NK Cells Influence Virally Triggered Autoimmunity

[Forbin]

TRAIL+ NK Cells Control CD4+ T Cell Responses during Chronic Viral Infection to Limit Autoimmunity (2014)
Iona S. Schuster, Matthew E. Wikstrom, Geraldine Brizard, Jerome D. Coudert, Marie J. Estcourt,
Mitali Manzur, Lorraine A. O’Reilly, Mark J. Smyth, Joseph A. Trapani, Geoffrey R. Hill, Christopher E. Andoniou, and Mariapia A. Degli-Esposti

SUMMARY

Natural killer (NK) cells have been reported to control adaptive immune responses that occur in lymphoid organs at the early stages of immune challenge. The physiological purpose of such regulatory activity remains unclear, because it generally does not confer a survival advantage.

We found that NK cells specifically eliminated activated CD4+ T cells in the salivary gland during chronic murine cytomegalovirus (MCMV) infection. This was dependent on TNF-related apoptosis inducing ligand (TRAIL) expression by NK cells.

Although NK cell-mediated deletion of CD4+ T cells prolonged the chronicity of infection, it also constrained viral-induced autoimmunity. In the absence of this activity, chronic infection was associated with a Sjogren’s-like syndrome characterized by focal lymphocytic infiltration into the glands, production of autoantibodies, and reduced saliva and tear secretion.

Thus, NK cells are an important homeostatic control that balances the efficacy of adaptive immune responses with the risk of developing autoimmunity.

http://www.cell.com/immunity/abstract/S1074-7613(14)00347-1

[Bolding Mine]

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Hopefully, my following thumbnail of the summary is correct:

Some NK cells (TRAIL+ NK cells) produce the TRAIL cytokine. This cytokine apparently can regulate the immune response to viral infection by suppressing (killing) responding CD4+ T cells. This prolongs the immune reaction by restraining the number of CD4+ T cells, but, counterintuitively, this turns out to be a good thing.

In the absence of TRAIL, either due to low NK cell numbers or low NK cell activity, CD4+ T cell numbers are not constrained and this can promote autoimmunity.

The study was in mice. When TRAIL+ NK cells were eliminated prior to murine cytomegalovirus (MCMV) infection, the mice developed an autoimmune response in the salivary glands similar in appearance to Sjögren's Syndrome.

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Media reports on the paper.

Scientists prove link between viral infection and autoimmune disease
https://medicalxpress.com/news/2014-10-scientists-link-viral-infection-autoimmune.html

Link between viral infection and autoimmune disease
http://www.labonline.com.au/content...l-infection-and-autoimmune-disease-1124013397


My ME/CFS related speculation:

Given the many findings of low NK cell activity in ME/CFS patients over the years, it is tempting to speculate that this may not be an effect of ME/CFS, but rather a cause, i.e., a predisposition for low NK cell activity leading to an unrestrained response to infection that winds up triggering autoimmunity.

Also, an unrestrained, rapid response to infection might explain why a subset of ME patients seem "immune" to the flu or other infections. The response is so overwhelming, that the infection never takes hold. The penalty is ME/CFS.

 

[Hip]

Very interesting. It looks like the TRAIL protein (TNF-related apoptosis inducing ligand) has been synthesized and is being tested for its ability to kill cancer cells as well as inhibit autoimmunity:

TNF-related apoptosis-inducing ligand as a therapeutic agent in autoimmunity and cancer

In cancer patients, phase 1 and 2 clinical trials using agonistic mAbs that engage the human TRAIL receptors DR4 and DR5 have also provided encouraging results. It is now evident that TRAIL suppresses autoimmune disease in various experimental animal models, suggesting that the therapeutic value of recombinant TRAIL and agonistic DR4 and DR5 mAbs might also extend to the suppression of autoimmune disease.

 

[nandixon]

Given the many findings of low NK cell activity in ME/CFS patients over the years, it is tempting to speculate that this may not be an effect of ME/CFS, but rather a cause, i.e., a predisposition for low NK cell activity leading to an unrestrained response to infection that winds up triggering autoimmunity.

There's a good connection between the low natural killer (NK) cell activity, commonly found in ME/CFS, and the high TGF-beta which seems to be equally commonly found (Montoya found the latter yet again in his most recent study here).

The study that @Murph referenced here seems to imply that with high circulating levels of TGF-beta that NK cell function is likely to be reduced.

(I don't have the references handy but high TGF-beta also explains another common laboratory finding in ME/CFS of low vasopressin; it may also explain the increased Treg activity seen in some ME/CFS studies.)

The high TGF-beta may be a response to increased proinflammatory cytokines.

The proinflammatory cytokines may be coming from activated/clonally expanded CD8+ T cells, if the work that Mark Davis presented at the recent Open Medicine Foundation (OMF) event is correct (link).

So the situation might look like:

CD8 clonal expansion→ proinflammatory cytokines→ increased TGF beta→ reduced NK cell activity→ failure to eliminate activated CD4 T cells (per the current study)→ autoimmunity

The CD8 clonal expansion might itself represent a T cell-mediated form of autoimmunity rather than the expansion being due to an ongoing infection, for example. And then any resulting autoantibodies (e.g.) that might arise from the flow diagram above might be more of a sideshow.