Scientists discover how to switch off autoimmune diseases

[knackers323]

Anyone else see this study? To those that understand this sort of thing, is it promising?

 

[Adster]

This is the one? http://www.nature.com/ncomms/2014/140903/ncomms5741/full/ncomms5741.html

Looks interesting!

 

[knackers323]

That's it

 

[Jonathan Edwards]

This is complete nonsense I fear. They assume that human autoimmunity involves autoreactive T cells, despite the fact that nobody has ever found such things in most autoimmune diseases. They then deliberately create autoreactive T cells by genetic engineering in mice - i.e. producing a disease that as far as we know has nothing to do with human disease. They then show that to treat this it is necessary to de-senstise in a particular way. So they are telling us the details of how to treat an imaginary disease.

Sad, really. They need a forum like PR where people can point out that rubbish might be rubbish.

 

[JamBob]

@Jonathan Edwards

Professor Edwards

Are there really no such thing as autoreactive T cells in autoimmunity or is it just in diseases like lupus and CFS/ME?

I was really hoping this research into T1 Diabetes that uses a TNF alpha inducer* (the BCG vaccine) to cause autoreactive Tcell apoptosis would be productive. Faustman's lab have had success in mice (I know it's not the same) but have also done a small proof of concept trial in humans and are about to start phase 2 trials. They say they found the same autoreactive Tcells in humans as they found in mice.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041756
http://www.faustmanlab.org/

* From what I understand Dr Faustman is going against the grain by inducing TNF-a rather than inhibiting it.

 

[Jonathan Edwards]

Are there really no such thing as autoreactive T cells in autoimmunity or is it just in diseases like lupus and CFS/ME?

I was really hoping this research into T1 Diabetes that uses a TNF alpha inducer* (the BCG vaccine) to cause autoreactive Tcell apoptosis would be productive. Faustman's lab have had success in mice (I know it's not the same) but have also done a small proof of concept trial in humans and are about to start phase 2 trials. They say they found the same autoreactive Tcells in humans as they found in mice.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041756
http://www.faustmanlab.org/

* From what I understand Dr Faustman is going against the grain by inducing TNF-a rather than inhibiting it.

On the basis of what I know from the literature and answers from colleagues expert in the relevant fields in recent times my understanding is that there are only two autoimmune situations where at least reasonable evidence exists for increased T cell autoreactivity. These are the very rare syndrome of multiple endocrine autoimmunity linked to a gene defect (AIR) and type 1 diabetes.

Type 1 diabetes is a very unusual autoimmune disorder because it has a high incidence in children. This is a time when T cell clones are being actively selected and mistakes could be made. Almost all other true autoimmune diseases are commoner in women in later life - which fits with the fact that they show autoreactive B cells but no increase in autoreactive T cells.

I say increase in autoreactive T cells because all of us have T cells that will respond to anything. What matters is the threshold of responsiveness to any particular antigen. So you have to compare responses quantitatively against normals in carefully matched conditions. The neatest paper I saw involved identical twins, one with scleroderma and one without. The researchers were honest enough to report that the T cell responses to the scleroderma antigen that the sufferer had antibodies to were exactly the same. This is a fairly crucial finding because it shows that th eidea that you need T cell autoreactivity to drive autoantibodies is wrong.

Type 1 diabetes is also a bit odd in that autoantibodies do appear but they may then disappear quite quickly. That raises the possibility that the damage to the islets is not in fact autoimmune at all, but something more like 'autoinflammatory'.

I do not know the literature on T cell autoreactivity in Type 1 diabetes but my understanding is that people do think it is increased. There may still be an issue as to whether or not the data are reliable because of statistical analysis issues. The problem with all animal studies is that any T cell autoreactivity in them will by definition have come about in a different way - it has been engineered in by researchers. That might not matter but there is no guarantee that animal studies are of any relevance in this context.

I do not understand the paper you flagged. They say they found dead insulin autoreactive T cells. But assessing autoreactivity to my mind involves measuring T cell responses in vitro and to respond the T cells would need to be live. (They used tetramer binding which I do not think tells you anything functional but I may be out of date.) And I cannot work out what dead cells in the blood would imply - since they are likely to be cleared within hours it suggests that there are plenty of live ones around to be ready to die for the next blood test. I do not understand this methodology well enough to be able to give a clear critique but it seems weird to me. It also seems very odd that the diabetics did not have any more insulin reactive T cells than controls at the start. And since controls were not given BCG we do not know if the dead insulin reactive cells had anything to do with having diabetes. It allseems a long way away from showing that the T cells cause the diabetes and that removing them will help.

 

[Valentijn]

Type 1 diabetes is also a bit odd in that autoantibodies do appear but they may then disappear quite quickly. That raises the possibility that the damage to the islets is not in fact autoimmune at all, but something more like 'autoinflammatory'.

This is an area I'm somewhat curious about. My fiance came down with autoimmune Type I diabetes a couple years ago, at around age 40. He had it a very short time prior to being diagnosed - his glucose was sky-high (literally too high for the GP to get a reading), but his HbA1c came back in a normal range.

I was under the impression that the damage done to the cells producing insulin is permanent and irreversible in Type I Diabetes. Yet he regularly has "remissions" where his glucose levels are completely normal without taking insulin for weeks or months at a time, and in fact he can't take any insulin during those times or his glucose levels get too low. Yet on the same diet, he'll sometimes need a fair bit of insulin for months at a time.

Any idea what might be going on? Are there different types of Type I Diabetes? Could certain types be hitting adults more than children, and vice versa?

 

[JamBob]

@Valentijn
It's fairly normal to get what's referred to as a "honeymoon" period in the early stages of T1 diabetes.

I'm not sure of the physiology behind it but people either have to dramatically reduce their doses or can come off insulin altogether for a short period of time. Over time, things progress and you have to either up your dose or start back on insulin (if you went off it). I went down to 4 units a day during my "honeymoon" which was a very small dose. I even stopped taking my insulin for 6 weeks without too much trouble. These days I take around 30 units per day.

They used to think that the beta cells were permanently destroyed but several studies this and last year showed that T1s continue to make very low levels of insulin and produce low levels of C-Peptide that can only be found if you use ultra-sensitive tests - which are a new invention. eg.
http://www.faustmanlab.org/docs/academic/Diabetes Care_March 2012_CPeptide_Faustman et al.pdf

Maybe your boyfriend is still producing some insulin of his own intermittently.

Oh and the good news (if I have read things right!) is that because they find we still have some insulin producing ability even decades later, scientists may be able to target therapies towards people who have had diabetes for a long time rather than just people who have had it for a year or so (which is what a lot of T1 research focusses on). If they can stop the autoimmune attack, scientists may be able to harness whatever beta cell functioning we have left.

 

[Valentijn]

@JamBob - Yes, we were prepared for the honeymoon phase. The odd thing is that he gets them repeatedly, at least twice per year.

 

[JamBob]

@JamBob - Yes, we were prepared for the honeymoon phase. The odd thing is that he gets them repeatedly, at least twice per year.

Interesting - maybe he should be part of some study!! It must make it difficult to manage his insulin if he can't anticipate when the changes will happen or how long they will last for.

 

[Valentijn]

Interesting - maybe he should be part of some study!! It must make it difficult to manage his insulin if he can't anticipate when the changes will happen or how long they will last for.

Yeah, it's almost always fluctuating somewhat, then there's suddenly times when he needs to drop the amount he's taking fairly quickly - but not too quickly, of course He keeps the dextrose manufacturers in business!

 

[Jonathan Edwards]

Any idea what might be going on? Are there different types of Type I Diabetes? Could certain types be hitting adults more than children, and vice versa?

What I have heard recently from a friend who is Professor of Diabetology at Imperial College is pretty much what JamBob has said. Type 1 diabetes does not fit very well with the standard theories. And late onset Type 1 (40ish) may not be the same thing as the childhood problem. Even with children they think that most present at a stage when there is still the potential for rescuing islet cells, although I gather that normally islet cells develop very early in life and do not increase after that.

And improvements do sometimes occur, not just at the beginning. Interestingly, I gather that in cats diabetes can be an acute and temporary illness. Maybe Type 1 covers a lot of different things - anything that isn't an insulin resistance problem due to overweight.

 

[alex3619]

What I have heard recently from a friend who is Professor of Diabetology at Imperial College is pretty much what JamBob has said. Type 1 diabetes does not fit very well with the standard theories. And late onset Type 1 (40ish) may not be the same thing as the childhood problem. Even with children they think that most present at a stage when there is still the potential for rescuing islet cells, although I gather that normally islet cells develop very early in life and do not increase after that.

And improvements do sometimes occur, not just at the beginning. Interestingly, I gather that in cats diabetes can be an acute and temporary illness. Maybe Type 1 covers a lot of different things - anything that isn't an insulin resistance problem due to overweight.

Over the last twenty years or so I have read the odd paper that indicates type 1 diabetes might be much more inflammatory than autoimmune, including a very old reference now to its reversal in rats I think via a severing of the vagus nerve. I am also aware of large numbers of skinny type 2 diabetics. The research on type 2 diabetes is often done on obese rats or people, as they are easier to identify or recruit or create. Yet I am not sure its about obesity, except in the sense that obesity is one risk factor, though possibly causal in a subset. Diabetes (type 2) is in my current opinion a syndrome described by a particular set of hormonal and energy failures. How we get there though might be variable. So there might be an obese group, and some others.

I told this to a researcher in the UK in about 2000. He doubted me. So he did the rounds at a major endocrinology clinic/ward in a major hospital. He found lots of type 2 diabetics who were skinny.

There is no question that diet and exercise are important impact and risk modifiers though. Yet Sumo wrestlers usually don't get it and are obese. They are also super fit however, and eat very healthy. High calorie consumption may occur, but their muscles have low internal fat and their diet is high in nutrients ... no junk food.

I suspect, like cancer, definitely CFS, and possibly ME, they will find many subtypes.

 

[Jonathan Edwards]

I am also aware of large numbers of skinny type 2 diabetics. The research on type 2 diabetes is often done on obese rats or people, as they are easier to identify or recruit or create. Yet I am not sure its about obesity, except in the sense that obesity is one risk factor, though possibly causal in a subset. Diabetes (type 2) is in my current opinion a syndrome described by a particular set of hormonal and energy failures. How we get there though might be variable. So there might be an obese group, and some others.

Quite agree Alex, I was oversimplifying even the Type 2 situation.

 

[Valentijn]

@alex3619 - When I was at a hospital for most of the day for some vascular testing, one of the volunteers taking care of us at lunch was a slender and athletic Type II diabetic. Additionally, overweight adult-onset diabetics (and maybe even normal weight) often aren't tested for autoimmunity either, so may actually be misclassified in some situations.

 

[daisybell]

My father is a skinny type II diabetic, who has other auto-immune issues.... He and I have discussed this more since I have developed autoimmune disease.