Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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HYPOTHESIS AND THEORY ARTICLE

Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.62802

Dominic Stanculescu1Lars Larsson2 and Jonas Bergquist3,4*

  • 1Independent Researcher, Sint Martens Latem, Belgium
  • 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
  • 3Analytical Chemistry and Neurochemistry, Department of Chemistry – Biomedical Center, Uppsala University, Uppsala, Sweden
  • 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.

Introduction

Critical illness refers to the physiological response to virtually any severe injury or infection, such as sepsis, liver disease, HIV infection, head injury, pancreatitis, burns, cardiac surgery, etc. (1). Researchers make a distinction between the acute phase of critical illness—in the first hours or days following severe trauma or infection; and the chronic or prolonged phase—in the case of patients that survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (i.e., “chronic ICU patients”). Independent of the nature of the critical illness, the acute phase is associated with an excessive response of pro-inflammatory cytokines (2) and is characterized by a uniform dysregulation of the endocrine axes (3). In prolonged critical illness, this dysregulation is maintained even once the initial inflammatory surge has settled (4). Regardless of the initial injury or infection, patients that suffer from prolonged critical illness experience profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc. (156). Whereas, the acute phase is considered to be an adaptive response to the severe stress of injury or infection (shifting energy and resources to essential organs and repair), the physiological mechanisms in the prolonged phase are now increasingly considered to be maladaptive responses to the stress of severe injury or infection, hindering recovery (710). Some have also suggested that the non-recovery from endocrine disturbances could explain the development of “post-intensive care syndrome” (PICS) (11); i.e., “the cognitive, psychiatric and/or physical disability after treatment in ICUs” (1213).

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, multi-system disease of unclear etiology (1415). The most common peri-onset events reported by patients are infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%) (16). “Impaired function, post-exertional malaise (an exacerbation of some or all of an individual’s ME/CFS symptoms after physical or cognitive exertion, or orthostatic stress that leads to a reduction in functional ability), and unrefreshing sleep” are considered to be core symptoms (14). The severity of the symptoms varies: “very severely affected patients experience profound weakness, almost constant pain, severe limitations to physical and mental activity, sensory hypersensitivity (light, touch, sound, smell, and certain foods), and hypersensitivity to medications” (17). We have listed a few hall mark symptoms that are often found in critically ill patients in chronic intensive care (ICU) patients and ME/CFS patients (Table 1).TABLE 1

Table 1. Comparison of the typical clinical picture of ICU patients and patients with ME/CFS.

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some ICU patients also underlie ME/CFS. Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. These mechanisms characterize prolonged critical illness regardless of the nature of the initial severe injury or infection (3810); similarly, we propose that these mechanisms could underlie the perpetuation of illness in ME/CFS regardless of the nature of the peri-onset event (i.e., infection, stressful incident, exposure to environmental toxins, or other). We provide an overview of these mechanisms in ICU patients and discuss their relevance for understanding ME/CFS. We also bring findings from fibromyalgia into the discussion here because ME/CFS and fibromyalgia are often jointly considered in the literature (2021); fibromyalgia is similarly a syndrome that is medically unexplained, often comorbid with ME/CFS, and “shares the core symptoms of fatigue, sleep problems and cognitive difficulties” (22). Additional research projects are required to investigate the validity of this hypothesis building on the findings from critical illness and ME/CFS summarized here.

This hypothesis may be particularly relevant in light of the current COVID-19 pandemic. Many COVID-19 patients continue to experience a variety of debilitating symptoms despite successfully defeating the virus—termed “post COVID-19 syndrome” or “long COVID-19”—that resemble ME/CFS (2326).

Suppression of Pulsatile Pituitary Secretions

Endocrine patterns observed during the initial acute phase of critical illness (in the first few hours or days) differ markedly from those observed during prolonged critical illness (after a few days) (2728). Indeed, the acute phase is characterized by increased release of pituitary hormones; the prolonged phase is characterized by suppression of the release of pituitary hormones. Simultaneously, hormone half-life and hormone up-take by the peripheral tissues differ markedly between these two phases (429). This biphasic pattern of the endocrine system during critical illness, however, is not readily observable in single or average measurements of circulating tropic and non-tropic hormone concentrations—which are a function of both hormone release and elimination from the blood stream. This pattern was thus only discovered in the early 1990s with measurements of the frequency and amplitude of pituitary secretions (i.e., pulsatility) performed as often as every 10 min over 24 h on ICU patients (29). The pulsatility of tropic hormone secretion is part of the signaling to the peripheral glands and thus considered a determining factor of hormone function (i.e., impact on target glands or tissues), in addition to overall volume of hormone release (3031). The finding that pulsatile pituitary secretions are suppressed during prolonged critical illness was critical in understanding the physiology of the syndrome and the curious failure of patients to recover (32). We describe the biphasic endocrine patterns during acute and prolonged critical illness for each of the main endocrine axes in further detail below, as well as the implications for the autonomic nervous system, metabolism and the immune system. We also provide evidence suggesting that the endocrine patterns observed in prolonged critical illness also underlie ME/CFS.

The Adreno-Cortical Axis (HPA Axis)

The adreno-cortical axis—also called hypothalamic-pituitary-adrenal (HPA) axis—is the body’s primary stress management system. The HPA axis responds to physical and mental challenges in part by controlling the body’s glucocorticoids levels, notably cortisol (33). Cortisol in turn modulates inflammation response, cardiovascular function and glucose metabolism (34). An inability to deal with stress, proneness to exaggerated immune responses and weight loss are associated with hypocortolism or poor HPA axis function (3538). The HPA axis also regulates mineralocorticoids that, in turn, regulate water and electrolyte balance (i.e., blood pressure). Low blood pressure and dizziness upon standing up are associated with a compromised HPA axis (35). Finally, the HPA axis (in addition to the gonadotropic axis not covered here) also contributes to the production of androgens, notably DHEA and testosterone, which are steroids that impact muscle mass, fat storage, pain, brain function and many other physiological traits. Low androgens are associated with muscle fatigue, joint pain, and noise intolerance (3942).

In normal conditions, the adrenal gland secretes cortisol during the day in pulses, with the highest amounts in the early morning hours and lower amounts at night. The hypothalamus signals to the pituitary with corticotrophin-releasing hormone (CRH), and to a lesser extent, arginine vasopressin (AVP), to produce adrenocorticotropic hormone (ACTH). This is in turn signals the adrenals to release cortisol and other hormones. Most cortisol circulating in the blood is bound to carrier molecules (2943). Production of cortisol is regulated by an inhibitory feedback loop. When free circulating cortisol attaches to glucocorticoid receptors on the hypothalamus and pituitary, these glands reduce production of CRH and AVP, and ACTH, respectively. The number and affinity of glucocorticoid receptors is thus considered one of the most important determining factors in the regulation of the HPA axis (43)

In Critical Illness

During the acute phase of critical illness, plasma cortisol concentrations rise rapidly. Increased cortisol availability is considered a vital response that allows for fluid retention, increased cardiac output and blood pressure, and induces an appropriate immune response while protecting against excessive inflammation (294445). Until recently believed to be the result of increased cortisol production by the adrenals, it is now known that high cortisol availability during this phase of critical illness is in fact largely driven by two peripheral mechanisms: a decrease in the abundance and affinity of the cortisol carrier molecules in circulation, and a slowing of cortisol breakdown in the liver and kidney (2934444647). Via inhibitory feedback loops, these higher cortisol concentrations suppress the HPA axis at the central level: the secretions of CRH and AVP by the hypothalamus and of ACTH by the pituitary fall, leading to an eventual drop in plasma cortisol levels (48).

Whereas, in critically ill patients that begin to recover, the HPA axis essentially normalizes within 28 days of illness, in cases of prolonged critical illness ACTH levels (surprisingly) continue to be depressed despite dropping cortisol levels (4950). Why and how this central suppression of ACTH is maintained is not clear and continues to be debated. Pro-inflammatory cytokines and O&NS likely play a leading role. Cytokines can mediate tissue-specific changes in the abundance and affinity of glucocorticoid receptors—which are major factors determining the activity of the HPA axis (244). Specifically, the cytokine IL-1β is known to modulate CRH release by the hypothalamus; TNF-α is known to impair ACTH release by the pituitary; and TNF-α is also known to impair cortisol production by the adrenal glands (2).

Without sufficient pulsatile stimulation by the tropic hormone ACTH, adrenal glands begin to atrophy and lose zonational structure. This is evidenced in the post-mortem dissection of patients that had been critically ill for a few weeks, but not in the patients that quickly died from their illness or trauma (3451). The weakening of adrenal glands not only compromises patients’ ability to cope with external stressors but also permits excessive inflammatory responses. In sum, the initial beneficial increase in cortisol availability induced by peripheral mechanisms during the acute phase of critical illness leads to a suppression of the HPA axis at the central-level from which a subset of patients appears unable to escape (Figure 1).FIGURE 1

Figure 1. The adreno-cortical axis (HPA axis) during normal conditions and prolonged critical illness.

In ME/CFS

Dysfunction of the HPA axis has been documented extensively in ME/CFS patients since the early 1980s (5263). Researchers have observed decreased baseline cortisol levels, blunted HPA axis responses to physical and psychological stressors, reduced HPA axis responsivity to provocation tests (such as CRH and ACTH administration), and a heightened inhibitory feedback loop (consistent with a higher abundance and affinity of glucocorticoid receptors at the level of the pituitary and hypothalamus). Strikingly, the magnitude of HPA axis dysfunction becomes more pronounced with illness duration and is associated with symptom severity (4364). Very few have studied pulsatility of ACTH release: one study of 36 study-pairs found no statistically significant differences in ACTH pulsatility between ME/CFS and matched controls (65), while another found a differential pattern of ACTH release over 24-h periods (66). Variations in the study-participants’ severity of illness—and methods used to control for these—may explain these apparently contradictory findings. Several studies have found the morning peak of ACTH is missing or weak in ME/CFS patients (43). A recent study assessing secretory events of cortisol found that CFS/ME patients have the same number of secretory events but secrete lower quantities in early morning hours (67). Significantly, a group of ME/CFS patients were found to have 50% smaller adrenals than controls (68), resembling adrenal atrophy in prolonged critical illness.

ME/CFS researchers have also proposed models to explain the persistence of a suppressed HPA axis (336970). Essentially, a short stress (i.e., a burst of cortisol) will produce a small perturbation in the glucocorticoid receptor concentration on the central glands that quickly returns to normal levels. However, long, repeated stress—from which the system doesn’t have time to recover—leads to a persistent high glucocorticoid receptor concentration, forcing the HPA axis to an alternate steady state. More recent models of the HPA axis have also included non-genomic feedback-controls (71), the endogenous effects of circadian rhythm (72), and interactions with the gonadotropic axis and the immune system (7374) to explain how HPA axis suppression is maintained even after the initial stress is gone.

HPA axis dysfunction is also present in the majority of fibromyalgia patients (7577). Various mechanisms have been suggested, including depressed secretion of CRH by the hypothalamus, a deficiency of CRH receptors on the pituitary, and adrenal atrophy due to chronic under-stimulation by reduced ACTH levels (78).

Moreover, the dysfunction of the HPA axis in ME/CFS and fibromyalgia has also been associated with pro-inflammatory cytokines and O&NS (43557980). A recent paper considering the bidirectional relationship between the function of the HPA axis and inflammation finds that immune-inflammatory and O&NS pathways induce HPA axis dysfunction in ME/CFS (81); the direction of causality is analogous to inflammatory pathways inducing endocrine dysfunctions in critical illness. Others have similarly theorized that local inflammation in the hypothalamus leads to a disturbed HPA axis in ME/CFS (82).

In sum, the HPA axis dysfunctions in ME/CFS are not unlike the dysfunctions in prolonged critical illness. However, to our knowledge a comprehensive study of the pituitary pulsatile secretions of ACTH in ME/CFS patients—which proved revelatory in understanding prolonged critical illness—does not yet exist. The relationship between the pituitary’s pulsatile ACTH secretions, severity of illness, the integrity and function of adrenal glands and resulting physiological alterations in ME/CFS thus remains largely unexplored.

The Somatotropic Axis (HPS Axis)

The somatotropic axis—also called hypothalamic-pituitary-somatotropic (HPS) axis—plays important roles in growth and development of children, but also contributes to a variety of physiological pathways in adults, including balancing catabolic (i.e., the break-down of molecules and tissues) and anabolic activities (i.e., the building of molecules and tissue) (4). An HPS axis dysfunction is known to cause loss of muscle and bone mass, induces weakness (29), and impacts gut mucosa integrity as well as glucose and fat metabolism (83). Low energy, exhaustion, mental fatigue, weak muscle strength as well as poor recovery after physical activity are associated with an inhibited HPS axis function (428485).

Uniquely, in the case of the HPS axis, the hypothalamus sends both stimulating (+) and inhibiting (-) signals to the pituitary for the production of growth hormone (GH): these are, respectively, the GH-releasing hormone (GHRH) and the GH-inhibiting hormone (GHIH, also called somatostatin) (4). In addition, ghrelin, mostly produced by the gut, also stimulates GH production by the pituitary. In normal conditions, GH is released by the pituitary in a pulsatile fashion under the control of these three signals, with peaks of GH levels alternating with virtually undetectable valleys in 3- to 5-h intervals over the course of the day (29). GH in turn has direct effects on some tissues and also stimulates the production of insulin-like growth hormone-1 (IGF-1), mostly by the liver. Nearly all of the IGF-1 hormones in the plasma are bound to IGF-binding proteins (IGFBP). IGF-1 and GH exert inhibitory feedback on the hypothalamus and the pituitary to maintain homeostasis. The half-life of GH is only 10 to 20 min, whereas the half-life of IGF-1 is more than 12 h. Thus, IGF-1 plasma concentrations are regularly used as proxies for GH secretion in clinical settings. This, however, overlooks the function of the pulsatile secretion of GH on the balance of anabolic and catabolic activities in the body (4).

In Critical Illness

In the acute phase of critical illness, the pituitary produces more GH: higher peaks, lower valleys and increased pulse frequencies (86). The rapid onset of two main peripheral mechanisms explain this finding: First, under the influence of cytokines, the liver expresses fewer GH receptors (i.e., becomes resistant to GH) and thus produces less IGF-1. Second, alterations in IGF binding proteins results in IGF-1 being cleared out faster from the system (i.e., IGF-1 has a shorter half-life) (87). The lower IGF-1 concentrations resulting from these two peripheral mechanisms will—via the feedback loop inherent to the axis—spur more GH production (29). The resulting increase in catabolic activity during the acute phase of critical illness serves to mobilize amino acids derived from the breakdown of peripheral tissues, such as skeletal muscle and bone, for use by the central organs (4).

However, if a critically ill patient fails to recover within a few days, GH secretion becomes erratic and almost non-pulsatile. Experiments have demonstrated that this is largely due to a lack of stimulation of the hypothalamus and pituitary by the hormone ghrelin. There is also evidence for changes in the relative amounts of GHIH and GHRH signals from the hypothalamus (4). As for the peripheral hormone, IGF-1, its levels are low or normal in prolonged critical illness. The liver’s resistance to GH (which previously suppressed IGF-1 production during the acute phase of critical illness) does not persist during prolonged critical illness (2987). However, without a concomitant pulsatile release of GH, the anabolic function of IGF-1 becomes inhibited (4).

In sum, although the increase in catabolic activity during the acute phase of critical illness may initially be beneficial because it serves to mobilize amino acids, the perpetuation of the imbalance in catabolic vs. anabolic activity (due in part to the loss of the pulsatile function of GH) during prolonged critical illness may be considered maladaptive (Figure 2). The imbalance in catabolic relative to anabolic activity in prolonged critical illness leads to protein break-down in skeletal muscle, liver, kidney and heart, reducing their cell mass and leading to impaired function (7). These processes are ultimately reflected in muscle and bone wasting typically present in prolonged critical illness (8889).FIGURE 2

Figure 2. The somatotropic axis (HPS axis) during normal conditions and prolonged critical illness.

In ME/CFS

GH regulation in ME/CFS has been studied since the 1990s. The findings are mixed, but almost none addresses the question of the pulsatility of GH release. Some described low nocturnal GH secretion (9091), while others have found normal levels of 24-h urinary GH excretion (92). Some have found reduced response to induced hypoglycemia (9091), while others describe normal GH responses to stimulation (93). One study describes unaffected diurnal patterns of GH release in ME/CFS, but it focused on assessing basal levels rather than the nature of secretory patterns (i.e., pulsatile vs. erratic) and may not have accounted for variations in the severity of illness of patients (66). In terms of IGF-1, there are no consistent differences between ME/CFS patients and controls (9394), which is consistent with findings from prolonged critical illness.

Studies in fibromyalgia show relative GH deficiency (76789599) and low or low-normal IGF-1 levels (9596100). Interestingly, some studies showed that fibromyalgia patients “failed to exhibit a GH response to exercise” (97101), consistent with a loss in pulsatility of GH release.

In sum, endocrine observations in ME/CFS are not unlike HPS axis dysfunctions found in prolonged critical illness. To our knowledge the pituitary pulsatile secretions of GH in ME/CFS patients has not been comprehensively studied. The relationship between the pituitary’s pulsatile GH secretions, severity of illness and the balance between catabolic and anabolic activities in ME/CFS thus remains largely undiscovered.

The Thyrotropic Axis (HPT Axis)

The thyrotropic axis—also called hypothalamic-pituitary-thyroid (HPT) axis—regulates the basal rate of our metabolism. Dysfunctions of the HPT axis are associated with tiredness, stiffness, constipation, dry skin and weight gain, among a myriad of other hypothyroid-like symptoms (3542).

In normal conditions, an inhibitory feedback loop works to maintain stable circulating thyroid hormone concentrations according to a daily rhythm (102). When unbound circulating thyroid hormone concentrations dip below a certain threshold, the hypothalamus produces thyrotropin-releasing hormones (TRH) in order to signal the pituitary to produce thyroid stimulating hormone (TSH), which in turn signals the thyroid gland to produce more thyroid hormones.

In Critical Illness

Dysfunctions of the HPT axis during critical illness have been studied extensively. Starting in the early 1970s, clinicians working in ICUs observed that patients with a wide range of critical conditions had low plasma concentrations of the active form of thyroid hormones (T3) relative to plasma concentrations of inactivated thyroid hormones reverse T3 (rT3) (103105). They gave this condition the name “non-thyroidal illness syndrome” (NTIS), also called “euthyroid sick syndrome” or “low T3 syndrome.” While NTIS was initially considered to be beneficial in critical illness—i.e., a state of “protective” down-regulation of metabolism during times of duress (106) —it is increasingly seen as maladaptive and hampering the recovery of patients in the case of prolonged critical illness (91029103104107108).

During acute and early stages of critical illness, peripheral mechanisms involving cytokines (notably IL-1β, IL-6, TNF-α) lead to the quick depression of thyroid hormone activity (104105109111) to help conserve energy resources (48104). The mechanisms include the alterations in the amount and affinity of thyroid hormone binding globulines in the blood (112114); modifications in the expression of the transporters that carry the thyroid hormone into the cells (115116); the down- and up-regulation of deiodinase enzymes that convert the thyroid hormone into active and inactive forms, respectively (113117); and the variation in the quantity and isoforms of cellular thyroid hormone receptors present (notably in the liver, adipose tissue and muscle) (118120). An alteration in any of these steps—which determine thyroid hormone function—can lead to large time- and tissue-specific adjustments in cellular metabolism (121122)—even without, or with only minor, changes in the blood concentrations of thyroid hormones (121123124).

During prolonged critical illness these peripheral mechanisms are supplemented by central mechanisms that also depress thyroid hormone function (125126). Cytokines (notably IL-12 and IL-18), in association with other signaling factors (including leptin, glucocorticoids, etc.), are believed to up-regulate the deiodinase enzymes D1 and D2 in the hypothalamus resulting in higher local levels of T3 that inhibit TRH release irrespective of circulating thyroid hormone concentrations (10127128). Moreover, cytokines (notably IL-1b and TNF-α) also suppress the release of TSH by the pituitary (129130). Finally, by reducing iodine uptake and thyroid hormone excretion, cytokines (notably IL-1) also impact the activity of the thyroid gland itself (103113). Together, these mechanisms can alter the inhibitory feedback mechanisms of the HPT axis (i.e., its “set-point”) during prolonged critical illness. Single measurements of circulating TSH, however, are ineffective in revealing such alterations in the set-point of the HPT axis.

In sum, an initial beneficial alteration of thyroid hormone activity in the periphery during acute critical illness is followed by a cytokine-mediated central suppression of the HPT axis resulting in a virtual complete loss of pulsatile TSH secretion (29). Peripheral mechanisms (notably variations in the conversion and transport of thyroid hormones) may further modulate thyroid hormone function in time- and tissue-specific ways resulting in complex physiological alterations in these patients (Figure 3) —not readily observable in blood concentrations of thyroid hormones. How these alterations of the HPT axis persist as well as their broader implications on metabolism and the immune system are further described below (see section A “Vicious Circle” Perpetuating Illness).FIGURE 3

Figure 3. The thyrotropic axis (HPT axis) during normal conditions and prolonged critical illness.

In ME/CFS

Dysfunctions of the HPT axis have long been suspected to play a role in ME/CFS (77131134) and fibromyalgia (135140). A recent study showed that ME/CFS patients had similar TSH levels as controls, but lower Free T3, Total T4, and Total T3, which the authors suggest resembles NTIS (141)—the typical feature of critically ill patients in ICUs described above.

In sum, alterations of the HPT axis in ME/CFS resemble dysfunctions found in prolonged critical illness. However, there does not to our knowledge exist a thorough study of the pulsatility of pituitary TSH secretion events in ME/CFS patients, nor a study of the tissue-specific alterations in thyroid hormone function—which proved revelatory in understanding prolonged critical illness. The relationship between the TSH axis dysfunctions, severity of illness, hypometabolic state and organ/tissue specific symptoms in ME/CFS thus remains largely unexplored.

Intermediate Conclusions

The endocrine axes control many of the most fundamental physiological processes; their suppression is associated with a myriad of symptoms (see Table 2). Essentially, the suppression of pulsatile pituitary secretions of ACTH, GH, and TSH are central to prolonged critical illness. Inflammatory pathways play a role in inducing and maintaining this suppression irrespective of the nature of the original illness or trauma (see Table 3). The resulting endocrine patterns may be considered maladaptive and have wide ranging implications, including dysfunction of the balance between anabolic and catabolic processes, metabolism, and the regulation of the immune system. The physiological parallels between ME/CFS and prolonged critical illness would suggest that the suppression of pulsatile pituitary secretions of these tropic hormones might also underlie ME/CFS, and that the severity of ME/CFS might be a function of the strength of the mechanism; this however remains largely unstudied. In the next section we provide an overview of a model from critical illness that explains the perpetuation of these endocrine dysfunctions and we describe the relevance of the model for understanding ME/CFS.TABLE 2

Table 2. Summary of endocrine axes and function of the main hormones in adults.TABLE 3

Table 3. Summary of endocrine dysfunctions and mechanisms in critical illness and ME/CFS.

A “Vicious Circle” Perpetuating Illness

Based on nearly five decades of research, critical illness researchers have proposed a model that describes how NTIS is maintained by reciprocal relationships between inflammation (notably pro-inflammatory cytokines), O&NS and reduced thyroid hormone function, forming a “vicious circle” (910) (Figure 4). This model can help to explain the perplexing failure to recover of some critically ill patients in ICUs that survive their initial severe illness or injury. We describe the main elements of this model in a simplified manner below, as well as the implications for metabolism and the immune system. We also provide evidence suggesting that the “vicious circle” observed in prolonged critical illness also underlies ME/CFS.FIGURE 4

Figure 4. Simplified model to explain the perpetuation of prolonged critical illness: a “vicious circle”.

In Prolonged Critical Illness

The key elements of the suggested “vicious circle” in prolonged critical illness include the following mechanisms:

(a) Cytokines depress thyroid hormone function: As described above [see section The thyrotropic axis (HPT Axis) In Critical Illness], in acute and early stages of critical illness, various peripheral mechanisms involving cytokines lead to the quick depression of thyroid hormone activity in tissue-specific ways. In prolonged critical illness, cytokines in association with other signaling factors targeting the hypothalamus, as well as the pituitary and the thyroid glands, also inhibit thyroid hormone production. The relative sequence and importance of these various mechanisms in depressing the HPT axis and thyroid hormone function in different tissues and phases of critical illness are the subject of most NTIS publications (10104105). Notwithstanding the effect of other mechanisms, alterations in the activity of the deiodinase enzymes lead to a decrease in T3 and an increase in rT3 and thus a reduction in thyroid hormone function in peripheral tissues during prolonged critical illness [based on biopsies on ICU patients who died (142) and studies on mice (143144)]. Circulating thyroid hormone concentrations, however, only reveal the “tip of the iceberg” of the alterations occurring at the tissue level (141145), which thus are often missed altogether in clinical settings (146).

(b) Low thyroid hormone function contributes to oxidative and nitrosative stress: The relationship between thyroid hormone function and O&NS is complex, and both hyperthyroidism and hypothyroidism have been associated with oxidative stress (147). Nonetheless, it seems clear that depressed thyroid hormone function hinders tissue cells from maintaining a healthy O&NS balance. Mechanisms include alterations to the lipid concentration of the cell membranes that maintain the cell’s O&NS balance (148), and reduced function of two proteins (Uncoupling Proteins-2 and -3) with anti-oxidant properties (149). Moreover, in low thyroid hormone function conditions, mitochondria damaged by O&NS are not cleared out of cells (9). In turn, it appears that oxidative stress depletes the glutathione required by the abovementioned deiodinase enzymes for the conversion of T4 into T3 (104). Similarly, competition for, and the resulting depletion of the trace mineral selenium—a component of both the deiodinase and the anti-oxidant enzymes (150) —may amplify the self-perpetuating link between increased oxidative stress and low thyroid hormone function.

(c) Oxidative and nitrosative stress stimulate the production of pro-inflammatory cytokines: The final mechanism which completes the “vicious circle” in prolonged critical illness is the link between O&NS and inflammation. O&NS stimulates the production of pro-inflammatory cytokines, notably leptin, resistin, TNF-α and IL-6 (151). In turn, pro-inflammatory cytokines (notably IL-6) further increase O&NS by triggering the production of superoxide radicals (104152). There is thus a tendency for O&NS and pro-inflammatory cytokines to perpetuate each other as well.

In sum, according to a model proposed by critical illness researchers, a “vicious circle” involving O&NS, pro-inflammatory cytokines, and low thyroid hormone function—as well as reciprocal relationships across these elements—can perpetuate a hypometabolic and inflammatory state, and thus help to explain why some critically ill patients fail to recover.

In ME/CFS

Similar patterns of O&NS, cytokines, and low thyroid hormone function have recently been documented in ME/CFS patients providing the elements for a similar “vicious circle.” We briefly summarize the findings from ME/CFS research relevant to each of these elements.

Reduced thyroid hormone function: An immune-mediated loss of thyroid hormone function in ME/CFS has long been suspected (132). As mentioned above [see section: The thyrotropic axis (HPT Axis) In ME/CFS], a recent study confirmed that CFS patients have lower circulating levels of Free T3, Total T4, and Total T3 than controls (141). Moreover, this study found a significantly higher ratio of rT3 to T3 hormones. These findings imply a depressed thyroid hormone function resembling NTIS. Given the possible tissue-specific alterations in thyroid hormone activity resulting from peripheral mechanisms, the authors suggest these circulating levels only reflect the “tip of the iceberg” of genuine T3 deficits in target tissues.

Oxidative & nitrosative stress: Numerous studies have found increased O&NS in ME/CFS and identified this as a factor in the observed metabolic dysfunction (153154). Indeed, Pall proposed a model that describes a “vicious circle” involving oxidative stress and cytokines in ME/CFS a decade ago (cf. the “NO/ONOO-Cycle”) (155). Researchers also suggest that high lactate and low glutathione levels found in the brains of ME/CFS patients likely derive from similar mechanisms involving oxidative stress (156). A recent study described the relationship between O&NS and immune-inflammatory pathways in ME/CFS (80).

Pro-inflammatory cytokines: Neuro-inflammation is central to ME/CFS, and many researchers have tried to develop diagnostic biomarkers for ME/CFS based on cytokine profiles of patients (157158). Montoya et al. found that some 17 cytokines were positively correlated with the severity of ME/CFS, of which 13 are pro-inflammatory. Similarly, circulatory levels of pro-inflammatory cytokines are altered in fibromyalgia patients (159). However, others have argued that given the innumerable sources of potential variance in the measurement of cytokines, it is “unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered” for ME/CFS (160). It may therefore be ineffectual to compare the cytokine profiles of ME/CFS and prolonged critical illness patients.

In sum, given the presence of reduced thyroid hormone function, O&NS and pro-inflammatory cytokines in ME/CFS, the “vicious circle” model proposed by critical illness researchers to explain prolonged critical illness may also help to understand why ME/CFS patients fail to recover.

Implications of the “Vicious Circle” and Its Elements

Reduced thyroid hormone function, increased O&NS and pro-inflammatory cytokines discovered in prolonged critical illness as well as in ME/CFS have important implications notably on metabolism, organ function, immune responses and the endocrine system. These are further described below:

Reduced thyroid hormone function: The prolonged down-regulation of thyroid hormone activity certainly has implications for the immune system. Authors describe the profound effects of circulating thyroid hormone levels on the activity of monocytes, lymphocytes macrophages, neutrophils, dendritic cells and natural killer cells; as well as cytokines (161170). Notably, depressed thyroid levels appear to depress the activity of natural killer cells (171)—a signature finding in ME/CFS (172). Such immune dysfunctions might explain other pathologies, such as viral reactivation observed in ICU patients (173175) and suspected in ME/CFS patients (176177). Experimenting on rats, researchers have shown that depressed thyroid hormone levels occur in a specific sequence, manifesting (from first to last) in the liver, kidney, brain, heart and adipose tissues (145). An implication of a tissue-specific down-regulation of thyroid hormone activity is differential impact on organ function. Some ME/CFS practitioners have argued that tissue-specific modulation of T3 can help explain the disparate and evolving symptoms in ME/CFS and fibromyalgia (133134138140). In aggregate, depressed thyroid hormone function would engender a general hypometabolic state. Finally, thyroid hormone function also impacts other endocrine axes as well (178179)—notably the HPA axis—setting the stage for further complex interactions between the various endocrine axes and the immune system.

Oxidative & nitrosative stress: The implications of chronic oxidative stress in the body are widely documented. In addition to inducing inflammation, oxidative stress causes cell damage and disrupts normal cellular transcription and signaling mechanisms (9). O&NS has been shown to cause mitochondrial damage during critical illness (180) and ME/CFS (153).

Pro-inflammatory cytokines: Researchers are finding that the more than 100 different cytokines play a part in determining the function of hormones through both central and peripheral mechanisms (32). As described in the previous section, cytokines are likely culprits in the central (i.e., hypothalamic and pituitary) suppression of the HPA, HPS and HPT axes in prolonged critical illness (29). Pro-inflammatory cytokines and inflammation also hinder normal mitochondrial function during critical illness (181). The alterations in cytokines found in critical illness likely have many further implications that have yet to be fully understood (182) which is also the case for ME/CFS (183).

Intermediate Conclusions

In sum, critical illness researchers have proposed that the self-perpetuating relationships between inflammation (notably pro-inflammatory cytokines), O&NS and low thyroid hormone function explains the maintenance of illness in some ICU patients following severe injury or infection. Given that the same elements of such a “vicious circle” have also been documented in ME/CFS, we suggest that the model can also explain the failure of ME/CFS patients to recover. Moreover, these elements have been shown to have profound implications on metabolism, as well as on the function of the immune and endocrine systems—which in in turn could explain the myriad of symptoms in prolonged critical illness and ME/CFS.

Relationship to Other Hypotheses of ME/CFS Pathogenesis

Our hypothesis that maladaptive mechanisms which prevent recovery in prolonged critical illness also underlie ME/CFS complements several other hypotheses of ME/CFS pathogenesis. In this section we provide an initial and non-exhaustive discussion of some of these complementarities.

Allostatic overload: Some researchers consider ME/CFS to be a maladaptive response to physical, infectious, and/or emotional stressors. They describe an “allostatic overload” (i.e., the cumulative effect of stressful situations exceeding a person’s ability to cope) or a “‘crash’ in the stress system” (184185). Our hypothesis fits into this theoretical framework and offers an explanation for the possible underlying physiological mechanisms by drawing on the research from critical care medicine.

Hypothalamic endocrine suppression: Researchers have suggested that hypothalamic endocrine suppression could explain ME/CFS (132186) and fibromyalgia (187189). Our thesis upholds this hypothesis and seeks to strengthen it by suggesting that the controversy around the existence of central endocrine suppression in ME/CFS may be resolved by studying the pulsatile secretions of the pituitary—rather than single or average measurements of circulating tropic and non-tropic hormone concentrations, which can fail to discern the dysfunctions of the endocrine axes.

Anomalies in thyroid hormone function: Numerous clinical practitioners and researchers believe that anomalies in thyroid hormone function—including changes in the conversion of thyroid hormones, a resistance of thyroid hormone receptors at cellular level, etc. —contribute to ME/CFS and fibromyalgia (133141). Indeed, practitioners have written about their successes in treating ME/CFS patients with thyroid hormone supplements (4277188190194); and patients have published books on their experiences (195197). Our hypothesis complements this reasoning: we propose that both the central and peripheral mechanisms altering thyroid hormone function during critical illness (c.f. NTIS, euthyroid sick syndrome or “low T3 syndrome”) also occur in ME/CFS. Moreover, by applying a model from critical illness, we suggest that low thyroid hormone function is one element of a “vicious circle” perpetuating illness in ME/CFS.

Viral Reactivation: It has long been suggested that viral reactivation plays a role in ME/CFS, particularly reactivation of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) (176177). Similarly, high incidences of viral reactivation have also been observed in ICU patients, notably in patients with sepsis and prolonged critical illness. ICU researchers propose that this viral reactivation is a result of immune suppression occurring during critical illness (173175). Thus, critical illness research would suggest that viral reactivation is a secondary pathology in ME/CFS—except in cases in which the viral infection was the onset event.

Viral infection: Viral infection is recognized to be a leading onset event of ME/CFS (16198201). This is particularly concerning in the context of the COVID-19 pandemic. Many COVID-19 patients continue to experience a variety of debilitating symptoms after defeating the virus that resemble ME/CFS. Building on our hypothesis, we would suggest that post COVID-19 syndrome is evidence of a maladaptive response to the stress of infection akin to that experienced in prolonged critical illness and ME/CFS.

Chronic inflammation: Researchers have found that chronic inflammation—auto-immune, allergic or bacterial/viral—underlies ME/CFS (194202203). Others also ascribe the perpetuation of ME/CFS to the relationship between inflammation and O&NS (80155). Our hypothesis is largely complementary to these findings and associated theories. Indeed, following a cytokine surge during the acute phase of critical illness, inflammation is believed to persist in the case of prolonged critical illness (4). Moreover, pro-inflammatory cytokines and O&NS are elements in the “vicious circle” model of prolonged critical illness, which we propose also serves to understand the perpetuation of illness in ME/CFS patients.

Neuroinflammation of the brain: ME/CFS is associated with inflammation of the brain (hence the name myalgic encephalomyelitis) (204205). Some have specifically proposed that inflammation of the hypothalamus underlies ME/CFS (8182). Similarly, alterations of the endocrine axes through mechanisms mediated by pro-inflammatory cytokines which impact the hypothalamus and pituitary are central to prolonged critical illness (see section Suppression of Pulsatile Pituitary Secretions).

Energy metabolic defect: Researchers have found impairment in energy production (205206), reduced mitochondrial activity (207209) and irregularities in the metabolites of ME/CFS patients (210211) —suggesting that they experience a hypometabolic or “dauer” state (212). Our hypothesis is compatible with analyses that emphasize metabolic defects in ME/CFS. Indeed, the suppression of pituitary secretions, depressed thyroid hormone function, O&NS and immune system dysfunction—hallmarks of prolonged critical illness—have severe impacts on metabolism, including on glucose utilization and mitochondrial activity (see section A “Vicious Circle” Perpetuating Illness). Certainly, prolonged critical illness resembles a hypometabolic “dauer” state as well.

Genetic predisposition: Research also suggests there may a genetic element in the pathogenesis of ME/CFS (213216). Our hypothesis is compatible with a possible genetic predisposition for ME/CFS. Indeed, it is not known why some critically ill patients succumb to prolonged critical illness while others begin recovery (217218); genetics may play a role. The findings from the field of ME/CFS in the area of genetics might inform the field of critical illness in this regard.

In sum, our hypothesis is largely complementary to hypotheses that emphasize metabolic, hormonal and/or immune dysfunctions in the pathogenesis of ME/CFS. Our hypothesis—drawing from research on critical illness—integrates these dysfunctions into a single framework and provides arguments for the direction of causality between them.

Conclusion

Decades of research in the field of critical medicine have demonstrated that in response to the stress of severe infection or injury, endocrine axes experience profound alterations. An assessment of the pituitary’s pulsatile secretions reveals that in the subset of patients which survive their severe infection or injury but do not begin recovery (i.e., prolonged critically ill patients), the suppression of endocrine axes is maintained irrespective of the initial severe infection or injury. Recent pathological models propose that mechanisms involving pro-inflammatory cytokines, O&NS and low thyroid hormone function explain the perpetuation of these endocrine dysfunctions (i.e., a “vicious circle”).

The symptoms, physiological abnormalities and endocrine patterns observed in severe ME/CFS are not unlike those of prolonged critical illness. Moreover, the same elements of a “vicious circle” also exist in ME/CFS. However, unlike in critical illness, the pituitary’s pulsatile secretion and its relationships to metabolic and immune functions remain largely unstudied in ME/CFS.

Without excluding possible predisposing genetic or environmental factors, we propose the hypothesis that the maladaptive mechanisms that prevent recovery of prolonged critically ill patients also underlie ME/CFS. The severity of ME/CFS illness may be a function of the strength of these mechanisms; very severe ME/CFS most resembles prolonged critical illness. We further argue that this hypothesis should be investigated through collaborative research projects building on the findings from critical illness and ME/CFS. If this hypothesis is validated, past trials to break the “vicious circle” that perpetuates critical illness, and the early successes to reactivate the pulsatile secretion of the pituitary in ICU patients, may provide avenues for a cure for ME/CFS—including cases onset by infections. Certainly, given the similarities described above, active collaboration between critical illness and ME/CFS researchers could lead to improved outcomes for both conditions.

Finally, we suggest that immediate collaborative efforts should be sought among the researcher community in order to conduct longitudinal studies with the aim of identifying similarities and differences across prolonged critical illness, post-ICU syndrome, ME/CFS, fibromyalgia and long-COVID in relation to the hormonal axes, O&NS and pro-inflammatory response with the objective of discovering diagnostic and therapeutic targets mitigating the functional disability that these conditions induce.

Data Availability Statement

The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Author Contributions

DS wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Funding

Open Medicine Foundation and Swedish Research Council (2015-4870 (JB)) are acknowledged for support.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

Text throughout this hypothesis is reproduced from DS’s blogposts on Health Rising (219221) licensed Creative Common–Attribution CC BY.

Abbreviations

ACTH, Adrenocorticotropic hormone; ARV, Arginine vasopressin; CRH, Corticotrophin-releasing hormone; DHEA, Dehydroepiandrosterone; GH, Growth hormone; GHIH, Growth hormone inhibiting hormone; GHRH, Growth hormone releasing hormone; HPA, hypothalamus-pituitary-adrenal axis: “Adreno-cortical axis”; HPS, Hypothalamic-pituitary-somatotropic axis: “Somatropic axis”; HPT, Hypothalamic-pituitary-thyroid: “Thyrotropic axis”; ICU, Intensive Care Unit; IGF-1, Insulin like growth hormone-1; IGFBP, Insulin like growth hormone binding proteins; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NTIS, Non-thyroidal illness syndrome; O&NS, oxidative and nitrosative stress; PICS, Post-intensive care syndrome; POTS, Postural Orthostatic Tachycardia Syndrome; TRH, Thyrotropin-releasing hormone; TSH, Thyroid stimulating hormone.

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Keywords: myalgic encephalomyelitis, critical illness, non-thyroidal illness syndrome, low t-3 syndrome, pituitary, cytokines, oxidative and nitrosative stress, post-intensive care syndrome

Citation: Stanculescu D, Larsson L and Bergquist J (2021) Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front. Med. 8:628029. doi: 10.3389/fmed.2021.628029

Received: 10 November 2020; Accepted: 08 January 2021; Published: 28 January 2021.

Edited by:Nuno Sepulveda, Charité–Universitätsmedizin Berlin, Germany

Reviewed by:Jose Alegre-Martin, Vall d’Hebron University Hospital, Spain
Klaus Wirth, Sanofi, Germany
Jonathan Kerr, Norfolk and Norwich University Hospital, United Kingdom

Copyright © 2021 Stanculescu, Larsson and Bergquist. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jonas Bergquist, Jonas.Bergquist@kemi.uu.se

ME/CFS: evidence for an autoimmune disease

Featured

Autoimmunity Reviews

Volume 17, Issue 6, June 2018, Pages 601-609

Autoimmunity Reviews

ReviewMyalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease

FranziskaSotznya

JuliàBlancobc

EnricaCapellide

JesúsCastro-Marrerof

SophieSteinera

ModraMurovskag

CarmenScheibenbogena on behalf of the European Network on ME/CFS (EUROMENE)

Citehttps://doi.org/10.1016/j.autrev.2018.01.009Get rights and content

Under a Creative Commons license open access

Highlights

The pathogenesis of ME/CFS is multifactorial, and immunological and environmental factors play a role.•

Autoimmune mechanisms can be linked with ME/CFS at least in a subset of patients.•

Autoantibodies mostly against nuclear and neurotransmitter receptors are found in a subset of ME/CFS patients.•

Immunomodulatory therapeutic strategies targeting autoantibodies may be beneficial and should be pursued.

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levelsT- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.

Abbreviations

AdRadrenergic receptorBAFFB-lymphocyte activating factordUTPasedeoxyuridine 5′-triphosphate nucleotidohydrolaseEBVEpstein-Barr virusFMfibromyalgia5-HT5-hydroxytryptanimeHHVhuman herpes virusIFNγinterferon gammaKIRkiller cell immunoglobulin-like receptorM AChRmuscarinic acetylcholine receptorME/CFSMyalgic Encephalomyelitis/Chronic Fatigue SyndromeMSmultiple sclerosisNKnatural killer cellsPBMCperipheral blood mononuclear cellsPOTSpostural orthostatic tachycardia syndromepSSprimary Sjögren’s syndromeRArheumatoid arthritisSLEsystemic lupus erythematosusSNPsingle nucleotide polymorphismsTCAtricarboxylic acidTfhT follicular helper cellsThT helper cellsTNFαtumor necrosis factor alphaTregregulatory T cells

Keywords

Autoimmune Biomarker Myalgic Encephalomyelitis Chronic Fatigue Syndrome Autoantibodies

1. Introduction

With an estimated prevalence of 0.2–0.3%, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem disease with unknown etiology. Patients suffer from persistent exhaustion, cognitive impairmentautonomic dysfunction, chronic pain and flu-like symptoms, leading to a substantial reduction of life quality [1].

ME/CFS disease onset is often reported to be triggered by infections and the link between infections and autoimmune diseases is well established [2]. Although the exact pathogenesis is still unknown, the most plausible hypothesis is that dysregulation of immune system, autonomic nervous system and metabolic disturbances contribute to this complex syndrome, in which severe fatigue and cognitive impairment are a central feature (Fig. 1). Stressful life events are frequently associated with disease onset concomitantly with a history of frequent recurrent infections, immune deficiency and autoimmunity [1,3]. There are numerous studies showing immunological, genetic and metabolic alterations consistent with an autoimmune mechanism. Further, the identification of autoantibodies in ME/CFS patients and the clinical benefit associated with B cell depleting therapy provide strong evidence that, at least in a subset of ME/CFS patients, the disease has an autoimmune etiology.

Fig. 1

2. Evidence for autoimmunity in ME/CFS

2.1. Role of infection

Infection by various pathogens, including the Epstein-Barr virus (EBV), the human herpes virus (HHV)-6 and the human parvovirus B19, but also intracellular bacteria, are known as triggers of disease [1,[4][5][6]]. In a subset of patients, ME/CFS begins with infectious mononucleosis and evidence for a potential role of EBV in ME/CFS comes from many studies [4,[7][8][9]]. In 1984, DuBois et al. first described patients with mononucleosis syndrome suffering from long-lasting fatigue and serological evidence of EBV reactivation [4] followed by a number of studies describing ME/CFS patients with serological evidence of chronic active EBV infection [[7][8][9]]. Infectious mononucleosis is known as a risk factor for various autoimmune diseases [2,10]. Several studies show homologies of EBV sequences with human autoantigens such as myelin basic protein for multiple sclerosis (MS) [11]. In a study from our group enhanced IgG reactivity against an EBNA-6 repeat sequence was found in ME/CFS patients [9]. Homologous sequences of various human proteins with an EBNA-6 repeat sequence might be potential targets for antigenic mimicry.

Detection of anti-HHV-6 IgM antibodies and HHV-6 antigen in peripheral blood mononuclear cells (PBMC) and mucosa as evidence for HHV-6 reactivation is more frequent in patients with ME/CFS compared to healthy donors, showing that reactivation of persistent HHV-6 infection could be a trigger factor for ME/CFS [[12][13][14][15]]. In studies from our group evidence for an active HHV-6, HHV-7 or B19 infection was found in a subset of patients and was associated with subfebrility and lymphadenopathy [16]. Others, however, showed no difference between severity of symptoms and viral load of HHV-6 and HHV-7 in DNA from saliva and PBMCs among ME/CFS patients and controls [17]. It should be noted that HHV-6 and HHV-7 infect immune cells, preferentially CD4+ T cells, but also CD8+, monocytes/macrophages and natural killer (NK) cells involved in cellular, humoral and innate immune response [18,19]. Infection of immune cells by these viruses lead to changes in cell surface receptor expression, pro-inflammatory and anti-inflammatory cytokine and chemokine expression level modulating local inflammation and immune response. A role for HHV-6 has been proposed in several autoimmune diseases, including MS, autoimmune connective tissue diseases, and Hashimoto’s thyroiditis [20]. Molecular mimicry between myelin basic protein and an HHV-6 cell membrane protein is suggested to explain this link in MS [21]. Further, for ME/CFS and Gulf War Illness antibodies against the human dUTPase were reported by Halpin et al. [22]. These autoantibodies mainly occur together with antibodies against at least one of multiple HHV-encoded dUTPases suggesting an antigenic mimicry.

Parvovirus B19 infection has been shown to lead to development of ME/CFS. B19-triggered ME/CFS may be associated with a persistent viremia or may occur without viremia [23] and increased circulating TNF-α and IFN-γ were shown [24]. B19-associated ME/CFS was, in some cases, effectively treated with intravenous IgG [5,25,26]. Documented mechanisms in the pathogenesis of B19-associated autoimmunity include cross reaction of anti-B19 antibodies with human proteins, B19-induced apoptosis which results in presentation of self- antigens to T lymphocytes, and the phospholipase activity to the B19 unique VP1 protein region [23].

2.2. Immune cell alterations

Enhanced levels of immunoglobulins and alterations in B cells are frequently found in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) [[27][28][29][30]]. Further frequencies of CD21low B cells are frequently increased in these autoimmune diseases [27]. Consistently, alterations of B cell subsets are reported in ME/CFS. Elevated numbers of CD21+ as well as CD19+ and activated CD5+ B cells were described in ME/CFS patients [31,32]. Bradley et al. showed enhanced frequencies of naïve and transitional B cells and diminished plasma blasts [33]. Differently, Brenu et al. did not observe an altered frequency of plasma blasts, but an increase of memory B cells [34]. However, no major alteration of major B cell subpopulations was observed in other studies [3,35]. Mensah et al. reported an increase in CD24+ B cells, a fraction found to be elevated in autoimmune diseases [35]. Further elevated IgG levels in a subset of ME/CFS patients were shown in several studies [3,35,36]. Recently, a whole blood gene expression study discovered a downregulation of genes being involved in B cell differentiation and survival in ME/CFS [37].

T cell activation by infections could play an important role in the onset of autoimmune diseases [38]. In ME/CFS individuals, an increased frequency of activated T cells expressing the activation marker CD26 and HLA-DR has been shown, concomitant to lower levels of CD45RA+CD4+ T cells [31]. Similarly, ME/CFS was associated with higher frequencies of CD38 and HLA-DR co-expressing CD8+ T cells [39]. However, other authors found similar or lower expression of these markers in ME/CFS patients compared to healthy individuals [40,41]. Similarly, there is also evidence for a decreased cytotoxicity of CD 8+ T cells in a subset of ME/CFS patients [[42][43][44][45]]. Of particular interest in autoimmune diseases are T follicular helper cells (Tfh) that induce humoral responses at the germinal centers [46], the anti- inflammatory regulatory T cells (Treg) and the inflammatory T helper 17 (Th17) cells that modulate the activity of autoimmune responses [47]. The frequency of Treg has been addressed by several authors, most of them reporting a paradoxical higher frequency of this cell population in ME/CFS [40,42,48]. However, no studies on the potential role of Tfh and Th17 cells are available in ME/CFS yet.

In contrast to inconsistent B and T cell alterations reported in ME/CFS, diminished numbers of circulating NK cells and reduction of their cytotoxic activity were uniformly shown [31,40,49]. However, enhanced secretion of IFNγ and TNFα by the immunoregulatory CD56 bright NK cell subset was described in ME/CFS [49,50].

In summary, immune dysfunction in ME/CFS, as for other autoimmune disease, is a multifaceted hallmark that requires further studies using new technologies, standardized assays and well defined cohorts to clearly define common patterns.

2.3. Autoantibodies in ME/CFS

Several studies described autoantibodies in ME/CFS mostly against nuclear and membrane structures and neurotransmitter receptors (Table 1).

Table 1. Autoantibodies in ME/CFS.

AutoantigenCohorts of patients/control (n)Autoantibody positive
patients/control (%)
Refs.
Nuclear structures
ANA60/5168/15[51]
22523[53]
6057[54]
6068[55]
139/1497/5 (BioPlex ANA screen) 4/6 (IIF)[57]
Nuclear envelope60/5152/2[51]
60/3052/3[55]
Reticulated speckles60/3025/0[55]
68/48 kDa protein114/3713/0[52]
dsDNA8112[56]
Membrane structures
Phospholipids4238[58]
Cardiolipin2692 (IgM)[59]
4095 (IgM)[60]
814[56]
Phosphatidylserine815[56]
Gangliosides42/100 (FM)43[58]
Neurotransmitter receptors and neurotransmitter
M AChR5/11PET: binding to brain
M AChR in ME/CFS
[61]
M1 AChR60/3053/0[54]
M3/4 AChR and ®2-AdR268/108significantly elevated compared to
healthy controls
[53]
5-HT4262[58]
819[56]
Other autoantibodies
Cytoplasmic intermediate filaments60/3035/13[55]
dUTPase55/15115/5[22]
Neopitopes formed by oxidative or nitrosative damage14/11Significantly elevated compared to healthy controls (IgM titers)[66]
16/17[67]

Abbreviations: ANA: antinuclear antibodies; 5-HT: 5-hydroxytryptamine; IIF: indirect immunofluorescence; dUTPasedeoxyuridine 5′-triphosphate nucleotidohydrolase; FM: fibromyalgia.

2.3.1. Autoantibodies against nuclear and membrane structures

Antinuclear antibodies (ANA) were found in one study in 68 % of ME/CFS patients with the majority directed against the nuclear envelope [51]. Further studies showed ANA in 68%, 57%, 23% and 13% of ME/CFS patients [[52][53][54][55]]. Ortega-Hernandez et al. found dsDNA antibodies in 12% of patients [56], but another study failed to show such antibodies in ME/CFS (0.7%) [57].

Klein and Berg described anti-ganglioside antibodies in ME/CFS patients, but not in healthy controls [58]. In addition, they and others found phospholipid autoantibodies in ME/CFS patients [56,58,59] and antibodies against cardiolipin were described in 92–95% of ME/CFS patients in two studies [59,60] but only in 4% in another study [56]. Further autoantibodies against endothelial and neuronal cells were described in 30% and 16% of patients, respectively [56].

2.3.2. Antibodies against neurotransmitter receptors and neurotransmitter

Antibodies against the muscarinic M1 acetylcholine receptor (AChR) were reported in ME/CFS patients and were associated with muscle weakness [54]. Evidence for a functional role of these antibodies comes from a PET study showing reduced binding of a M AChR ligand in brain in antibody positive ME/CFS patients [61]. Antibodies against ß1 and ß2 adrenergic receptors (AdR) and M2/3 AChR were described in postural tachycardia syndrome, characterized by an increased heart rate in the absence of significant hypotension, as well as in orthostatic hypotension. This finding is of relevance for ME/CFS as 11–40% of ME/CFS patients concurrently suffer from postural orthostatic tachycardia syndrome (POTS) [[62][63][64][65]]. In a study from our group, elevated autoantibodies against both ß2-AdR and M3/4 AChR were found in a subset of ME/CFS patients compared to healthy controls [53]. A high correlation was found between levels of ß2 AdR autoantibodies and elevated IgG1–3 subclasses, activated HLA-DR+ T cells and thyroid peroxidase autoantibodies and ANA. The association of ß2 AdR autoantibodies with immune markers suggests an activation of B and T cells expressing ß2 AdRs. Further, disturbance of the AdR and M AChR function may explain symptoms of autonomic dysregulation in ME/CFS.

No differences between ME/CFS patients and controls were found in levels of autoantibodies directed against receptors for angiotensinendothelinmu-opioid, serotonin and dopamine [53,54]. However, autoantibodies against serotonin have been associated with ME/CFS [56,58].

2.3.3. Other autoantibodies

The IgM response against autoantigens formed by oxidative or nitrosative damage was studied by Maes et al. [66]. Autoantibodies directed against these neo-antigens, comprising oleic, palmitic and myristic acidS-farnesyl-l-cysteine, by-products of lipid peroxidation, e.g. malondialdehyde, and N-oxide modified amino acids, e.g. nitro-tyrosine and nitro-tryptophan, were significantly higher in ME/CFS patients than in controls. In addition, they observed that the level of these autoantibodies correlates with severity of illness and symptoms. Although increased IgM antibodies against these oxidatively damaged antigens were shown in major depression, too, a higher immune response was found in ME/CFS [67].

2.4. Soluble markers of autoimmunity

Autoimmunity is associated with enhanced levels of circulating inflammatory cytokines playing an important role in the pathogenesis of autoimmune diseases [68]. Elevated levels of cytokines related to Th1- as well as Th2-driven responses were reported for ME/CFS in several studies [42,[69][70][71][72][73][74]]. Further cytokine levels in ME/CFS were associated with severity and duration of illness [[72][73][74]]. However, alterations in cytokine profiles in ME/CFS were not found in all studies [75,76].

Elevated levels of B lymphocyte activating factor (BAFF) were described in a variety of autoimmune diseases including RA, SLE and pSS [77]. BAFF regulates the survival and maturation of B cells and mediates the IL-10 production of regulatory B cells [78,79]. Elevated levels of BAFF were shown in a subset of patients with ME/CFS in comparison to healthy controls [80]. As the gene expression of the BAFF receptor (TNFRSF13C) is reduced in ME/CFS, increased serum BAFF levels may represent a compensatory mechanism [37]. Interestingly, elevated serum BAFF levels correlated with the autoantibody production in RA, SLE and pSS [81]. In ME/CFS an association between BAFF and autoantibodies was not described so far.

Activin A and B, members of the Transforming Growth Factor β family, are involved in the control of inflammation and muscle mass [82]. Elevated levels of activin B as well as an elevated ratio of activin A or B to the binding protein follostatin in ME/CFS patients were demonstrated in a recent study [83]. An association of increased activin A with inflammatory bowel disease, RA, and asthma was already shown [82].

CD26 is a peptide-cleaving enzyme associated with immune regulation. In various autoimmune diseases, such as MS, Grave’s disease, and RA increased numbers of CD26 T cells were found in inflamed tissues and peripheral blood [84]. Fletcher et al. reported a higher frequency of CD26 expressing CD2+ lymphocytes in ME/CFS, but a decreased expression level on T and NK cells [85]. Further, they observed a reduction of the soluble CD26. Reduced serum CD26 levels were also reported for SLE and RA showing an inverse correlation with disease activity [84]. Low CD26 expression on PBMCs in ME/CFS was shown to correlate with reduced post-exercise muscle action potential, increased exercise- mediated lipid peroxidation, reduced quality of life and enhanced pain [86].

Other serum factors, frequently elevated in autoimmune disease like sCD30, sCD23, soluble cytotoxic T lymphocyte-associated antigen-4 (sCTLA-4) or the soluble IL-2 receptor (sIl-2R) are not described in ME/CFS so far [[87][88][89][90][91][92]].

2.5. Genetic variants associated with autoimmunity

It is well established that certain HLA alleles are associated with autoimmune diseases. Smith et al. showed an increased prevalence of the class II major histocompatibility complex HLA-DQB1  01 allele in ME/CFS patients [93]. Two others variants of HLA-DQB1 in combination with two RAGE-374A variants were associated with ME/CFS [94]. In another study the interaction of killer cell immunoglobulin-like receptors (KIRs) and their HLA class I epitopes were studied. An excess of KIR3DL1 and KIR3DS1 missing their HLA-Bw4Ile80 binding motif was shown in ME/CFS, leading potentially to an ongoing activation [95].

In the last years, genome-wide association studies revealed variants of various genes with either gain- or loss-of-function that are associated with the risk to develop autoimmune diseases. These single nucleotide polymorphisms (SNP) in receptors, enzymes or transcription factors play a role in B cell activationT cell development, activation and proliferation, and cytokine signaling which are crucial in autoimmune diseases [[96][97][98][99][100]]. Further, it is becoming increasingly clear that elements of the non-coding genome regulate a variety of normal immune functions and that dysregulation of enhancer elements or long non- coding RNA may play a key role in autoimmunity [101]. So far only polymorphisms in cytokine as well as toll-like receptor signaling pathways and complement cascade were studied showing an association with ME/CFS [102,103]. Due to its regulation of the inflammatory response the glucocorticoid receptor gene NR3C1 has gained interest. Several variants (SNPs) within NR3C1 gene were shown to be significantly associated with ME/CFS [104,105].

2.6. Energy metabolism and autoimmunity

Immunometabolism represents the interface between immunology and metabolism and is an exciting emerging field of research in autoimmunity [[106][107][108]]. The metabolic requirements of immune cells depend on their state of resting or activation and differentiation. Their activation results in a metabolic switch to aerobic glycolysis in order to provide enough energy and bio-precursors to meet the requirements for supporting rapid cell proliferation and immune functions. A growing body of evidence suggests that energy metabolism is crucial for the maintenance of chronic inflammation, not only in terms of energy supply but also in the control of the immune response through metabolic signals [106,107]. It has been suggested that disturbances in this intricate metabolic-immune cross-talk may be closely linked with and contribute to autoimmunity, although the precise pathomechanisms involved still remain to be elucidated [107,108]. It is also striking that several glycolytic enzymes act as autoantigens in rheumatic inflammatory disorders [109], although their role in ME/CFS remains unclear.

The profound and debilitating fatigue experienced by ME/CFS individuals led to the hypothesis that energy metabolism may be dysregulated. Defects in mitochondrial function in ME/CFS were shown in various studies from our group and others [[110][111][112][113]]. Metabolic profile had revealed disturbances related to energy, amino acids, nucleotidesnitrogen metabolism and oxidative stress in ME/CFS [[114][115][116][117][118][119]]. A metabolic shift toward aerobic glycolysis resulting in insufficient tricarboxylic acid (TCA) cycle and inadequate ATP production was reported recently, although the underlying basis has yet to be established [116,119]. Interestingly, the 2016 Fluge et al. study points to a secondary metabolic change driven by a serum factor in ME/CFS patients [116].

As dysfunctional metabolic pathways can directly influence and exacerbate defective immune responses, establishing the bioenergetic metabolism status of the different subsets of immune cells in ME/CFS has become a topic of increasing interest.

2.7. Comorbidity with autoimmune diseases

Comorbidity of ME/CFS with various autoimmune or immune-mediated diseases including fibromyalgia (FM), Hashimoto’s thyroiditis and POTS is observed (Fig. 2). Especially for FM there is considerable overlap with up to 77% of patients fulfilling disease criteria for both ME/CFS and FM [120]. FM is characterized by chronic widespread pain and is common in autoimmune diseases with around 50% of prevalence in patients with RA and SLE [121,122]. According to the modified ACR 2010 criteria FM has an overall estimated prevalence of 5.4%. In a recent study from our group analyzing clinical subgroups in a large Spanish ME/CFS cohort was reported FM comorbidity ranging from 26% to 91% [123]. In another study including patient cohorts from Norway, UK and USA, a comorbidity for ME/CFS and FM of 30% was observed [124]. In a similar manner Hashimoto’s thyroiditis characterized by elevated antibodies against thyroid peroxidase is frequent in autoimmune disease, whereas the overall prevalence is around 0.8% in the general population [125]. Hashimoto’s thyroiditis is found in 17–20% in ME/CFS patients [53,123]. Moreover, 11–40% of ME/CFS patients suffer from POTS [[62][63][64][65]]. Interestingly, for both disorders elevated frequencies of autoantibodies directed against AdRs and M AChRs were shown [53,[126][127][128]]. Furthermore, a substantial number of ME/CFS patients have a family history of autoimmune diseases [129,130].

Fig. 2

3. Therapies targeting autoimmunity in ME/CFS

First clear evidence for a pathogenic role of autoantibodies in ME/CFS comes from two clinical trials with the monoclonal anti-CD20 antibody rituximab [129,131]. Upon depletion of CD20+ B cells with rituximab, a monoclonal antibody directed against the B cell surface protein CD20, approximately 60% of patients experienced a partial or complete, and in some patients sustained clinical remission (Table 2). The delayed onset of response with a median of approximately 4 months in both trials suggests that clinical effects are not directly mediated by depletion of CD20+ B cells, but by diminishing short-lived antibody-producing plasma cells arising from CD20+ memory B cells, followed by subsequent wash-out of autoantibodies. Results from a multicenter controlled trial with rituximab are awaited in spring 2018.

Table 2. Clinical trials targeting autoimmunity in ME/CFS.

DosageStudy designPatients (n)EvaluationOutcomeRefs.
Intravenous IgG
1 g/kg/m2

RCT28FI & SRNo difference[133]
2 g/kg/m2

RCT49FI & SRFollow-up m3: 43% vs. 12%[134]
0.5 g/1 g/2 g/kg/m2

RCT99FI & SRNo difference[135]
1 g/kg/m2

RCT70 (adolescents)FIFollow-up m6: 72% vs. 44%[136]
Rituximab
500 mg/m2

RCT30FI & SRImprovement 67% vs. 13%[131]
500 mg/m2 6×Single arm29FI & SRImprovement 62%[129]
Ongoing Trials
Cyclophosphamide (Endoxan®)Fluge et al., unpub.
Immunoadsorption[137]

Abbreviations: RCT = Randomized controlled trial; FI=Functional Improvement; SR = Symptom reduction, assessed by questionnaires; unpub.: unpublished data.

Few other treatment modalities targeting autoimmunity were evaluated in clinical trials in ME/CFS (Table 2). High dose intravenous IgG therapy is efficacious in autoantibody-mediated diseases. Several intravenous IgG studies were performed in ME/CFS during the 80’s with two randomized controlled trials with positive and two with a negative outcome [132]. Preliminary data from an ongoing trial in Norway with cyclophosphamide suggests therapeutic efficacy of this broadly immunosuppressive drug (Fluge et al., unpublished data). Immunoadsorption is an apheresis in which IgG is specifically removed from plasma resulting in clinical improvement in various types of autoimmune disease. We performed a pilot trial in 10 patients with ME/CFS and observed first evidence for efficacy [137].

4. Conclusion

There is compelling evidence that autoimmune mechanisms play a role in ME/CFS. However clinical heterogeneity in disease onset (infection versus non-infection triggered), presence of immune-associated symptoms, and divergent immunological alterations point to the existence of subgroups of ME/CFS patients with possibly different pathomechanisms. Therefore, it is important to identify clinically useful diagnostic markers to select patients with autoimmune-mediated disease for clinical trials. The search for autoantibodies is of great importance enabling to develop potential biomarkers for diagnosis and providing a rationale for therapeutic interventions. Encouraging results from first clinical trials warrant larger studies with rituximab and other strategies targeting autoantibodies.

Funding

This review is based upon work from European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) as part of Cost Action CA15111 supported by the EU Framework Program Horizon 2020. Website: http://www.cost.eu/COST_Actions/ca/CA15111.

Author contributions

FS and CS were responsible for the first draft of the protocol, which was critically reviewed, further developed and approved by all authors.

Declaration of competing interests

JB reports personal fees from ALBAJUNA THERAPEUTICS, S.L., outside the submitted work; CS has received grant support for clinical trials and research from Fresenius, Shire, Lost Voices, SolveME, MERUK, IBB, and speaking honoraria from Octapharma and Shire. FS, EC, JCM, SS and MM have no conflict of interest to declare.

Acknowledgements

Not applicable.

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Published by Elsevier B.V.

ME/CFS and autoimmunity

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The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/cfs)

Molecular Neurobiology volume 49, pages741–756(2014) Cite this article

Abstract

The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses. A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies. The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host’s immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia.

ME/CFS as a Breakdown in Homeostasis

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Here I present a new theory of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling and complex illness affecting millions of people worldwide.

The Centers for Disease Control and Prevention (CDC) defines ME/CFS as follows:

People with ME/CFS are often not able to do their usual activities. At times, ME/CFS may confine them to bed. People with ME/CFS have overwhelming fatigue that is not improved by rest. ME/CFS may get worse after any activity, whether it’s physical or mental. This symptom is known as post-exertional malaise (PEM). Other symptoms can include problems with sleep, thinking and concentrating, pain, and dizziness.

There is no agreed scientific explanation of the disorder, no treatment and no cure. The most popular theory has been that the condition is psychosomatic. In my view, this theory is completely wrong.

Here I present a new theory suggesting that ME/CFS is a multi-system disorder in which the homeostasis of the body is broken. Homeostasis is a fundamental physiological principle that ensures equilibrium, stability and safety of the organism in a continuously changing and potentially life-threatening environment.

The featured illustration above is courtesy of Scientific American.

Bodily Homeostasis

The body uses three biological systems for the maintenance of equilibrium: the nervous system, the endocrine system and the immune system. The three systems communicate using electrical and chemical signals. They activate and de-activate tissues, organs and muscles to control and regulate the body, the emotions and the mind. The principal objective of the three systems is to preserve homeostasis. It is proposed that the complex multi-system disorder known as myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is caused by a breakdown of homeostasis. This Homeostasis Theory of ME/CFS is supported by a substantial number of studies in the recent literature.

The three systems and their relationships to the brain and behaviour are illustrated in Figure 1.

Figure 1 The nervous, endocrine and immune systems, and their relationships to brain and behaviour. Reproduced with permission from Marks, Murray and Estacio (2020, p. 26).

Continuous, reciprocal interaction between the brain, organs and gut is essential for smooth and efficient control and coordination of bodily functions, experience and behaviour. Endocrine substances directly affect the nervous and immune systems. The CNS innervates every organ and tissue of the immune system with reciprocal connections. The continuous interactions of the nervous, endocrine and immune systems was termed ‘neuroimmunomodulation’ by Spector and Korneva (1981). If a breakdown in homeostasis occurred, an individual would be in serious trouble. This may precisely be the case in people with ME/CFS (pwME/CFS).

The chronic nature of ME/CFS suggests that its pathogenesis involves a disruption of homeostasis leading to chronic inflammation and immunological dysfunction. Biomarkers of inflammation and leaky gut syndrome as a possible result of microbiome disturbance and bacterial translocation have been reported (Shukla et al., 2015; Cortes Rivera et al., 2019; Mandarano et al., 2018; Sweetman et al., 2019). According to this theory, an aberrant state of homeostasis is the central cause of ME/CFS (Hatziagelaki et al., 2018; Nacul et al., 2020; Sweetman et al., 2019).  To quote Sweetman et al. (2020):

In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states. Thus, the predominantly neuro-immune manifestations, underlined by a hyper-metabolic state, that characterize early disease, may be followed by various processes leading to multi-systemic abnormalities and related symptoms. This abnormal state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production. These processes do not seem to happen uniformly; although a spiraling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium.” (Figure 2).

Figure 2. Homeostasis breakdown in three hypothetical stages of disease in ME/CFS. Reproduced by permission from Nacul et al. (2020).

In line with what is known about the typical course of the disease, it can reasonably be assumed that the hypothesized state of aberrant homeostasis can be aggravated by new stressors in the form of infection (Shepherd & Chaudhuri, 2019), physical exertion, cognitive effort such as reading or solving mental puzzles, triggering a post-exertional malaise (PEM), comorbid conditions such as sleep disturbances (Chu, Valencia, Garvert & Montoya, 2018) and other factors (Nacul et al., 2020). In people who happily do not develop ME/CFS or prolonged illness following an acute infection or other insult, external stressors initially cause short-term physiological changes but the usual state of homeostatic equilibrium that operated before the insult is quickly restored.  Hatziagelaki et al. (2018) suggested that the abberant state of homeostasis could be caused by inflammation in the hypothalamus, which I discuss next.

The Neuroimmune Hypothesis

Patients with ME/CFS often present with an acute onset of illness, with symptoms similar to an influenza infection, but these symptoms do not subside. Many of the symptoms are inflammatory, i.e. myalgia, arthralgia or joint pains, sore throat and tender lymphadenopathy. The immune system is a network of cells, tissues and organs that protects the body against disease or other potentially damaging foreign bodies. When properly functioning, the system identifies and attacks a variety of threats using billions of diverse antibodies, including viruses, bacteria and parasites, while distinguishing them from the body’s own healthy tissue. For each type of invader the body needs a distinct antibody. Antibodies are made by B cells using a combination of 20,000 genes and an enzyme called ‘RAG’, which is a DNA shuffler. This enables the immune system to create a vast diversity of antibodies and respond to diseases it has never encountered before.

Inflammation is a critical defence response in our innate immune system wherein white blood cells protect us from infection by foreign organisms, bacteria and viruses. Inflammation occurs following infection or tissue damage when a rapid and complex series of reactions takes place to prevent tissue damage, isolate and destroy the infective organism, conserve and protect some micronutrients and activate the repair processes to restore normal function (Thurnham, 2014). Inflammation is a homeostatic process that is only intended to last a few days but, if it is continued indefinitely, there is a poor prognosis in many conditions. Inflammatory responses take precedence over normal body metabolism with the objective of restoring normality as quickly as possible.

Immune activation indicated by elevated levels of cytokines in pwME/CFS have been studied since 2001 (Patarca, 2001). Recent studies have used immune system profiling to determine whether an abnormal profile of circulating cytokines could be identified in pwME/CFS and whether this profile correlated with disease severity and/or fatigue duration. In one study, serum cytokines of 192 pwME/CFS and 392 healthy controls were measured (Montoya et al., 2017). Seventeen cytokines showed a statistically significant upward linear trend that correlated with ME/CFS severity of which 13 were proinflammatory, which is likely to be a contributing factor to the symptoms.

Strawbridge, Sartor, Scott and Cleare (2019) carried out a systematic review and meta-analysis of 42 studies of circulating inflammatory proteins in pwCFS and non-affected control groups. Patients with CFS had significantly elevated tumour necrosis factor, interleukin-2, interleukin-4, transforming growth factor-β and c-reactive protein. The authors concluded: “These data provide some support for an inflammatory component in CFS, although inconsistency of results indicates that inflammation is unlikely to be a primary feature in all those suffering from this disorder.”

The generic cause cause of the abnormal inflammatory response in pwME/CFS is a breakdown in homoeostasis. The precise mechanism is still unknown (Komoroff, 2019). But that inflammatory response is definitely present.

The Microbiome Hypothesis

The field of microbiome research studies the microbes within the gut and the effects of these microbes on the host’s well-being. The microbiome is the community of symbiotic and pathogenic microorganisms, that live on the skin and genitals and in the nose, ears, mouth and gut. Microbes influence metabolism, immunity and behaviour. One mechanism appears to involve hormones because specific changes in hormone levels correlate with the presence of the gut microbiota. The microbiota produce and secrete hormones, respond to host hormones and regulate expression levels of host hormones. Hormones and the microbiome are linked to immune responses under both healthy  conditions and autoimmune disease. There are many interconnections and the microbiome and hormones may work through shared pathways to affect the immune response (Neuman et al., 2015).

Zhang et al. (2018) illustrate the homeostasis system’s response to changes in diet and drug ingestions using this diagram (see Figure 3 below):

Figure 2. Graphical representation of the commensal homeostasis of gut microbiota-host under the intervention of diet and drugs. Diet and drugs can be digested, absorbed, and metabolized by the host and gut microbiota. The host and gut microbiota can interact synergistically to impact the physiological status of the human body. They not only support themselves directly by using nutritional substrates but also impact each other indirectly by enterotype, genotype, metabolites, and related functions. Ultimately, the host and gut microbiota achieve a commensal homeostasis of composition, interactions, metabolites, and energy utilization.

Organisms within the gut play a role in the early programming and response to stress. The gut contains 1013– 1014 micro-organisms, ten times the number of cells in the human body, and contains 150 – 360 times as many genes as our genome. That’s a heck of a lot. When a pathogen such as Escherichia coli (aka E coli) enter the gut, the HPA can be activated. Stress can induce increased permeability of the gut, allowing bacteria and bacterial antigens to cross the epithelial barrier and activate a mucosal immune response, which in turn alters the composition of the microbiome and leads to an enhanced HPA drive.

Patients with irritable bowel syndrome and major depression show alterations of the HPA which are induced by increased gut permeability. In the case of irritable bowel syndrome, the increased permeability can respond to probiotic therapy. The gut microbiota play a role in regulating the HPA. Verdino (2017) cautiously concludes his review of the connection between gut health and emotional well-being as follows: “… it is crucial not to oversimplify the idea that nutritional intervention and a healthy gut will be the panacea for profound psychological difficulties. Severe mood and paralyzing anxiety disorders are not going to be cured with probiotic yogurt and prebiotic fiber, alone” (Verdino, 2017: 4).

The immune and neuroendocrine systems share a set of hormones and receptors. Glucocorticoids, such as corticosterone and cortisol, regulate inflammation levels and have effects both on the innate and adaptive immune responses. Additionally, vitamin D affects immune cell responses by enhancing antigen presentation. Moreover, sex hormones affect the immune response in numerous ways.

Dysbiosis, an imbalance in the microbiome, seems to be involved in the pathophysiology of ME/CFS. Shukla et al. (2015) studied changes in the gut and plasma microbiome following exercise challenge in pwME/CFS.  In exercise challenge, changes occurred in the amount of bacterial phyla in the gut in pwME/CFS that were not observed in healthy controls. Also, bacteria clearance from the blood was delayed in pwME/CFS following exercise. Altered gut microbiome and increased bacterial translocation following exercise thus appear to play a role in ME/CFS that may account for the post-exertional malaise experienced by many pwME/CFS.

Mitochondrial Failure

Mitochondrial failure is another part of the jigsaw puzzle posed by ME/CFS (Myhill et al. 2009, 2013). Mitochondria generate cellular energy by manufacturing ATP (adenosine triphosphate). Infections with pathogens, including viruses, bacteria, parasites and toxins can cause changes in the function of mitochondria and deplete energy metabolism. Metabolomics, the systematic identification of metabolic products (the metabolome) of a biological system is revealing a possible chemical pattern of chemical abnormalities or metabolite abnormalities in pwME/CFS. Myhill, Booth and McLaren-Howard (2009) developed interventions based on the biochemistry of the illness, specifically the function of mitochondria in producing ATP, the energy currency for all body functions, and recycling ADP to replenish the ATP supply as needed. Patients attending a private medical practice specializing in ME/CFS were diagnosed using the Centers for Disease Control criteria. A correlation was obtained between the degree of mitochondrial dysfunction and the severity of illness (P<0.001). Only 1 of 71 patients overlapped the normal region.

Figure 4. Main stages and location of energy metabolism in a human cell (left), and simplified details of a mitochondrion showing the main metabolic cycles and the oxidative phosphorylation respiratory chain (right). The outer mitochondrial membrane is highly permeable whereas the inner membrane is permeable only to water and gases. Special carrier and Translocator proteins pass reactants through it. At the top are the proteins involved in the respiratory electron transfer chain (ETC) and in the transfer of ATP and ADP between the cytosol and mitochondrion. ADP and Pi are combined by ATP synthase to make ATP. The ADP/ATP Translocator opens OUT to transfer ADP into the matrix and opens IN to transfer ATP to the cytosol. Nicotinamide adenine dinucleotide plays a key role in its oxidised form NAD+ and its reduced form NADH + H+ in carrying and transferring protons (H+) and electrons (e). Reproduced from Sarah Myhill et al. 2009.

The authors concluded that “the “ATP profile” test is a powerful diagnostic tool and can differentiate patients who have fatigue and other symptoms as a result of energy wastage by stress and psychological factors from those who have insufficient energy due to cellular respiration dysfunction. The individual factors indicate which remedial actions, in the form of dietary supplements, drugs and detoxification, are most likely to be of benefit, and what further tests should be carried out” (Myhill et al., 2009).

Morris and Maes (2014) support Myhill et al.’s approach in arguing that mitochondrial dysfunctions in the form of lowered ATP production may play a role in the onset of ME/CFS symptoms and help to explain in part the central metabolic abnormalities observed in ME/CFS, e.g. glucose hypometabolism and cerebral hypoperfusion.

The results of a study by Sweetman et al. (2020) also “support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress.” 

Developing diagnostic biomarkers will be a significant next step.

Conclusion

Whatever the specific causal mechanism turns out to be – and whoever solves this problem will deserve the Nobel prize – homeostasis breakdown seems the most likely candidate as the underlying problem.

Role of Exosomes in the Regulation of T-Cell Mediated Immune Responses and in Autoimmune Disease

Anel, A., Gallego-Lleyda, A., de Miguel, D., Naval, J., & Martínez-Lostao, L. (2019). Role of exosomes in the regulation of T-cell mediated immune responses and in autoimmune disease. Cells8(2), 154.

Abstract

T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes. In this review, we revise the role of exosome secretion in the different pathways of immune regulation described to date and its importance in the prevention or development of autoimmune disease. The expression of membrane-bound death ligands on the surface of exosomes during AICD or the more recently described transfer of miRNA or even DNA inside T-cell exosomes is a molecular mechanism that will be analyzed.

Keywords: exosomes; extracellular vesicles; immune regulation; autoimmunity.

 

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Homeostasis and Self-Tolerance in the Immune System: Turning Lymphocytes off

Van Parijs, L., & Abbas, A. K. (1998). Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science280(5361), 243-248.

Abstract

The immune system responds in a regulated fashion to microbes and eliminates them, but it does not respond to self-antigens. Several regulatory mechanisms function to terminate responses to foreign antigens, returning the immune system to a basal state after the antigen has been cleared, and to maintain unresponsiveness, or tolerance, to self-antigens. Here, recent advances in understanding of the molecular bases and physiologic roles of the mechanisms of immune homeostasis are examined.

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