Sunday, 4 October 2015

Is ME/CFS an immunodeficiency disorder?

ME/CFS has long been associated with infections. A large variety of viral ,bacterial and even protozoan infections have been implicated as triggers 1–4 . There is also some evidence for persisting chronic infections - elevated antibody responses to several viruses are found in at least some CFS subsets 1,2,5,6, and increased viral presence has been found in blood cells, muscle tissue and the GI tract 7–10. CFS patients also appear to have an increased rate of upper respiratory tract infections (URTIs), as recently confirmed by objective virology and antibody levels 11.

Interestingly, most of these infections are fairly common and contracted by healthy people, yet for some reason people with ME/CFS seem more susceptible. This suggests some kind of mild immunodeficiency exists in ME/CFS, and there is some accumulating evidence to back this up:

  • Genetics. Genetic variants which might impair innate immune function (e.g. complement system and NK cell function) have been associated with CFS 12,13.
  • Poor cellular function. Low NK cell cytotoxicity is the most replicated of all immunological findings since the late 1980s 14. Also CD8+ cytotoxicity may be low 15. Low neutrophil respiratory burst activity has been reported in one study 16. Low lymphocyte proliferation is evident in several studies 17–19. Increased immune cell apoptosis has been reported in several studies (i.e. PBMCs 20,21, lymphocytes 22,23 and neutrophils 23,24).
  • T cell skewing. Low Th1 and increased Th2 activity is evident in some studies 25–30. Tregs are also elevated 15,17,31,32 and inversely correlate NK cell function 32.
  • Antibody deficiencies. Primary antibody deficiencies have been associated with the development of CFS symptoms 1. Also antibody subclass deficiencies (mainly IgG1, 3 and 4) occur in many with CFS 33,34, and have been linked to COMT polymorphism and susceptibility to infections 35.
  • Impaired viral control. Deficient T and B cell memory responses to EBV have been reported 10. Also a small study found attenuated viral clearance and altered immune reactivity in response to live poliovirus vaccination 30.

Immunodeficiencies, in addition to increasing susceptibility to infection, can also facilitate chronic inflammation and autoimmunity. A classic example here would be Crohn’s disease, a major form of inflammatory bowel disease (IBD), which is characterised by severe inflammation throughout the intestine. In Crohn’s, both genetic and functional testing have revealed impairments in innate immunity 36–39. This may increase susceptibility to infection and allow bacterial overload in the intestine, two events which may provoke chronic and unremitting gut inflammation and damage. Also immunodeficiencies of a similar nature to those in ME/CFS (e.g. NK/CD8+, phagocyte and antibody deficiencies) are associated with autoimmune disorders. Here they may promote autoimmunity by hindering clearance of infections and cellular debris (which stimulate adaptive immune responses, with potential for molecular mimicry), and modulation of Teff/Treg balance (which determines tolerance to self-antigens).

Typical treatment for inflammatory and autoimmune conditions is based around immunosuppression (e.g. monoclonal antibodies against cytokines and B cells). Going deeper by targeting aetiological factors, such as immunodeficiencies, is another approach which might better achieve sustained remission and disease prevention. With this in mind various immunomodulators have been used in ME/CFS with good results.

  • IV IgG can cure CFS caused by parvovirus B19 infection 3. However a placebo-controlled trial found no benefit in a general CFS cohort despite partial correction of IgG subclass deficiency 34.
  • Rintatolimod (aka. Ampligen) is a TLR3 agonist which has been shown to improve objective measures of fatigue (cardiopulmonary exercise tolerance) in 2 placebo-controlled trials in CFS 40.
  • Isoprinosine (aka. Immunovir) is an immunomodulator which improved CFS symptoms and objective measures of immune function (CD4+, Th1/IL-12 and NK cell activity) in one small placebo-controlled trial 41.
  • IFNα is a cytokine which stimulates antiviral activity and has been shown to improve CFS symptoms and NK cell activity 8,18.
  • IL-2 is another cytokine which stimulates T cells and antiviral activity. Adoptive transfer of IL-2 stimulated immune cells into CFS patients was shown to promote Th1 skewing and improve symptoms in one study 42.
  • Staphylococcal toxoid vaccine has been shown to markedly improve FM and CFS symptoms in a few controlled trials, which may result from unspecific stimulation of Th1/cell-mediated immunity 43.
  • Olmesartan is a VDR agonist (amongst other things) which has apparently been used with clinical success in CFS, although this may occur after long periods of ‘immunopathology’ 44.

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