In Brief: Autoimmunity and ME

October 8, 2013

The second in series of short articles attempting to explain the science behind fairly common topics and exploring how they relate to ME. This time the topic is Autoimmunity – by Andrew Gladman.

Electron microscopic image of a single human lymphocyte,

Electron microscopic image of  a human lymphocyte.

In the last few years it’s fairly safe to say that the topic of autoimmunity has moved from a fairly unknown entity in the ME field to perhaps the leading hypothesis in many peoples’ eyes. This surge in attention likely comes from the rituximab trials in Norway undertaken by Doctors Fluge and Mella. By chance they discovered that ME patients, who then went on to develop lymphoma, treated with rituximab for their cancer also experienced significant, albeit transient, relief from near all of their ME symptoms. These published and ongoing trials appear to be suggesting that up to 67% of ME patients are responding well to this drug. Given the B-cell destroying mechanism of rituximab this has led the Norwegian doctors to conclude that ME is perhaps best described as an autoimmune condition mediated primarily by autoreactive B-cells.

What is Autoimmunity?

Autoimmunity is generally regarded as the lost ability of the body to differentiate between certain parts of the normal organism’s anatomy and pathogenic invaders. All cells and tissues within an organism have molecules known as antigens on their surface that act simply like little flags, allowing the patrolling cells of the immune system to recognise them as a part of the organism (‘self’). If for some reason the circulating immune cells lose the ability to recognise these flags, the cells displaying them are then treated as a foreign invader (‘non-self’) and an immune response is initiated against them. The body now attacks itself. This is often described as a loss of ability to differentiate between self and non-self

The immune response is generally comprised of an innate component and an adaptive component:

  • A fast-acting, non-specific innate response, which is the first line of defence, eg macrophages and to a degree natural killer cells (however these cells play a role in both the adaptive and innate systems.)
  • A slower but specific and targeted adaptive response, eg B-cells and T cells

The innate response, as the first line of defence, also helps trigger the adaptive response however the adaptive response is considered the major player in autoimmunity. These responses interact with one another through various immune cells and chemical messages which they secrete such as cytokines. Until quite recently the innate immune system was thought to be of little importance in autoimmune conditions, however it is now clear that the inability of the innate immune system to recognise self often results in the initiation of inflammatory mechanisms in autoimmune diseases.

The left branch represents the cells of the adaptive immune response which involves B and T cells. The right branch are the cells of the innate immune response. There are many interactions between these two arms, with nearly every cell having mechanisms to communicate with all the other immunological cells.

The left branch represents the cells of the adaptive immune response which involves B and T cells. The right branch are the cells of the innate immune response. There are many interactions between these two arms, with nearly every cell having mechanisms to communicate with all the other immunological cells.

The adaptive response is comprised of T-cells and B-cells (sometimes referred to as lymphocytes). There are numerous different kinds of T-cells and each has it’s own job to do. Some send chemical instructions in the form of cytokines to the rest of the immune system, signalling and triggering responses – allowing the body to produce the most effective ‘weapons’ against the invading pathogens. Other types of T-cells recognise and kill infected cells directly. 

B-cells produce small proteins known as antibodies which bind to the antigens of invading pathogens sticking them together and alerting the other cell of the immune system to their presence. In a normal immune response this antigen targeted will be that on the surface of a virus or bacterial pathogen, however in autoimmunity the target for the antibody is an antigen on the surface of a human ‘self’ cell. These antibodies are detected by the T-cells as well as cells involved in the innate immune response which may then in turn attack and the destroy the cell through inflammatory and other mechanisms. 

It is important however to realise that the involvement of each system in autoimmune diseases differs greatly. Not all autoimmune diseases involve inflammatory mechanism and not all involve antibody production. It is a topic of great debate in autoimmunity whether the B-cells or T-cells are the initiating factor, however it appears that autoimmunity has a wide spectrum and certain cells and mechanisms are more involved in some diseases than others.

Short video explaining the immune response.

Short video explaining the immune response.

Under the heading of autoimmunity there exist hundreds of different conditions which are fundamentally differentiated by which cells, tissues or organs are targeted by the aberrant immune response. In theory, any cell type could be the target for such an immune response which explains the wide differentiation in symptoms between different autoimmune diseases – through the damage, dysfunction or destruction of many different cells.

Generally autoimmune diseases are grouped into two types: local and systemic. Local autoimmune diseases are autoimmune diseases where the cells being attacked are specific to only one tissue or organ in the body. Local autoimmune conditions include type 1 Diabetes and Coeliac disease. In systemic autoimmune diseases however, the cell being targeted has a broader range or roles in numerous different organs and tissues within the body. As such, in systemic autoimmune diseases the symptoms are often more extensive and damage cause by the immune response is often more widespread: examples being Lupus and rheumatoid arthritis.

The trouble lies however in that many of the symptoms of autoimmune diseases are quite non-specific which makes diagnosis of many autoimmune diseases quite difficult unless there are specific biomarkers known, whether this be autoantibodies or otherwise, or significant changes in the standard laboratory tests.

Why is autoimmunity important to ME?

The idea of an aberrant immune response is nothing new to the field of ME research. Following the Lake Tahoe outbreak, after which ME/CFS came to the forefront of many doctors and researchers minds, it has been well established and accepted that the immune system in ME patients is not working as intended. Symptoms such as swollen lymph nodes and the characteristic sore throat in ME all point towards a  dysregulated immune response and the predominance of ME in women ,with estimates that typically the ME/CFS cohort is comprise 75-85% with women. is further compounding evidence that ME could well be an autoimmune condition, given that this is often the case with autoimmune conditions; it is of note that this is also the case in many psychological diseases however this sex predominance is much more pronounced in autoimmune diseases and ME. 

In recent years the evidence continues to mount for the possibility of autoimmunity as a central mechanism within ME. There is evidence of dysregulation in cytokines – substances produced by cells of the immune system which have effects upon other cells – as reported very recently by Dr. Lipkin.  There is also evidence, although somewhat disparate, of generic autoantibodies being found in ME patient blood samples. In a recent statement, Dr. Charles Shepherd, Honorary Medical Adviser of The ME Association, quite eloquently summed up these findings:

“A wide range of immune system abnormalities have been reported in ME/CFS. These include the presence of low levels of autoantibodies in some people. Autoantibodies are antibodies that can harm normal body tissues. Among the autoantibodies that have been reported in research studies in ME/CFS are antinuclear antibodies and rheumatoid factor – typically in low concentrations without evidence of lupus or rheumatoid arthritis. Antibody to thyroid gland and other tissues are occasionally reported. There is also an interesting report indicating that antinuclear antibodies, rheumatoid factor and anti-Ro may be present in some people with ME/CFS and a Sjogren’s Syndrome-like presentation.”

Autoimmunity may appear to be something of a revelation, however there have been numerous hypotheses suggested for how different autoimmune mechanisms and loops could explain and be the causative agent for ME. First there is the hypothesis of Dr. Kenny De Meirleir that Plasmacytoid dendritic cells (a sentinel cell and part of the innate immune system that circulates in the blood steam) are autoreactive to Human Endogenous Retrovirus (HERV) proteins – HERVs being viral remnents that remain in the human genome and being passed from parent to child over many generations. Generally they are considered harmless and non-functional, however some may occasionally produce proteins which could act as a target for an autoimmune response. This hypothesis is discussed at much greater length in a recent article by Joel for Phoenix Rising

Another hypothesis is that autoimmunity may be targeted towards molecules known as vasoactive neuropeptides. These molecules are small peptides comprised usually of around 20-30 amino acids residues. These molecules have numerous functions within the body including acting as neurotransmitters, vasodilators and also play a role in immune regulation. Such an autoimmune response would likely deplete these peptides hence causing the wide array of nondescript and seemingly unrelated symptoms ME patients experience. Interestingly such depletion of these molecules would be virtually undetectable through standard laboratory tests.

Doctors Fluge and Mella are themselves still working on their own hypothesis to explain their positive findings with rituximab which is due for publication, along with results from their latest trial of rituximab, imminently. It is clear that B-cells may be of great importance for the disease pathology of ME. Given that the Invest in ME/UCL rituximab trial is also now well on its way to being funded, the autoimmune hypotheses are now beginning to gain more attention and momentum as time progresses. Hopefully this new ‘hot topic’ in ME research holds more answers in store for us going forwards.

If anyone has any requests or suggestions of topics for future installments be sure to let me know in the comments below. 

Next time we delve into a topic that is often discussed at great length by ME patients and researchers alike, the mitochondria.

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14 comments

{ 14 comments… read them below or add one }

justy October 8, 2013 at 3:07 am

Agreat article, thanks Andrew! I'm looking forward to the publication of Fluge and Mellas work – any ideas of a timescale for this?
I am always struck by how similar to other autoimmune diseases M.E is (especially for me) at times looking very much like Lupus and at others like MS. Also as other autoimmune diseases can be relapsing and remitting which could explain this feature in some PWME (just as there is a relapsing remitting subtype of MS)

The general finding of low levels of autoantibodies in some PWME bothers me though as we know that for exam[ple those with thyroid antibpodies (hashimotos) may be under or incorrectly treated and due to lack of proper treatment be diagnosed with M.E/CFS, the same is true for ANA – if i had low levels of these, alongside my set of symptoms i would not allow a diagnosis of M.E, but would strongly suspect i DID have Lupus. Again if you go on Lupus boards you will see many many patients that have fought for years for a diagnosis – some of whom actually have anti body negative lupus (it is possible) The internet is full of stories of various missed diagnoses and people undiagnosed for years. I worry that many of these findings are in fact people who have a missed autoimmune disease because perhaps they have an atypical presentation.

Finding and pinning down clinical signs, ymptoms and biomarkers for M.E/CFS and then using strict criteria for entry into trials should help to sort this out, but at the moment it is still a bit of a nightmare.

Hope my ramblings make sense
Justy.

Legendrew October 8, 2013 at 3:20 am
justy

Agreat article, thanks Andrew! I'm looking forward to the publication of Fluge and Mellas work – any ideas of a timescale for this?

As far i'm aware it's expected any week now, doubtless we will have articles discussing the findings here at Phoenix Rising as soon as we can!

justy

I am always struck by how similar to other autoimmune diseases M.E is (especially for me) at times looking very much like Lupus and at others like MS. Also as other autoimmune diseases can be relapsing and remitting which could explain this feature in some PWME (just as there is a relapsing remitting sub-type of MS)

The general finding of low levels of autoantibodies in some PWME bothers me though as we know that for example those with thyroid antibodies (hashimotos) may be under or incorrectly treated and due to lack of proper treatment be diagnosed with M.E/CFS, the same is true for ANA – if i had low levels of these, alongside my set of symptoms i would not allow a diagnosis of M.E, but would strongly suspect i DID have Lupus. Again if you go on Lupus boards you will see many many patients that have fought for years for a diagnosis – some of whom actually have anti body negative lupus (it is possible) The internet is full of stories of various missed diagnoses and people undiagnosed for years. I worry that many of these findings are in fact people who have a missed autoimmune disease because perhaps they have an atypical presentation.

Finding and pinning down clinical signs, symptoms and biomarkers for M.E/CFS and then using strict criteria for entry into trials should help to sort this out, but at the moment it is still a bit of a nightmare.

Yes, the one thing that strikes me with ME is the clinical similarity to many existing autoimmune diseases; the female predominance, relapse/remitting nature and autoimmune type symptoms ought to be telling us something! Suffice to say that I personally am looking forward to the latest Fluge and Mella paper publication, along with the IiME UCL trial and the phase 3 trial which are both expected to start early next year.

With regard to the general autoantibody findings I believe it is common in many autoimmune diseases for antibody levels to many unrelated antigens to raise due to the ongoing immune activation, it is therefore very difficult to pin down who has what unless the results prove very conclusive – and as you rightfully say, some people have Lupus and other conditions with a seemingly normal antibody reading which only helps to further muddy the water!

aimossy October 8, 2013 at 3:23 am

Great article Andrew!
Interesting comments too justy it did make sense to me.
A Rheumatologist has told me I have 60 percent chance of developing lupus.
I do feel that they will refine autoimmune diagnosis overtime and treatments.
How would you know or not if some people that are fighting for a diagnosis of lupus may have something not found yet maybe even ME.
There are a serious amount of autoimmune diseases. The rheumatologist said over 150 to me at the time and said that I could have CFS. Then he said to me that we may find that(CFS) to be a autoimmune disease at some stage.
He was trying to convey how difficult it can be I think.
We have true hope though I feel and we are getting more info about ME all the time.
Which is fantastic!

Oh geeze too fast.

Yours to legendrew I just figured who is who.tehe
Hanging out for publishing im excited:)

Marlène October 8, 2013 at 12:57 pm

"Another hypothesis is that autoimmunity may be targeted towards molecules known as vasoactive neuropeptides."
Interesting! Where can I read more about this? My VIP are undetectable low in number.

MeSci October 8, 2013 at 1:04 pm
Marlène

"Another hypothesis is that autoimmunity may be targeted towards molecules known as vasoactive neuropeptides."
Interesting! Where can I read more about this? My VIP are undetectable low in number.

Just did a quick internet search and found this.

There may be more recent ones.

redrachel76 October 8, 2013 at 1:10 pm

The ciguatera epitope or ciguatera like substance being produced by the body of patients is also said to prove that this is an autoimmune desease. It's a shame Invest In ME never publised this bit of research or publicise it now because that came even earlier than Fluge and Mella's research. It is another proof that this is autoimmune, on top of the female/male ratio and the relapsing remitting nature.

voner October 8, 2013 at 6:27 pm

what a clear and well written article! thank you.

i too am interested in …..

"Another hypothesis is that autoimmunity may be targeted towards molecules known as vasoactive neuropeptides."

I always wonder how much they autonomic system dysfunction underlies many symptoms.

thanks again.

knackers323 October 9, 2013 at 12:59 am
redrachel76

The ciguatera epitope or ciguatera like substance being produced by the body of patients is also said to prove that this is an autoimmune desease. It's a shame Invest In ME never publised this bit of research or publicise it now because that came even earlier than Fluge and Mella's research. It is another proof that this is autoimmune, on top of the female/male ratio and the relapsing remitting nature.

Hi could you tell me more about the ciguatera toxin findings. I have never heard of this. Thanks

Simon October 9, 2013 at 2:32 am

Nice work, Andrew – thanks for the clear primer on this important area.

Legendrew October 9, 2013 at 6:08 am
voner

what a clear and well written article! thank you.

i too am interested in …..

"Another hypothesis is that autoimmunity may be targeted towards molecules known as vasoactive neuropeptides."

I always wonder how much they autonomic system dysfunction underlies many symptoms.

thanks again.

Thanks for the compliment. With regard to vasoactive neuropeptides, they are an incredibly exciting area of research and have the potential to explain a lot of the symptoms. As you mention they have a role to play in the autonomic nervous system however they also play roles generally in the nervous system and the vascular system so you almost have a 'double whammy' with regard to ability to cause symptoms. In the future it's likely there will be further articles in this series exploring both the vascular and nervous systems which might be worth a read if you're interested in these areas – stay tuned!

GcMAF Australia October 10, 2013 at 1:05 am

Lyme Disease is known as the great imitator, Possibly most diseases are a on a spectrum of these inflammatory diseases. i forget the researchers but about 8 years ago they used a CFS treatment for cancers with success. Also i personally have used CFS treatments for cancer.
There is a recent paper about bacteria in cancer, as well as many older ones.
http://www.ncbi.nlm.nih.gov/pubmed/?term=Bacteria-Human+Somatic+Cell+Lateral+Gene+Transfer+Is+Enriched+in+Cancer+Samples
GcMAF was originally used for cancer but is now being used for CFS.

redrachel76 October 11, 2013 at 10:57 am
knackers323

Hi could you tell me more about the ciguatera toxin findings. I have never heard of this. Thanks

It's just that in 2003 they discovered that the body in CFS patients are creating a toxic substance that bothers the cells in some way I don't understand. This toxic substance was discovered using a test for ciguatera. So they called it the ciguatera epitope.
Ciguatera is a poisonous toxin produced by a fish. The test for ciguatera came out high in CFS patients even though we don't have ciguatera poisoning.
This was proof of autoimmunity because here you have the body producing a chemical that attacks the body itself, or body cells.

Well that is my understanding. I might have got it all wrong. There are a few links on it here:

http://forums.phoenixrising.me/index.php?threads/ciguatera-toxin-in-cfs.4445/

Anaesthesia – they made an anaesthesia protocol for M.E patients because they found that this ciguatera epitope substance uses a specific channel in cells and so they recommend an anesthetic that does not block the sodium channel.
http://www.ncf-net.org/patient-physician.htm

If you google Hokama, Hawaiee ciguatera cfs you can find the original paper although it is too hard for me to understand. It was first published in 2003. I think it was at the university of Hawaiee.

knackers323 November 2, 2013 at 9:27 pm
redrachel76

It's just that in 2003 they discovered that the body in CFS patients are creating a toxic substance that bothers the cells in some way I don't understand. This toxic substance was discovered using a test for ciguatera. So they called it the ciguatera epitope.
Ciguatera is a poisonous toxin produced by a fish. The test for ciguatera came out high in CFS patients even though we don't have ciguatera poisoning.
This was proof of autoimmunity because here you have the body producing a chemical that attacks the body itself, or body cells.

Well that is my understanding. I might have got it all wrong. There are a few links on it here:

http://forums.phoenixrising.me/index.php?threads/ciguatera-toxin-in-cfs.4445/

Anaesthesia – they made an anaesthesia protocol for M.E patients because they found that this ciguatera epitope substance uses a specific channel in cells and so they recommend an anesthetic that does not block the sodium channel.
http://www.ncf-net.org/patient-physician.htm

If you google Hokama, Hawaiee ciguatera cfs you can find the original paper although it is too hard for me to understand. It was first published in 2003. I think it was at the university of Hawaiee.

If this is true for at least the majority of cfs'ers, why isn't it a case of mystery solved?

alex3619 November 3, 2013 at 2:34 am

There are another class of immune cells in this picture. Gamma delta T cells. Like macrophages or NK cells they react to specific substances. So their reaction is innate. Yet they are capable of replication if stimulated, increasing the response to a particular substance. So they are adaptive. They also have a very important function in initiating tissue repair, particularly in the gut. Finally while they can trigger an immune response, they can also suppress an immune response, and are thought to do this quite a lot in damaged tissue and the gut.

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