 ∙ Yumiko Imai 9 ∙ Marcus Müller 10 ∙ Susan E. Goelz 11 ∙ Darren P. Baker 12 ∙ Markus...

• Hutan
• blood brain barrier bone marrow endothelial cells interferon isg15 sickness behaviour
• Replies: 31
• Forum: Other health news and research

• 

Immune signaling at the brain endothelium triggers a chain reaction resulting in sickness behavior in mice. Whatever this process is, it can be triggered by diffuse cytokine. So a bunch of aberrant infected cells scattered across the endothelium, reacting to constant brain activity, makes perfect sense.

And, as mentioned, the ME/CFS is too early for peak EBV, not a bit late.

And that first peak seems to shift around by country, and we may be wrong to assume a uniform peak EBV incidence across countries.

 

[jnmaciuch]

This seems a bit paradoxical. Is this due to increased responsiveness to other cytokines?

I should actually correct my earlier post--ARFGEF2 knockdown inhibited export of TNFR1 in exosomes. Maybe it's a biological mechanism where those exosomes fuse to nearby cells and create rafts of concentrated TNF receptors to quickly enhance the cytokine responsiveness of other cells. So it might not affect TNFR1 expression levels on the surface of these knockdown endothelial cells themselves.

 

[jnmaciuch]

Is this the kind of neural vasculature you’re talking about?

Neurovascular mechanisms of migraine and cluster headache

Migraine is frequently talked about as a neurovascular disorder. This recent GWAS paper says:

The two sources for that statement are:

• Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles
• Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

Probably not. Migraine involves arterial or arteriolar calibre change I think. We are talking about events at the capillary and venule surface. Stimulation of very small vessel nerves might produce reflexes active on arterioles but i think this is probably off target.

But we're talking about a genetic risk here, which can work in indirect ways (especially for genes picked up in a GWAS, which are going to be skewed for low effect size genes with more indirect mechanisms of altering disease risk).

 

[Jonathan Edwards]

Doesn't have to be a big niche. A sprinkling will do.

But Esiri showed the size of the niche. You get plaque lesions or nothing much. My experience with RA is very similar. Lone B cells simply fall apart (you can see them exploding on fluorescence microscopy) but in a cluster with other cells they can survive and produce lesions.

 

[Jonathan Edwards]

Whatever this process is, it can be triggered by diffuse cytokine.

It would need to be diffuse cytokine specifically in the hypothalamus, presumably? We don't have reason to think cytokines in other bits of brain produce sickness behaviour as far as I know.

 

[jnmaciuch]

But Esiri showed the size of the niche. You get plaque lesions or nothing much. My experience with RA is very similar. Lone B cells simply fall apart (you can see them exploding on fluorescence microscopy) but in a cluster with other cells they can survive and produce lesions.

I’m not saying the EBV would directly be causing lesion formation. It would just be increasing the likelihood of an auto reactive B cell eventually making its way across the BBB and eventually causing lesions by influencing a lot of B cells to hang around with one toe lodged into the door of the CNS via these adhesion molecules.

 

[Jonathan Edwards]

And that first peak seems to shift around by country, and we may be wrong to assume a uniform peak EBV incidence across countries.

The size of the peak is very different in Spain (which could be less late EBV) but fairly similar in other countries and at the same time point to within a year in all countries except perhaps Germany. So it doesn't shift in time - it is quite remarkably consistent a bit too early for the kissing disease.

 

[Jonathan Edwards]

I’m not saying the EBV would directly be causing lesion formation. It would just be increasing the likelihood of an auto reactive B cell eventually making its way across the BBB and eventually causing lesions by influencing a lot of B cells to hang around with one toe lodged into the door of the CNS via these adhesion molecules.

But why bring in B cells when we have no pathology to link to antibody - which demyelination does beautifully. Why bring in autoreactivity, when we don't even have good evidence for it in MS?

I prefer a much simpler model where there is a shift in monocyte traffic.