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.
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 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.
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.