Converging lines of evidence support MCA as a plausible unifying explanation for a host of previously unexplained illnesses, including CI.
Mast Cell Activation Syndrome: Mast Cells (MCs) are components of the ancient cellular, or intrinsic, immune system which evolved over 500 million years ago, predating adaptive immunity and immunoglobulins [19]. For a variety of reasons, including the fact that MCs do not circulate in the blood in significant numbers, they have been difficult to study. MCs are present—generally in low numbers and sparsely distributed—typically at the interfaces between our tissues and the external environment, including the skin, and the respiratory, gastrointestinal, and genitourinary tracts, as well as in the walls of all vessels—precisely where one would expect a principal host defense effector cell to be sited. These tissue-dwelling cells originate in the bone marrow and then migrate via the bloodstream to reach their target tissues, where they continue to mature and reside for an average of 2-4 years, with little mobility or chemotaxis compared to other leukocytes [20].
Once MCs reach their destinations, they continue to differentiate in ways that are specific to the tissue and the intrinsic and extrinsic environment, including any chemicals, foods, and drugs encountered. Once triggered, MCs can release more than 1000 distinct mediators [21] resulting in inflammation, allergy-like symptoms, or altered tissue growth and development. A real-time video shows how quickly mast cells degranulate and release mediators (Video S1). Notably, too, these MC mediators can continue to provoke the very MCs that produced them, resulting in a vicious, self-stimulating feedback loop. For example, the presence of activating histamine H1 and H2 receptors on the surface of the MC provides at least part of the rationale for use of both H1 and H2 blockers in MCAS patients, most of whom gain distinct benefits from each of these therapeutic classes [22-25].
Fully differentiated MCs bear a wealth of specific cell-surface receptors (more than 250 [21]), e.g., the KIT transmembrane tyrosine kinase receptor which is the principal MC regulatory element, and the FcεRI receptor for IgE-class immunoglobulin [26, 27]. Although IgE antibodies can stimulate FcεRI once they bind antigen [28], MCs respond to a wide variety of environmental cues that can trigger them to release pre-stored and/or newly synthesized mediators. The final stages of MC differentiation occur in the tissues in which they reside, with different types of MCs present in different tissues. MCs respond by releasing mediators particular to the insult and its anatomic location. Upon triggering, whether by docking of a triggering substance with a MC-surface receptor, or by action of a triggering force (e.g., temperature change, pressure change, specific wavelength exposure) on a force-sensing element of the MC, MCs can release mediators in a fraction of a second [13, 14]. In contrast, neutrophils require minutes, and lymphocytes hours, to activate [29,14]. MCs’ ability to respond precisely and rapidly to a vast range of environmental triggers suggests they may possess unique epigenetic and transcriptional capabilities that enable them to adapt rapidly to environmental challenges [30].
Although the proposed diagnostic criteria for MCAS [31- 34, 17] differ in some specific respects, MCAS diagnosis typically rests upon: 1) chronic and/or recurrent symptoms consistent with aberrant MC mediator release; 2) the exclusion of other conditions that might better explain the patient’s symptoms; and 3) laboratory evidence of MC activation. Generally accepted laboratory markers of MCAS include elevated levels (in blood or urine, as appropriate for each metabolite) of tryptase or a few other mediators relatively specific to the MC (e.g., heparin, histamine and its principal immediate urinary metabolite N-methylhistamine, prostaglandin D2 and its immediate metabolite 11-beta-prostaglandin-F2-alpha, chromogranin A, and leukotriene E4). Clinical experience to date has shown that most patients diagnosed by these criteria respond to MC-targeted treatments. One of the most specific laboratory tests for MC activation is serum tryptase, although this typically is elevated, and only mildly, in about 9-16% of MCAS patients [34,35]. Further, tryptase is somewhat thermolabile and is constitutively released and thus may not be found elevated in many patients with MC activation [35].
Drugs that inhibit MC degranulation (e.g., cromolyn, ketotifen) or block mediator effects (e.g., well-tolerated combinations of histamine type H1 and H2 receptor antagonists administered simultaneously, typically twice daily) often help reduce symptoms. At present, it is not possible to predict which drugs are most likely to help which symptoms in which MCAS patients, thereby requiring both patient and physician to practice great patience, persistence, and a methodical approach for empirically testing the fortunately large array of treatments that have been already found helpful for some MCAS patients. Treatment is palliative, not curative [31-34, 36]. For example, topical diphenhydramine or cromolyn may be helpful for female MCAS patients suffering chronic dyspareunia, vaginitis, or dysfunctional uterine bleeding consequential to their MCA [37]. Although severe morbidity and early mortality may occur, limited data suggest most MCAS patients can expect a normal lifespan.
Chemical Intolerance: Characteristically, CI individuals report multi-system symptoms and new-onset intolerances triggered by structurally unrelated chemicals, foods, and drugs—substances that these individuals say never bothered them previously and do not other most people. Many patients attribute onset of their illness and intolerances to a well-defined exposure event, such as the Gulf War, disasters like the World Trade Center, indoor air contaminants, or flood or water-damaged buildings resulting in mold and bacterial growth [38]. Different family members or co-workers who become ill frequently exhibit different manifestations, thus confounding physicians and public health investigators [6].
The steps, or process, leading to CI differ from those preceeding infectious diseases or classical toxicity. Individuals affected by a particular infectious agent or toxicant generally share recognizable constellations of symptoms. This is not the case for CI patients, which explains, in part, why this condition has defied numerous attempts to establish a consensus case definition. Indeed, it appears we may be dealing with a new mechanism and category of disease.
Accumulating worldwide reports by patients, physicians, and researchers point to a two-step process [39-43]. Miller [6, 44,45] proposed Toxicant-Induced Loss of Tolerance (TILT). This term captures the wide variety of multi-system symptoms and intolerances associated with the condition. TILT develops in two stages: Initiation by a major exposure event, or a series of exposures (Stage I, Initiation), followed by triggering of multisystem symptoms in response to everyday chemical inhalants, foods/food additives, and/or medications/drugs (Stage II, Triggering), often at much lower exposure levels than those found in classical toxicity. Initiating exposures include chemical spills, pesticides, cleaning agents, solvents, combustion products, medications and medical devices, as well as indoor air contaminants associated with materials used in construction or remodeling [6, 44 - 46] (see Figures 1 and 2).
The reigning paradigms in allergy, immunology, and occupational/environmental medicine have not widely embraced MCAS or TILT, or agreed upon case definitions for them [47-49]. Although most doctors have some awareness of CI, few are aware of MCAS at all. It follows that the few doctors who evaluate TILT patients are not testing for MCAS. Based upon our prior work, it appears that MCAS and TILT may be part of the same “iceberg,” both submerged below a waterline of clinical recognizability [7].
Prevalence of CI and MCAS: By one estimate, 10-17% of the German population may have MCAS [50]. CI prevalence estimates range from 8-33% in population-based surveys [51-53]. Hojo et al. [2] in Japan and Steinemann [1] in the U.S. each conducted surveys of chemical intolerance in their respective countries on two separate occasions, a decade apart. According to their research, in just 10 years, substantial increases in CI occurred in both countries.
The Quick Environmental Exposure and Sensitivity Inventory (QEESI), developed by the senior author of this paper, is considered the reference standard for assessing CI and has become a surrogate case definition used by researchers in more than 15 countries in approximately 80 peer-reviewed studies [1,39,41-43,54]. This validated, self-administrable, 50-item questionnaire is used for: (1) Research—to characterize and compare study populations, and to select subjects and controls; (2) Clinical Evaluations—to obtain profiles of patients’ self-reported symptoms and intolerances; the QEESI can be used at intervals to follow symptoms over time or to document responses to treatments or exposure avoidance; and (3) Workplace, Community, or Epidemiological Investigations—to identify those who may be more chemically susceptible and/or measure changes in symptoms and intolerances in exposed versus control groups.
The QEESI has four scales: Symptom Severity, Chemical Intolerances, Other Intolerances, and Life Impact. Each scale item is scored from 0 to 10 (0 = “not a problem” to 10 = “severe or disabling problem”). There is also a 10-item Masking Index which gauges ongoing exposures (such as to caffeine or tobacco) that can reduce individuals’ awareness of their intolerances [55].
Connecting MCAS and TILT: Our understanding of the possible role for MCs in TILT is recent. Both patients with MCAS and those with TILT commonly report symptoms in multiple organ systems and often several systems simultaneously. MCs produce and release scores of chemical signals (generically termed “mediators”) that can affect organs, tissues, and systems throughout the body.
TILT encompasses exposures that may have initiated illness and exposures that continue to trigger symptoms. However, until now, TILT has lacked a clear biological mechanism, which MCAS may provide. An understanding of TILT initiation and triggering offers strategies for prevention and intervention, many of which appear applicable to MCAS. Knowledge of the MCAS mechanism has the potential to inform new medical interventions and treatments for TILT. Failure to eliminate or reduce initiators such as pesticides or mold can result in chronic, even lifelong, illness in susceptible people. This suggests persistent MC activation and degranulation. The symptoms and findings in TILT patients may be best understood in the context of MCs and the mediators they release.
Together, MCAS and TILT satisfy the principle of parsimony (i.e., Occam’s Razor). Table 2 summarizes prominent features of each. TILT serves as an umbrella category for these exposure-driven illnesses, while MCAS offers an umbrella mechanism uniting illnesses driven by MC activation.
Table 1. Representative Examples of Key Mast Cell Mediators
Pro-inflammatory cytokines
|
IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL-16, IL-18, IL-21, IL-23, IL-25, IL-31, IL-33, IFN-γ, TNF-α
|
|
Chemokines
|
MCP-1, IL-8, RANTES, eotaxin, leukotrienes B4, C4, D4, E4 (SRS-A), CCL2, CCL3, CCL4, CCL5, CCL11, CCL19, CCL20, CCL21, CXCL8, CXCL10, XCL-1
|
|
Proteases
|
Tryptase, chymase, angiotensin converting enzyme (ACE), ACE2, carboxypeptidase, cathepsin G, cysteinyl cathepsins, metalloproteinases
|
|
Growth factors
|
IL-3, GM-CSF, bFGF, VEGF, TGF-β, PDGF, EGF, NGF, SCF, angiopoietin
|
Vascular permeability, vasodilatation
|
Histamine, 5-hydroxytryptamine, tryptase, NO, VLA4
|
Platelet aggregation and thrombosis:
|
PAF, thromboxane
|
|
Neurohormones
|
Adrenocorticotrophin (ACTH), CRH, endorphins, HKA, leptin, melatonin, NT, SP, VIP
|
|
Heparin proteoglycan
|
Chondroitin sulfate proteoglycan
|
Superoxide dismutase
|
Acid hydrolases
|
Glucuronidase, galactosidase, hexosaminidase, peroxidase
|
Arylsulphatase A
|
Prostaglandin D2, thromboxane
|
Serotonin, dopamine
|
Antimicrobial agents
|
IFN-α, IFN-β, IFN-γ, human cathelicidin (LL-37)
|
TSLP
|
Table 2. Features of TILT and MCAS Compared
|
TILT
|
MCAS
|
Multisystem symptoms
|
√ Driven by high level or repeated low level exposures
|
√ Lifelong susceptibility exacerbated by exposure
|
Age at diagnosis
|
√ Exposure driven, wide range
|
√ Wide range (mean 49y/o, 16-92)
|
Age symptom onset
|
√ Wide range
|
√ Wide range
|
Brain fog
|
√
|
√
|
Diverse initiators and triggers
|
√ Emphasis on synthetic chemicals
|
√
|
Female predominance
|
√
|
√
|
Parallels to addiction
|
Emphasized; chemical, food, and drug addictions common
|
Possible, but unknown
|
Withdrawal symptoms
|
Reported for many chemicals, foods, and drugs
|
Unknown
|
Avoidance of major triggers (abdiction)
|
√
|
√
|
Biomarkers/lab tests
|
None diagnostic
|
Few (PgD2, heparin, histamine); unstable; special handling required
|
Brain imaging
|
Several studies; mixed results and interpretations
|
Possible, but unknown
|
Symptoms and severity vary greatly over time in an affected individual
|
√
|
√
|
Induction (that is, sensitization) by a wide range of environmental agents
|
√
|
√
|
Subsequent triggering by lower levels of exposure than those involved in initial induction of the illness
|
√
|
Possible, but unknown
|
Concomitant chemical, food, and drug intolerances
|
√ Multiple intolerances to chemicals, foods, and drugs
|
√ More emphasis on drugs
|
“Spreading” of sensitivity to other, often chemically dissimilar substances; each substance may trigger a different constellation of symptoms
|
√
|
Possible, but unknown
|
Adaptation (masking), that is, acclimatization to environmental incitants, both chemical and food, with continued exposure; loss of this tolerance with removal of the incitant(s); and augmented response with reexposure after an appropriate interval (for example, 4 to 7 days)
|
√
|
Possible, but unknown
|
Medical evaluation and treatment
|
Detailed exposure history to identify chemical, food, and drug initiators and triggers. Avoidance of problem exposures and synthetic products. Organic foods, clean air (HEPA and charcoal filters), clean water (filters), natural medicines/supplements, and consumer products.
Rotary/elimination diet
|
Avoidance of anything provoking symptoms including “stress.” Use of drugs to stabilize mast cells and prevent mediator release and/or block mediator effects.
|
An apparent threshold effect sometimes referred to as the patient’s “total load”
|
√
|
Possible, but unknown
|
MCAS, TILT, and the Nervous System: Our proposal that MCA could be the biological mechanism for TILT arises out of recent recognition that the realm of MC disease extends beyond clinically recognized allergic phenomena (e.g., allergy, anaphylaxis, urticaria, angioedema, atopic dermatitis or eczema) and is apart from the rare MC malignancy, mastocytosis. Mastocytosis, first described in cutaneous form in the latter part of the 19th century and then in systemic form in the mid-20th century, manifests as chronic MC activation together with grossly excessive (indeed, frankly neoplastic) proliferation of MCs. Only recently (1980s) have researchers hypothesized the existence of MCAS [56,57]. In 2007, the first MCAS reports appeared, describing patients with heightened release of MC mediators, yet without the excess numbers of MCs that characterize mastocytosis. Many of these mediators have potent but short-lived effects. They are released locally in sensitized tissues and are exquisitely thermolabile, posing major challenges for clinical measurement. This menagerie of MC mediators produces multisystem inflammation at minimum, and not uncommonly allergic-type phenomena, and sometimes aberrancies in growth and development (typically benign) in virtually any tissue.
As immunologic "first responders" in the central nervous system, activated MCs can initiate, amplify, and prolong wide-ranging neuroimmune responses [58]. Several investigators have pointed to neurogenic inflammation as a mechanism for CI [59-61]. We suggest that rather than being the mechanism for CI, neuro-inflammation may be the result of mast cell activation and mediator release initiated by xenobiotic/chemical exposures. MCs can affect neuronal function from afar via their released mediators which bind with specific neuronal receptors [62]. Also, MCs physically abut neurons in many tissues, and wherever such dyads are present, there is constant mediator “cross-talk” between the two cells. Thus, MC activation can provoke nearby neurons, inducing their associated symptoms; similarly, neurons can provoke nearby MCs, inducing their associated symptoms.
Correspondingly, quieting of MCs can help reduce neuronal activation, and, again, vice versa. For a comprehensive review of mast cells, mediators, and their effects on the central nervous system, see Song et al. [63]. Table 1 lists mast cell mediators involved in neuroinflammation (after Theoharides et al. [20]; also, [64-66]). This is not an exhaustive list. Many investigators have documented neuroinflammation and inflammatory mediators in chemical intolerance [61, 67-69].
With permission from Theoharides TC et al., Immunol Rev 2007, Theoharides TC, Exp Dermatol 2017, Theoharides TC, Biofactors 2020. Abbreviations: bFGF: basic fibroblast growth factor; CCL: chemokine (C-C motif) ligand; CRH: corticotropin releasing hormone; CXCL: chemokine (C-X-C motif) ligand; EGF: epidermal growth factor; GM-CSF: granulocyte-macrophage colony stimulating factor; HKA: hemokinin-A; IFN: interferon; IL: interleukin; MCP: mast cell protease; NGF: nerve growth factor; NO: nitrogen oxide; NT: neurotensin; PAF: platelet activating factor; PDGF: platelet-derived growth factor; RANTES: Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted; SCF: stem cell factor; SP: Substance P; SRS-A: slow releasing substance of anaphylaxis; TGF: transforming growth factor; TNF: tumor necrosis factor; TSLP: thymic stromal lymphopoietin; VEGF: vascular endothelial growth factor; VIP: vasoactive intestinal peptide; VLA: very late antigen.
Historically, physicians have struggled to differentiate between complex, multisystem illnesses and psychiatric disorders, particularly when symptoms involve cognition and mood [70]. Before biological mechanisms are established, there is an initial tendency to attribute complex and unfamiliar conditions like TILT and MCAS to stress and/or psychogenic causes. Unaware of MCAS, some physicians may mistakenly diagnose psychosomatic disorders or even Munchausen syndrome (or, in children, Munchausen syndrome by proxy) in these patients, with adverse consequences for the patients’ mental health and further delaying accurate diagnosis and effective treatment.
Both MCAS and TILT have prominent neurological features. For example, organophosphate pesticides, which bind irreversibly to cholinergic receptors in the parasympathetic nervous system, appear to be among the most severe and permanently damaging TILT initiators. Correspondingly, organophosphates have been shown to trigger degranulation in human and animal mast cells [71]. The parasympathetic nervous system also modulates MC activity via a cholinergic pathway [72]. MCs play pivotal roles in regulating cerebral blood flow [73], directly affecting brain function. Notably, both MCAS and TILT patients commonly report cognitive difficulties which may be the result of reduced cerebral blood flow due to chemical exposures, such as vehicle exhaust or pesticides [74]. Brain MCs lie close to cerebral blood vessels, nerves, and the meninges, and inhabit the area postrema, choroid plexus, thalamus, hypothalamus, and limbic system, thus affecting memory, mood, and concentration. MCs can migrate between nerve tissue and lymphatics, and appear to contribute to neuroinflammation in many disorders [75-77]. For more information regarding mast cells, see Afrin et al. [78] Molderings et al. [79]; and Moon et al. [80].
Notably, during stress, corticotropin-releasing factor is secreted by the hypothalamus and, together with neurotensin, triggers MCs to release inflammatory and neurotoxic mediators, thereby disrupting the blood-brain barrier and resulting in neuroinflammation [81]. Referring to ADHD, Song et al. [63] cite increasing evidence that MCs are involved in brain inflammation and neuropsychiatric disorders. Selective release of inflammatory mediators by MCs, interacting with glial cells and neurons, may activate the hypothalamic‑pituitary-adrenal axis and disrupt blood‑brain barrier integrity.
This physiology fits the two stages of TILT—initiation and triggering, that is, initiation by a single intense exposure, or repeated lower level exposures (pesticides, implants, drugs, etc.), which immunologically sensitize mast cells in the brain and/or other key sites. Thereafter, both chemically related and chemically unrelated, xenobiotic exposures may readily trigger mediator release by these now “twitchy” mast cells. Anticipated cognitive and mood effects might include: sudden rage (e.g., “road rage”); impulsive, violent, or abusive behaviors; addictive tendencies; mental confusion/fatigue; and/or a sense of depersonalization. MC “twitchiness” renders these cells vulnerable to a host of unrelated exposures that never bothered the person before and do not bother most people. Therefore, it is plausible that MC sensitization and triggering could explain the two stages of TILT.
By the time either MCAS or TILT is suspected, most patients have accumulated numerous diagnoses, each of which may explain a portion of their problems, but none of which account for the full range and duration of their illness. At present, most MCAS cases are classified as "idiopathic" rather than primary (i.e., of proven clonal or autoimmune origin) or secondary (i.e., due to some other inflammatory or neoplastic condition). Published preliminary findings suggest that most “idiopathic” cases likely are clonal and involve varying mutations in at least the transmembrane tyrosine kinase receptor KIT, the dominant mast cell regulatory element, and likely other MC regulatory elements. The widely variable MC mutations and epigenetic changes result in diverse MC mediator expression profiles, which in turn drive diverse clinical presentations [82].
If, in fact, TILT and MCAS are closely related conditions, they should share the same underlying pathophysiology and patients should manifest similar symptoms and intolerances. As a first step in testing this hypothesis, we used the QEESI to explore similarities and differences between TILT and MCAS.