There is now some pretty good evidence that autoimmunity is involved in ME/CFS.
Firstly there are similarities in both the demography (e.g. female dominance) and general immunological milieu of ME/CFS with established autoimmune conditions 1–4. Secondly, a large array of autoantibody responses to various signaling molecules, cell-surface receptors and intracellular molecules have long been reported in ME/CFS 1,5,6. Note however that the number of people with these autoantibody responses varies wildly, and their functional significance is not yet clear 7. Thirdly, several preliminary trials have shown that Rituximab (CD20 antibody which depletes peripheral B cells) can induce a moderate-major remission in around 60% of people (followed by relapse). The delayed response (2-7 months) seems consistent with the gradual removal of existing antibodies 8,9, and autoantibodies to autonomic receptors do decline with clinical response 6.
However to properly treat and prevent disease we need to understand why there is autoimmunity at all. Why would the body start attacking itself? Bad luck, or system failure? Here is a little exploration of just that.
Autoimmunity starts here!
The potential for autoimmunity is an intrinsic part of adaptive immunity. Each individual T or B cell can recognise a specific antigen via their receptors (TCR and BCR respectively). During early T and B cell development the process of V(D)J recombination semi-randomly generates massive TCR and BCR diversity, enabling recognition of most antigens, including those relating to self (i.e. autoreactivity). In other words, the body is continually creating immune cells which could potentially initiate autoimmune responses.
However, this is balanced by an ability to recognise and eliminate autoreactive cells. Briefly, central tolerance (negative selection) in primary lymphoid tissues (bone marrow for B cells, thymus for T cells) deletes most T and B cells autoreactive to ubiquitous self-antigen, while converting others into thymic regulatory T cells (tTregs). Central tolerance is however imperfect, and does not even eliminate cells with reactivity to some tissue-specific antigens 10. Consequently mechanisms of peripheral tolerance are also crucial for suppressing autoreactive cells, which is achieved via anergy, activation-induced cell death (AICD) and Tregs (tTregs 10 and pTregs 11).
All these mechanisms ensure we have an effector T/B cell pool biased toward recognition of foreign antigen, and a regulatory pool recognizing self. Despite this however, some low-level autoimmunity mediated by effector T cells 12 and natural autoantibodies (polyreactive IgM/IgG) 13–15 is present in healthy individuals, and may even promote beneficial responses to tissue damage. Importantly, natural autoreactive B cells are controlled by peripheral tolerance, which prevents the generation of high-affinity autoantibodies 16. However under pathological conditions, various processes may either promote the selection of autoreactive cells or disrupt self-tolerance, resulting in overt autoimmune disease.
Selecting autoreactive cells
Most autoimmune diseases are characterised by an increased presence of autoreactive T cells, B cells and autoantibodies. So far in ME/CFS we only have evidence for B cells and autoantibodies. There are several processes which may favour the selection of autoreactive cells, foremost of which being infections. Microbial antigens can have sequence similarity with self-tissue proteins (i.e. molecular mimicry) and therefore may be recognised by autoreactive T/B cells. Both microbial HSP60 17 and translocation of gut bacteria 18 have been implicated as sources of molecular mimicry in ME/CFS, but really anything could be relevant.
Another possibility is that self-antigens undergo modifications which make them immunogenic and appear as non-self to the immune system. For instance oxidative and nitrosative stress can lead the emergence of neo-epitopes, which may be elevated in some with ME/CFS 1. Similarly, antibody paratopes can be modified resulting in altered reactivity. The immune system is also normally naive to certain intracellular antigens (cryptic epitopes), which can be released and unveiled as a result of cell damage. Note some autoimmune responses in ME/CFS are to intracellular antigens.
Loosing tolerance to self
While various things may stimulate autoreactive cells, for these cells to become highly active this would also require a failure of self-tolerance. Adaptive immune responses develop in secondary lymphoid tissues (e.g. lymph nodes), where antigen presentation selects and stimulates responsive T/B cells. B cells mature in germinal centres, where they undergo class-switch recombination (CSR) and somatic hypermutation (SHM), resulting in affinity maturation of the antibody response. Crucially, this whole process is regulated by peripheral tolerance, including a specialised population of follicular Tregs which prevent the development of autoantibodies 19. Even once autoreactive B/plasma cells escape lymphoid tissues, they are still subject to peripheral tolerance (incl. direct inhibition by Tregs 20,21).
Therefore, in most autoimmune diseases there is a failure of self-tolerance. This typically involves decreased Treg activity, allowing autoreactive T/B cells and autoantibodies to go unchecked. On the other hand, improved self-tolerance may mediate the benefits of various therapies. For instance Rituximab does not actually eliminate all autoreactive cells (B cells in secondary lymphoid tissues 22 and plasma cells) or autoantibodies, and seems to boost markers of immune tolerance (e.g. Tregs and Bregs) in several autoimmune diseases. Also the profound therapeutic activity of IV IgG in many autoimmune diseases may involve Tregitopes 23.
In ME/CFS it is not yet clear what type of B cell activity and autoantibody responses are involved (e.g. natural/mutated, low/high affinity, IgG isotype, etc.), making it hard to speculate on pathogenesis. There is some very vague evidence that immune tolerance might be altered, such as an increased presence of TCR genetic variants 24, and inconsistent changes to B cell maturation subsets 1,25 and Bregs 26,27. However there also appears to be a relatively consistent increase in Tregs (5/6 studies 28–33), which seems contradictory at first. Further analysis of Tregs with regard to phenotype (origins, antigen specificity and suppressive activity) and demographic associations (illness characteristics, duration ,etc.) might provide some reconciliation. For instance, chronic infections and immune exhaustion can expand pTregs, which may be pathogen-specific. Tregs are also relatively plastic with their activity being regulated by the local microenvironment 34–36. So increased Tregs may not necessarily preclude the presence of autoimmunity.
Interestingly, there is some indirect evidence that increasing Treg activity might lower inflammatory activity in ME/CFS. A trial with the probiotic B. infantis 35624, which acts via induction of Tregs 37, lowered blood inflammatory markers in CFS 38. Perhaps this could imply a deficit in Treg activity in the gut (GALT)?
Finally, many factors which have been linked to impaired self-tolerance in autoimmune diseases might also be relevant in ME/CFS, including gut dysbiosis (e.g. low SCFAs/butyrate), proinflammatory milieu (e.g. TLR signaling and Th17 activity) and metabolic dysfunction (e.g. DNA hypomethylation).
Aetiological treatments for autoimmunity?
At a clinical level, autoimmune diseases are typically considered life-long and irreversible. The only option is therapies to support organ function and/or broadly suppress the immune system, resulting in side-effects and long-term complications. However, once we understand the aetiology of autoimmunity, perhaps more precise treatments which prevent and cure disease are actually possible? As discussed above, there may be two general perspectives to consider: (1) things which stimulate autoreactive cells, and (2) things which suppress self-tolerance (e.g. Tregs).
Consider celiac disease, an autoimmune condition which results in damage to the small intestine. This is one of the few autoimmune conditions where we know the specific trigger - gluten. Once gluten is removed from the diet, the autoimmune response stops, the gut heals and most people return to full health. Unfortunately the precedents and triggers are less well defined for other autoimmune diseases. While genetics establish susceptibility, the environment seems key, as evidenced by the increasing prevalence of allergic, inflammatory and autoimmune conditions (incl. celiac disease) in western, industrialised countries. In parallel we have a growing body of research gradually revealing which environmental factors (e.g. infections, gut microbiota, diet and toxins) can promote or ameliorate autoimmunity; and even some scant reports of related therapies inducing remission of human autoimmune disease. I look forward to when we have a better understanding of what drives autoimmunity in ME/CFS!
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