The 4I Hypothesis: A Neuro-Immunological Explanation for
Characteristic Symptoms of Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome
Frank
NM Twisk
Frank
NM Twisk, ME-de-patiënten Foundation, Zonnedauw 15, 1906 HB,
Limmen, The Netherlands
Correspondence to: Frank NM Twisk, ME-de-patiënten
Foundation, Zonnedauw 15, 1906 HB, Limmen, The Netherlands
Email: frank.twisk@hetnet.nl
Telephone: +31-72-505 477
Received: February 4,
2015
Revised: March 22, 2015
Accepted: March 28, 2015
Published online: May 13, 2015
ABSTRACT
Characteristic
symptoms of Myalgic Encephalomyelitis (ME) are (muscle) weakness, muscle pain,
cognitive deficits, neurological abnormalities, but above all post-exertional
malaise: a long-lasting increase of symptoms after a minor exertion. In
contrast, Chronic Fatigue Syndrome (CFS) is primarily defined by chronic
fatigue. Since chronic fatigue is not mandatory for the diagnosis ME, and
post-exertional malaise and cognitive deficits are not obligatory for the
diagnosis CFS, the case criteria for ME and CFS define two distinct, partly
overlapping nosological entities. ME and CFS are considered to be enigmatic
diseases, qualified by some authors as medically unexplained syndromes of
functional syndromes. However, specific abnormalities consistently observed
over the years and their direct and indirect sequels can plausibly explain
characteristic symptoms, e.g. exhaustion and pain. Abnormalities established
repetitively incorporate immunological aberrations (inflammation, immune
activation, immunosuppression, and immune dysfunction), persistent and/or
reactivating infections, gastro-intestinal dysbiosis, oxidative and nitrosative
stress, mitochondrial dysfunction, a (prolonged) deviant response to exertion
and orthostatic stress, circulatory deficits, and neurological
abnormalities.This article depicts the 4I hypothesis, an explanatory model for
ME (CFS) with a central role for four types of immunological abnormalities:
inflammation, (Th2-predominated) immune activation, immunosuppression, and
immune dysfunction. The potential direct sequels of these abnormalities, e.g.
increased oxidative and nitrosative stress, (reactivating or chronic)
infections, and their possible indirect consequences, e.g. mitochondrial
dysfunction, hypothalamic-pituitary-adrenal axis (HPA) axis hypofunction, and
cardiovascular dysregulation, can plausibly explain various distinctive
symptoms of ME/CFS, e.g. exhaustion, (muscle) weakness, pain, cognitive
deficits, a flu-like feeling, and post-exertional malaise.
© 2015 ACT. All
rights reserved.
Key words: Myalgic Encephalomyelitis; Chronic fatigue syndrome;
Immunology; Neurology; Oxidative stress; Nitrosative stress; Pathophysiology;
Hypothesis; Post-exertional malaise
Twisk FNM. The 4I
Hypothesis: A Neuro-Immunological Explanation for Characteristic Symptoms of
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International
Journal of Neurology Research 2015; 1(2): 20-38 Available from: URL:
http://www.ghrnet.org/index.php/ijnr/article/view/1058
CORE TIPS
ME and CFS are two distinct, partially overlapping
diagnostic entities.
More consistent findings in
ME and/or CFS relate to four types of immunological abnormalities: inflammation
(I1), (Th2-dominated) immune activation (I2), immunosuppression (I3), and
immune dysfunction (I4).
The potential sequels of
these abnormalities encompass oxidative/nitrosative stress and infections.
The possible indirect
consequences of the immunological aberrations and increased
oxidative/nitrosative stress include neurological abnormalities, mitochondrial
dysfunction and cardiovascular disturbances.
The direct and indirect
sequels of the immunological abnormalities can plausibly explain distinctive
symptoms of ME/CFS, e.g. cognitive deficits, and post-exertional malaise: a
prolonged aggravation of characteristic symptoms, e.g. cognitive impairments
and pain, after a minor exertion.
INTRODUCTION
Although ME and CFS are often used interchangeably, the case criteria
for ME[1] and CFS[2] define two distinct, partially
overlapping diagnostic entities[3]. The diagnosis ME requires
specific neurological/neurocognitive and immunological symptoms and energy
production and/or transport impairment, but the distinctive feature of ME is
post-exertional malaise or neuro-immune exhaustion: a pathological inability
to produce sufficient energy on demand resulting into symptom exacerbation,
e.g. flu-like symptoms and pain, after minor exertion[1]. The
distinctive feature of CFS[2] on the other hand is (unexplained)
chronic fatigue, which should be accompanied by at least four out of a eight
symptoms, e.g. sore throat, unrefreshing sleep, and headaches. While
post-exertional malaise is not obligatory for CFS[2], fatigue is
not mandatory for the diagnosis ME[1]. The distinction between
patients with post-exertional malaise and without post-exertional malaise seems
to be reflected by specific immunological differences[4,5]. Although
ME and CFS criteria select partially overlapping, partially disjoint patient
groups, the majority of the research into ME/CFS in the last decades has been
conducted in patients selected by CFS criteria[2]. However, since
many optional symptoms of CFS are mandatory for the diagnosis ME, the CFS
criteria also apply to a substantial ME patient subgroup reporting fatigue
(Figure 1). In conclusion, while ME is a neuro-immunological disease in nature[1],
the CFS criteria[2] select a heterogeneous patient population of
people with self-reported chronic fatigue.
SYMPTOMS
Notwithstanding the debate about the distinction between ME and CFS[6-8]
and definitional criteria of ME and CFS[9], including obligatory
symptoms, many patients with ME/CFS experience a plethora of symptoms[3],
which differ inter-individually and seem to fluctuate in number and severity
within an individual over time as a consequence of daily activity[10].
Symptoms experienced by substantial patient subgroups are: post-exertional
malaise, fatigue/lack of energy, muscle weakness, (muscle/joint) pain,
cognitive impairment (brain fog), a flu-like feeling, sleep dysfunction
(unrefreshing sleep), hypersensitivity to food, light, sound and odours
(central sensitisation), stress intolerance, orthostatic intolerance and
depression[9] (Table 1). Various characteristic symptoms can be
assessed objectively using well-accepted methods[3], e.g.
neurocognitive tests, while other symptoms due to their nature, e.g. (muscle)
pain, cannot be assessed objectively.
ABNORMALITIES
Partly due to the heterogeneity[32] of the CFS[2]
patient population and the variety of methods employed and samples
investigated, research into ME/CFS has yielded contradictory results. However,
various typical aberrations (Table 2) have been observed repetitively in the
ME/CFS patient population or subgroups thereof[1,33], Several
abnormalities are confirmed by differential gene expression[34-37].
Onset
Contrary to gradual onset ME/CFS, sudden-onset ME/CFS is often preceded
by a (viral) infection/flu-like illness[94,95]. The onset is
reflected by distinctive immunological aberrations[96,97] and other
abnormalities[98,99]. Several pathogens have been reported to
initiate ME/CFS, e.g. Epstein-Barr virus[100], parvovirus B19[101],
and enteroviruses[48]. For example, 10-15% of individuals do not
recover from infectious mononucleosis and fulfil the criteria for CFS[2]
after six months[100,102]. The severity of the acute infection seems
to predict the clinical outcome, rather than demographic, psychological, or
microbiological factors[102,103].
Infections
Although contradicted by some studies, applying various methods various
studies have found (multiple) infections or related antigens in patient
subgroups (Table 3).
Intestinal
dysbiosis and hyperpermeability
Some studies have observed intestinal dysbiosis[49,51],
intestinal inflammation and immune activation[52,130] and intestinal
hyperpermeability, conceivably resulting into translocation of enterobacteria
to the blood stream, thereby inducing systemic inflammation[50].
Inflammation and immune activation observed in ME/CFS have been associated with
these gastro-intestinal abnormalities[53,54]. Bacteriotherapy
(transcolonoscopic infusion of non-pathogenic enteric bacteria) showed
long-term positive effects (15-20 year) in a substantial subgroup of ME/CFS
patients with gastrointestinal complaints in a retrospective follow-up study[131].
Immunological
abnormalities
Consistent findings in ME/CFS relate to immunological aberrations: (a)
inflammation[41,132,133]; (b) (Th2-predominant) immune activation[48,134-136];
(c) immunosuppression, especially low NK cell activity (NKCA)[43,137,138],
blunted responses to mitogens[38,139,140], and IgG deficiencies,
most often Igg1 and IgG3[141,142]; and d) immune dysfunction, e.g.
predominance of the humoral (Th2) immune response accompanied by suppression of
the cellular (Th1) immune system, possibly due to altered glucocorticoid
regulation of the immune response[143,144], and dysregulation of the
RNase-L pathway, likely due to cleavage of the native 83-kDa RNase L[145,146].
Increased
oxidative and nitrosative stress
Elevated oxidative and nitrosative stress[36,88], increased
levels of superoxide (O2-), nitric oxide (NO) and peroxynitrite (ONOO-),
oxidative and nitrosative damage to DNA, proteins, lipids etc.[147-149],
and antioxidant depletion / increased antioxidant activity, e.g. vitamin A[150],
B[151], C[56], D[152], E[56],
glutathione[153], super oxide dismutase[62] and zinc[154],
have been observed repetitively.
Mitochondrial
dysfunction and damage
Some studies have found structural mitochondrial damage, e.g. branching
and fusion of mitochondrial cristae /mitochondrial degeneration[63],
substantially higher rates of deletion of common 4977 bp of mitochondrial DNA[155]
and unusual patterns of mitochondrial DNA deletions in skeletal muscle[59],
while other studies implicate mitochondrial dysfunction[60,61,156].
Future research should provide clarity whether hypometabolism[157]
and low oxygen uptake[75,78] and extraction[158] in
ME/CFS is due to mitochondrial dysfunction and/or mitochondrial damage,
circulatory deficits (see next paragraph) or other causes.
Low blood
volume, cardiac output and/or blood and oxygen supply
Several studies have established markedly reduced blood volume[64,65,75]
and impaired cardiac function, indicated by decreased cardiac index/output and
stroke volume[65,66,74], when compared to healthy sedentary
controls. Post-exertional malaise, flu-like symptoms and cognitive deficits
seem to differentiate those with severe CFS from those with less severe CFS and
to predict lower cardiac output[74]. In addition, some studies
indicate low cardiac mass[66,159]. So, low cardiac output in ME/CFS
could be due to reduced cardiac mass (a small heart)[160] and/or
hypovolemia[65]. Low cardiac output and/or blood/oxygen supply to
muscles[69] and brain[67] and/or mitochondrial
abnormalities could explain the low exercise capacity/oxygen uptake[75,161]
and elevated (ventricular) lactate levels[68].
Orthostatic
abnormalities
Orthostatic intolerance, (delayed) orthostatic hypotension and/or
tachycardia (POTS), in patient subgroups has been implicated by various studies[73,162,163].
Orthostatic stress seems to induce cognitive deficits[24,164] and
reduced angle-related mental task-activated cerebral blood flow velocity[164].
According to some authors[165], POTS marks a distinct group of
patents with distinct phenotypical features. Some studies have also observed
abnormalities in (parasympathetic and sympathetic) heart rate variability at
rest and on standing[166].
Neurological
abnormalities
Over time various researchers have observed various neurological
aberrations in ME/CFS patient subgroups[79,81], e.g. diminished grey[82,167]
and white matter[82,168], reduced blood flow and hypoperfusion[169,170],
glucose hypometabolism in specific regions of the cerebrum and the brain stem[171],
an increased number of defects on SPECT cans, predominantly in the frontal and
temporal lobes[172], intracranial abnormalities on MRI and SPECT
scans[173], neuro-inflammation in various brain areas[174],
cerebrospinal fluid anomalies suggesting inflammation and immune activation[175,176],
and elevated ventricular lactate levels[68].
HPA axis
dysfunction
HPA axis hypofunction in ME/CFS[83,177] can potentially
manifest itself in (a) low basal levels and diurnal production levels (total
production, variation during the day) of stress hormones, especially cortisol
(hypocortisolism)[178,179]; (b) hyporesponsiveness of the HPA axis:
blunted responses of the pituitary and the adrenal glands to provocation, e.g.
reduced cortisol response to ACTH[85,180]; (c) diminished HPA axis
responses to stress and exercise[181,182] and (d) enhanced
sensitivity of the HPA axis to negative feedback to cortisol[183,184]
and increased sensitivity of the cellular immune system to the
immunosuppressive effects of cortisol[143,144].
Abnormal
responses to exercise
Several studies have established (long-lasting) deviant responses to
physical exertion in ME/CFS, when compared to sedentary controls, e.g.
substantially lower values for oxygen uptake and workload at peak exercise and
at the ventilatory or anaerobic threshold at a second exercise test 24 hours
later[77,91,185]; a long-term increase of gene expression of
metabolite-detecting receptors after sustained moderate exercise[31];
decreased prefrontal oxygenation during exercise and recovery[71];
(prolonged) severe oxidative stress[93] and (long-lasting)
suppression of protective heat shock proteins[92] in response to
exercise, especially when a history of high level physical activity and
infection is present[150], cognitive deficits induced by exercise[186];
and substantially higher increments of NO metabolites in relation to workload
during exercise[187]. Post-exertional malaise in ME/CFS seems to be
related to exercise-induced inflammation and immune activation[188,189].
PLAUSIBLE CAUSAL
RELATIONSHIPS BETWEEN ABNORMALITIES
Figure 2, the
4I hypothesis: a key role for four types of immunological abnormalities
Four immunological abnormalities underpin the 4I hypothesis for ME/CFS
(Figure 2): inflammation (I1), (Th2-predominant) immune activation (I2),
immunosuppression (I3) and immune dysfunction (I4).
Potential
immunological stimuli in ME/CFS
The immune system seems to face three potential stimuli in ME/CFS:
pathogens and associated antigens, due to acute, chronic and/or reactivated
infections (Figure 2, A, B1 and B2), gastro-intestinal inflammation and
hyperpermeability of the intestines, possibly resulting into translocation of
enterobacteria to the blood stream (Figure 2, D), and auto-epitopes, due to
oxidative and nitrosative damage to proteins, lipids etc. (Figure 3, K).
ME/CFS is often precipitated by infections, the severity of which seems
to predict the clinical outcome[102,103]. Some studies implicate
persistency of the pathogens[48] or antigens related to the pathogen[190]
that instigated ME/CFS. Various infectious agents linked to ME/CFS are able to
produce a persistent active infection, thereby establishing a constant
incitement to the immune system[45]. In addition, some pathogens
associated with ME/CFS, e.g. EBV[191] and HHV-6A/B[192],
are known to induce a life-long latent infection. Several studies suggest
reactivation of these pathogens[111,193], possible due to
immunosuppression and immune dysfunction, e.g. a deficient EBV-specific B- and
T-cell response[191]. The chronic or reactivated
infection-hypothesis is contested[194]. However, as summarized, many
studies have observed active infections in substantial patient subgroups.
Infections would explain inflammation and immune activation in ME/CFS (Figure
2, A). It is also known that certain pathogens evade the immune system by
immune modulation (Figure 2, B1 and B2), e.g. inhibiting the innate immune
response, disrupting of T-cell function, and inducing a Th1->Th2 switch[195,196].
Another
possible immunological challenge relates to intestinal dysbiosis[49,51]
and inflammation[130] and increased permeability of the intestinal
barrier, thereby allowing enterobacteria to enter the blood stream, as
indicated by elevated serum IgA levels against lipopolysaccharides (LPS) of
gram-negative enterobacteria[50]. Intestinal dysbiosis and
inflammation[54] and increased IgA responses to the LPS of commensal
bacteria[53] have been associated with systemic inflammation and
immune activation (Figure 2, D). It is known the gastro-intestinal tract can
modulate the central nervous system by various blood-brain-barrier mediated
mechanisms, e.g. through the secretion of NO and cytokines, thereby influencing
behaviour[197].
Finally,
auto-epitopes, originating from oxidative and nitrosative damage to proteins
and lipids (Figure 3, J), can induce autoimmune responses[198,199]
(Figure 3, K). Although insufficiently explained, elevated levels of
auto-antibodies have frequently been observed in ME/CFS, e.g. against serotonin[200,201],
gangliosides[200], phospholipids[200], including
mitochondrial cardiolipins[202,203], antinuclear antibodies[47,204],
muscarinic cholinergic receptor[204] and ssDNA[205].
A vicious cycle
of oxidative and nitrosative stress induced by inflammation
Oxidative and nitrosative stress play an important intermediate role in
the 4I hypothesis. Inflammation will generate oxidative and nitrosative stress[206,207]
(Figure 3, E), while oxidative and nitrosative stress can induce or amplify
inflammation[208,209] (Figure 3, F). NO and reactive oxygen species
(ROS) exert multiple immune-modulating effects[210,211]. ROS and
reactive nitrogen species (RNS), including NO, can suppress NK[212,213]
and T[214,215] cell cytotoxicity, which could contribute to
immunosuppression (Figure 3, G). High levels of NO, produced by cytotoxic
activated macrophages[216] may also play an important role in the
shift from a Th1 to Th2 response[217,218] (Figure 3, H). While NO
seems to suppress both Th1- and Th2-cell-mediated immunity at the early
proliferation stage, high levels of NO appear to inhibit the Th1-cell
differentiation of mature T helper (Th) cells[219]. Through several
feedback loops oxidative and nitrosative stress can induce a self-perpetuating
cycle of elevated oxidative and nitrosative stress, inflammation, elevated
N-methyl-D-aspartate (NMDA) receptor activity, and ATP depletion, which is
mediated by O2-, NO and ONOO-[220] (Figure 3, I).
The HPA axis and the immune system
are bidirectionally interconnected[221]. Some authors have suggested
that the immunological abnormalities in ME/CFS, e.g. inflammation, are
secondary to HPA axis hypofunction[177], possibly due to a stress
crash: a switch from HPA axis hyper- to hypofunction[26]. However
looking at various observations this doesnt seem very likely. Hypocortisolism
is only present in a minority of the patients[222], HPA axis
dysfunction is not present during the early stages of ME/CFS[223]
and seems to develop gradually and to be more pronounced the longer ME/CFS
exists[224], whereas immune activation and inflammation are often
already present at the onset of the illness[102]. In contrast,
chronic inflammation and immune activation can induce adrenal exhaustion
gradually through various pathways (figure 4, L1): (a) (synergistic) suppression
of cortisol release and the cortisol response to adrenocorticotropic hormone
(ACTH) by tumor necrosis factor alpha (TNF)[225,226], possibly
mediated by NO[227], and interleukin (IL)-1[228]; (b) HPA
axis desensitizing[229], resulting into a long-lasting state of LPS
tolerance to a second exposure of LPS, affecting the response of plasma TNF
and HPA-hormones to LPS[230]; (c) reduced adrenal response to ACTH
as a consequence of elevated levels of interleukin-10[231],
associated with Th2 and Treg immune responses. Adrenal responses can also be
inhibited by oxidative[232,233] and nitrosative stress/NO[234,235]
(Figure 4, L2). A typical endocrine abnormality in ME/CFS relates to increased
sensitivity of the cellular immune system[143,144] and HPA axis[183,184]
to glucocorticoids (Figure 4, M1 and M2), plausibly explaining the paradoxical
combination of hypocortisolism and Th2 predominance in ME/CFS.
Mitochondrial
dysfunction induced by oxidative and nitrosative stress
In addition to causing damage to lipids, proteins and DNA, inducing
neo-epitopes, oxidative and nitrosative stress can have various other negative
effects (Figure 5).
ROS and RNS,
including ONOO-, exert multiple effects on mitochondria, including
mitochondrial dysfunction, damage, and apoptosis[236,237] (Figure 5,
N). NO and RNS inhibit the respiratory chain, leading to elevated O2
production, and, after reaction with NO, to increased ONOO- levels, further
impeding mitochondrial respiration[238] (Figure 5, O).
Cardiovascular
abnormalities due to oxidative and nitrosative stress
NO plays an important role in the cardiovascular system and increased
levels of NO can have various adverse cardiovascular effects[239]
(Figure 5, P). NO is a potent vasodilator[240,241] and seems
essential in autoregulation of blood flow, both in large arteries and at the
microcirculatory level, thereby determining the distribution of flow among the
various vascular networks[239]. Therefore elevated basal NO levels
in ME/CFS could explain decreased peripheral resistance and low blood pressure
(hypotension)[242]. Although possibly mediated by other pathways,
these phenomena are induced in healthy subjects by exercise[243].
Exercise-induced NO, added to elevated basal levels, might partially account
for post-exertional hypotension and delayed recovery in ME/CFS[242].
Furthermore, elevated NO levels could also be involved in reduced myocardial
contractility, disrupted autonomic modulation of myocardial function and
abnormalities in heart rate variability[239,244,245]. The
cardiovascular aberrations and/or mitochondrial dysfunction/damage could
plausibly explain reduced oxygen uptake[158] and oxygenation[71]
during exercise in ME/CFS (Figure 5, Q).
Neurological
aberrations as potential consequences of inflammation, oxidative and
nitrosative stress, cardiovascular abnormalities and reduced oxygen uptake
Various neurological abnormalities could be induced by the
abnormalities in ME/CFS. First, systemic inflammation can induce
neuroinflammation and sickness behavior[246] (Figure 5, R).
Pro-inflammatory cytokines, induced by peripheral inflammation, can access the
central nervous system through various pathways, and induce cytokines, amplify
cytokine signals and release secondary messengers, e.g. NO, in the brain
thereby influencing virtually every aspect of brain function[247].
Peripheral inflammation affects neuroendocrine function, NMDA receptor
activity, neurotransmitter metabolism, and neurogenesis[248]. The
behavorial effects of peripheral inflammation include depression, fatigue,
psychomotor slowing, cognitive dysfunction and sleep disruption[247].
In addition to systemic inflammation-induced sickness behaviour, other
mechanisms by which immunological aberrations affect the nervous system in
ME/CFS have been suggested, e.g. an elevated release of cytokines by glial
cells[249], auto-immune pathways, involving vasoactive neuropeptides
damaging the blood-brain barrier and blood-spinal barrier[250], and
infections of the nervous system by neurotropic viruses[45]. A
recent study established evidence for brain glial activation in patients with
chronic pain, a phenomenon repetitively observed in animal models[251].
Activation of microglia or astrocytes, related to neuro-inflammation, in
widespread brain areas[174] could account for the chronic pain
experienced by many patients with ME/CFS.
Second,
increased levels of NO-stimulated glutamate release and hypersensitivity of
NMDA receptors[252,253] could account for central sensitisation,
manifesting itself in enhanced sensitivity of the central nervous system to
various stimuli, e.g. sound, and hyperalgesia (Figure 5, S). Others have
proposed an NO-independent O2-mediated pathway to induce hyperalgesia[254,255].
Third, cardiovascular abnormalities, resulting into reduced cerebral blood flow[70]
(Figure 5, T1) and cerebral oxygenation[256] (Figure 5, T2), induced
or intensified by exertion[71], would account for reduced ATP
synthesis in the central nervous system, as implicated by increased ventricular
lactate levels[68].
The
physiological effects of exercise and stress can explain post-exertional
malaise
Exercise and psychological stress could amplify pre-existing
immunological abnormalities, oxidative and nitrosative stress, and intestinal
hyperpermeability (Figure 6). Since these anomalies can plausibly explain
various typical symptoms of ME and CFS (next paragraph), the physiological
effects of exercise and psychological stress would intensify abnormalities
already present in rest. This could explain a (prolonged) aggravation of
symptoms after a minor exertion: post-exertional malaise.
Exercise has
well-known beneficial effects[257,258]. Strenous exercise induces an
increase in the pro-inflammatory cytokines TNF, IL-1, and IL-8 and the
inflammatory cytokine IL-6, produced locally in the skeletal muscle in response
to exercise[259,260]. This release is counterbalanced by the release
of IL1 and TNF inhibitors and IL-10[259]. In chronic inflammatory
diseases, exercise could have adverse effects through a combination of
exercise-induced stimulation of immune signals with leukocytes previously
affected by other stress, inflammatory, or immune mediators[261].
Deviant effects of exercise on inflammation and immune activation in ME/CFS
(Figure 6, X1) are illustrated by the observations that the severity of symptom
flare after moderate exercise is directly linked to increased levels of IL-1,
IL-12, IL-6, IL-8, IL-10, and IL-13 8 hours post-exercise[188], that
travelling from home to the hospital is sufficient for significantly elevated
TGF- levels[262], that exercise induces a sustained increase in
plasma TNF- in patients, not in controls[262], and that moderate
exercise induces a larger 48 hours post-exercise area under the curve for IL-10[15].
In addition, since acute[263] and chronic[264] stress can
induce inflammation[264], psychological stress could amplify
pre-existing (low-grade) inflammation in ME/CFS.
Exercise can
also have immunosuppressive effects. While moderate exercise seems to stimulate
immunity, prolonged strenuous exercise seem to suppress immune function, e.g.
NK cell activity and antibody synthesis[265,266]. Since the aerobic
threshold seems (profoundly) decreased in ME/CFS, low-level anaerobic
exercise can amplify immunosuppression, e.g. diminished NK cell cytotoxicity
and antibody levels, observed in ME/CFS (Figure 6, X2).
In addition,
eccentric exercise could induce and/or intensify immune dysfunction in ME/CFS
(Figure 6, X3), e.g. inducing or amplifying a Th2-predominance[267,268].
Acute, subacute or chronic stress can suppress cellular (Th1) immunity and
boost humoral (Th2) immunity, due to a differential effect of glucocorticoids
and catecholamines on Th1/Th2 cells and type 1/type 2 cytokine synthesis[263].
In general, physiological and psychological stress may cause a selective
suppression of Th1 functions and a shift towards a Th2 response, protecting the
host from systemic 'overshooting' with pro-inflammatory cytokines[269].
Another
mechanism by which exercise can amplify pre-existing abnormalities is
intestinal hyperpermeability[270,271] (Figure 6, X4). Psychological
and physiological stress can compromise the intestinal barrier function[272,273].
Intestinal hyperpermeability could result in translocation of enterobacteria to
the blood stream, instigating inflammation in response to endotoxins.
An additional
pathway by which exercise can amplify pre-existing aberrations is oxidative[274,275]
and nitrosative[274,276] stress as a result of exercise (Figure 6,
X5). ME/CFS seems to be associated with a prolonged accentuated oxidative
stress and reduced heat shock proteins responses to incremental exercise[93].
Several observations suggest an abnormal adaptive response to exercise in
ME/CFS[92], the severity of which seems to be related with premorbid
physical activity and severe acute infections[150]. Through elevated
glutamate release and subsequent NMDA receptor activation and induction of
nuclear factor kappa-B (NF-kB), psychological distress enhances levels of NO
and pro-oxidants in various brain areas[277,278].
CONCEIVABLE
ETIOLOGY OF CHARACTERISTIC SYMPTOMS
The abnormalities observed in ME/CFS patients or substantial subgroups
could explain the presence and variability of various characteristic symptoms
(Figure 7 and Table 4). As explained in the previous paragraph the
physiological effects of exercise in general and in ME/CFS in particular could
account for the post-exertional malaise: exercise-induced intensification of
symptoms[279].
DISCUSSION
The subjective and ambiguous criteria for CFS define a heterogeneous
population of patients with chronic fatigue[32]. While chronic
fatigue is obligatory for the diagnosis CFS[2], easy muscle
fatigability and cognitive impairment, but above all, post-exertional malaise
are mandatory for the diagnosis ME, whether defined by the original criteria[304]
or the recently proposed new[1] criteria. ME and CFS are two
distinct, partially overlapping clinical entities[8]. Based upon
observations, it is estimated that 30-60% of people fulfilling the criteria for
CFS[2] meet the more strict criteria for ME.
Fatigue is not obligatory for the diagnosis ME, and since the majority
of the research in the last decades have used the CFS criteria for patient
selection, it is unknown how many patients fulfilling the ME criteria dont
meet the case definition for CFS. Despite the confusion created by the use of
the CFS criteria, various studies have observed typical abnormalities in the
ME/CFS patient group or significant ME/CFS patient subgroups.
More
consistent findings relate to four types of immunological abnormalities in
ME/CFS: inflammation (I1), (Th2-predominated) immune activation and
counteractive immunoregulatory responses (I2), immunosuppression (I3), and
immune dysfunction (I4). These immunological abnormalities and their direct and
indirect sequels can account for various abnormalities observed in ME/CFS and
several typical symptoms, including post-exertional malaise and weakness.
ME/CFS often has an sudden, flu-like onset. Whether the original infection
persists and perpetuates the illness or is only a hit-and-run infection
remains subject to debate. However, using different methods and samples,
various infections have been observed in substantial ME/CFS patient subgroups.
Immunosuppression (I3) and immune dysfunction (I4), either due to pathogens
modulating and evading the immune system (as an effect) or enabling
chronic/reactivating infections (as a cause) or both, seem to play a key role
in the etiology. (Chronic) inflammation (I1) and immune activation (I2), both
observed repetitively in ME/CFS, can induce and sustain a vicious circle of
reactive oxygen and nitrogen species and peroxynitrite. Elevated
oxidative/nitrosative stress has various detrimental effects: inflammation
(I1), immunosuppression (I3), immune dysfunction (I4), the generation of
auto-epitopes (due to oxidative and nitrosative damage to proteins,
mitochondria etc.), mitochondrial dysfunction, cardiovascular deficits, et
cetera-. Gastro-intestinal dysbiosis and inflammation and intestinal
hyperpermeability, found by some studies, could result into translocation of
enterobacteria into the blood stream, thereby inducing a third potential
immunological stimulus in ME/CFS (i.e. LPS). HPA axis dysfunction, especially
hypocortisolism and HPA axis hyporesponsiveness, can explain some immunological
abnormalities, but seem to arise at a later stage of the disease. On the other
hand, inflammation, immune activation and oxidative and nitrosative stress can
induce hypocortisolism and a blunted adrenal response to ACTH through various
pathways gradually. The endocrine and immunological anomalies in ME/CFS reflect
a paradox: reduced adrenal output (cortisol) combined with suppression of the
(cellular) immune system, (possibly) due to enhanced glucocorticoid sensitivity
of the Th1 arm of the immune system. Finally, inflammation/immune activation,
cardiovascular impairment and low oxygenation/oxygen uptake could account for
various neurocognitive and neuropsychological abnormalities found in ME/CFS.
Other authors
have proposed alternative explanatory models for ME/CFS. The ONOO-model, with a
key role for the self-perpetuating vicious circle of elevated oxidative and
nitrosative stress, resulting into peroxynitrite (ONOO-), proposed by Pall et
al[305] is incorporated within the 4I explanatory model. The 4I
explanatory model is also in line with the NO-induced central
sensitisation-model of Meeus et al[306]. The 4I model has
commonalities with the neuro-immunological (NI) model for ME/CFS, put forward
by Morris and Maes[307]. However, there also some relevant differences.
In essence, the NI model is a linear model in which a non-persistent infection
induces a vicious circle of oxidative and nitrosative stress and inflammation,
neo-epitopes (induced by oxidative and nitrosative damage to proteins) and
autoimmunity. The 4I hypothesis embodies key roles for reactivating and chronic
infections, immune dysfunction and Th2-dominated immune activation (next to
inflammation), HPA axis dysfunction, e.g. hypocortisolism and blunted adrenal
responses, enhanced sensitivity of the HPA axis and the (cellular) immune
system to the suppressive effects of cortisol, and circulatory deficits[3].
In contrast with the hypothesis that maladaptive stress responses, either due
to a stress crash[26] or allostatic overload[308], are
causing the immunological abnormalities seen in ME/CFS, the 4I hypothesis is
based upon the premise that the immunological aberrations and
oxidative/nitrosative stress can induce and sustain the endocrine abnormalities
and defective stress responses through various pathways. The 4I hypotheses is
consistent with the alternate homeostatic state-hypothesis of Craddock et
al[309], although, the 4I incorporates an opposing
cause-and-effect-relationship between the immunological and endocrine
abnormalities in ME/CFS.
LIMITATIONS
While the abnormalities incorporated in the 4I model have been observed
in ME/CFS patients or major patient subgroups repetitively, the
cause-and-effect relationships between these abnormalities have often been
established in general, non-ME/CFS-specific circumstances. However, the causal
relations underpinning the 4I hypothesis, although speculative, collectively
offer a plausible explanation for various abnormalities frequently observed in
ME/CFS and characteristic symptoms.
Due to the heterogeneity
of the CFS[2] patient group, the duration of the illness of the
patients investigated, and the essential role of exertion-induced
abnormalities, none of the abnormalities will be present in all CFS patients at
all times and it is unlikely that here will ever be one abnormality present in
all CFS[2] patients. In order to establish which abnormalities and
causal relationships are applicable to specific patients, it is also essential
to make a distinction between patients with post-exertional malaise,
cognitive deficits and other characteristic symptoms of ME[1], and
CFS[2] patients without these typical symptoms and to investigate
well-defined biological and symptomatic ME and CFS patient subgroups in more
detail.
The 4I
hypothesis can be tested by investigating the abnormalities in biological and
clinical subgroups defined by biomarkers and objective measures of the clinical
status[3], by applying correlational analyses on the abnormalities
present in patient subgroups, and by testing interventions aimed at reversing
specific aberrations in patients, e.g. infections, immunological aberrations
and oxidative/nitrosative stress.
Conclusions
Immunologic abnormalities frequently observed in ME/CFS, inflammation
(I1), (Th2-biased) immune activation (I2), immunosuppression (I3) and immune
dysfunction (I4) seem to play a crucial role in the etiology and
pathophysiology of ME/CFS. These immunological aberrations, combined with three
potential immunological stimuli, can explain various other abnormalities
observed in ME/CFS and underpin the 4I explanatory model for ME/CFS, which
accounts for several characteristic symptoms.
Future
research should confirm various abnormalities and explore the aberrations in
more detail in specific clinical and biological subgroups. Correlational
analysis of co-existing abnormalities in patient subgroups and the outcomes of
interventions aimed at specific abnormalities could be used to accept, refine
or reject the cause-and-effect relationships incorporated in the 4I explanatory
model for ME/CFS.
CONFLICT OF INTERESTS
The Author has no conflicts of interest to declare.
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Peer reviewer: Thorsten Rudroff,
Department of Health and Exercise Science, Colorado State University, USA.
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