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T-cell exhaustion, infection and autoimmune disease NEW research

natasa778

Senior Member
Messages
1,774
An 'exhausted' army of immune cells may not be able to fight off infection, but if its soldiers fight too hard they risk damaging the very body they are meant to be protecting, suggests new research.

In research published today in the journal Nature, scientists from the Cambridge Institute for Medical Research looked at patterns of genes that were turned on and off in patients with autoimmune diseases and found similarities with those seen in people with chronic infection, such as hepatitis C, and cancer: in other words, they have shown that the same process of T cell 'exhaustion' known to be involved in the immune response to chronic infection and cancer is also important in many autoimmune diseases.

http://www.sciencedaily.com/releases/2015/06/150629110803.htm

full paper http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14468.html

During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence1. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory ‘help’ signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced.

... Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities...
 

msf

Senior Member
Messages
3,650
Which hypothesis though? Autoimmunity or infection? Or both? I think it is interesting that the CD-8 T-cell exhaustion was associated with a poorer prognosis in chronic infection, but a better one in autoimmunity. It's also interesting that this was observed in Hepatitis C infection, as the disease progression seen with Hepatitis C was one of the reasons why the Lipkin paper divided the patients into those who had been ill for less/more than 3 years.
 

lansbergen

Senior Member
Messages
2,512
This is obviously happening in long-term ME but the question is what is driving it.

I think the chronic infection/the reaction to that infection. I do not know what exactly goes wrong but I am pretty sure it starts early in the disease proces. Levamisole which helps me a lot made the difference between live and dead in young animals during the acute infection.
 

heapsreal

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Could we call low nk function or even low cd8 function, some type of immune exhaustion, even though numbers are within normal range?
 

lansbergen

Senior Member
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2,512
Could we call low nk function or even low cd8 function, some type of immune exhaustion, even though numbers are within normal range?

If they do not work well one might but only untill more is known. Exhaustion is such a general term.
 

heapsreal

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If they do not work well one might but only untill more is known. Exhaustion is such a general term.

Agree.

i wonder if by some fluke someone has had an nk function test done and later developed cfsme. Its very possible as many studies on nk function compare cfs vs healthy controls.

it would be interesting to know if the low nk function developed over time or a predisposing factor in getting cfsme. If its developed over time, maybe the 6 months needed before a cfs diagnosis , than a type of immune exhaustion??
 

Mij

Messages
2,353
An observation in my own case, CD8 etc all normal within normal range (unfortunately never had an NK function test) no immune reaction to flu, etc for the first 11yrs, then retested and everything is way below range and now I feel 'viral' 90% of time. I feel as though I am constantly fighting something for the last 13yrs. Something changed for sure.
 

natasa778

Senior Member
Messages
1,774
This is obviously happening in long-term ME but the question is what is driving it.


It would be REALLY interesting to see if this could any way be related to that 3-year immune shift in ME patients that Lipkin and Hornig have observed.
 

Jon_Tradicionali

Alone & Wandering
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Zogor-Ndreaj, Shkodër, Albania
Which hypothesis though? Autoimmunity or infection? Or both? I think it is interesting that the CD-8 T-cell exhaustion was associated with a poorer prognosis in chronic infection, but a better one in autoimmunity. It's also interesting that this was observed in Hepatitis C infection, as the disease progression seen with Hepatitis C was one of the reasons why the Lipkin paper divided the patients into those who had been ill for less/more than 3 years.

Viral persistance resulting in immune exhaustion.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Does @Jonathan Edwards think that this study makes sense and/or that it may have relevance for us?

The findings seem to me very obscure. There does not seem to be any suggestion that T cell exhaustion is part of the cause of autoimmunity - the more patients showed it the less bad their disease it seems. It is a very odd selection of autoimmune diseases too. I rather get the impression that they checked a whole lot of genes for expression in a rather motley collection of patients, found correlations with something once they had looked hard enough and tried to make a story out of it. The press release seems off target.

In other words I cannot make sense of it.
 

heapsreal

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An observation in my own case, CD8 etc all normal within normal range (unfortunately never had an NK function test) no immune reaction to flu, etc for the first 11yrs, then retested and everything is way below range and now I feel 'viral' 90% of time. I feel as though I am constantly fighting something for the last 13yrs. Something changed for sure.


I have been the opposite with high cd t cell subsets, nk cd56 in normal range and nk cd3 above range. My nk function was very low, nk bright cells low and nk dim cells normal.

what does it mean?? My dr just says it looks like im fighting some infection.
 

Mij

Messages
2,353
@heapsreal I seem to recall the doctor telling me that a high CD4/CD8 ratio was due to a viral infection. Mine was/is high.

My CD56 is the only one in normal range.
 

Simon

Senior Member
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Monmouth, UK
There does not seem to be any suggestion that T cell exhaustion is part of the cause of autoimmunity - the more patients showed it the less bad their disease it seems.
I thought that was the point of the paper:
Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases.
ie those with T cell exhaustion early in their illness had better long-term outcomes than those without. It's still only an association, but the fact that T cell exhaustion comes first surely indicates it could have a causal role.

I also thought this was interesting as it implies T cell exhaustion (and treating it) has a clinically important role in other illnesses
A focus on T cell exhaustion in cancer has led to a revolution in treatment and a multi-billion dollar industry.
Though I worry about the reference to 'multi-billion dollar industry', which sounds like dollar signs appearing in researchers' eyes - not necessarily the right focus.
At least they are testing the approach. Always a useful reality check for a theory built on associations.
Professor Ken Smith, lead author of the study and Head of the department of medicine, says: "We believe the clinical implications of this study could be profound. A test based on the concept is soon to enter the clinic, and we are exploring new treatments for autoimmunity based on manipulating T cell exhaustion.

Oh, and it all focuses on T cells in humans, rather than mice, which I thought you might like :).


It is a very odd selection of autoimmune diseases too. I rather get the impression that they checked a whole lot of genes for expression in a rather motley collection of patients, found correlations with something once they had looked hard enough and tried to make a story out of it.
Though it does appear they selected diseases on the basis of having the right type of data for their analysis, rather than the right 'result' from their perspective:
Methods section said:
Published data sets were accessed through either National Center for Biotechnology Information (NCBI) Gene Expression Omnibus or ArrayExpress...

Search criteria incorporated the name of individual diseases and were filtered to human data sets but not by [microarray] platform used.
Studies were only included if they met the following criteria.
(1) Similar quality control filters as applied to the data produced in-house were satisfied (described below).
(2) Samples were taken at an analogous time-point to those from which the co-stimulation and exhaustion signatures in autoimmunity were identified; that is, samples taken during active disease without concurrent immunosuppressive
therapy.
(3) Clinical outcome data were available.