Review ArticleMast Cell Activation Disease and Microbiotic Interactions
Introduction
First identified in 1863, mast cells (MCs, from the German mastzellen, or “well-nourished cells,” from rich granular content seen on metachromatic staining) soon were associated with disease in the rare neoplastic skin malady urticaria pigmentosa and then a half-century later with even rarer internal neoplasia, now called systemic mastocytosis (SM).1 MCs crucially effect and regulate adaptive and innate immunity. The identification of variably expressed signaling molecules, or “mediators,” in MCs began in 1937 with heparin. More than 200 MC mediators are known (although few specific to MCs), including tryptase, histamine, and certain prostaglandins and leukotrienes.2 MCs secrete prestored mediators and synthesize mediators in response to allergic, microbial, and nonimmune triggers. Widely, sparsely distributed, and of hematopoietic origin, MCs essentially contribute to many processes, including defense, growth, and healing. Among the oldest host defense cells, putatively arising in multicellular eukaryotes some 500 million years ago,3 MCs possess large arrays of potent sensory and response mechanisms, with tissue-specific sensitivities activating numerous intracellular pathways intersecting to modulate the quality and magnitude of response. Best characterized among MC activation mechanisms is antigenic cross-linking of immunoglobulin (Ig) E bound to MC-surface high-affinity IgE receptor (FcεRI). MCs also express G-protein–coupled receptors and other IgE-independent recognition sites. Basic insights into MC biology continue emerging, including the recent recognition that serum tryptase reflects more the body’s MC load than activation state.1
Apart from the involvement in allergy, MCs leverage mediators to crucially assist in maintaining integrity and function in all tissues.2 MCs regulate defense by acting as innate immune cells, by interacting with the specific immune system, and by inducing and regulating inflammation.2 MCs orchestrate microbial, toxic, and physical environmental defenses and recruit other immune cells to injury sites.2 MCs regulate homeostasis, too, contributing crucially to tissue remodeling, including wound healing.2 MCs promote homeostasis by degrading endogenous and bacterial toxins.2 MCs release mediators via classic degranulation, selective secretion (“piecemeal” or “differential” degranulation), and transgranulation.4, 5 Evolutionary success of these mechanisms is due to fine regulation, inferring potential for multisystem havoc from dysregulated MCs.
Classic thought attributed much of allergy to aberrant MC reactivity, while constitutive activation drove MC neoplasia (cutaneous mastocytosis [CM], SM, and rare solid MC tumors). We now understand that frankly malignant MC proliferation drives stark MC accumulation in aggressive forms of mastocytosis, whereas antiapoptosis drives modest accumulations seen in more common, indolent forms of mastocytosis.1 Speculation about MC disease featuring constitutive activation without neoplasia emerged in 19916; case reports were first published in 2007.7, 8 Crucial insight into the marked clinical heterogeneity of relatively nonproliferative MC activation syndrome (MCAS) came with the discovery of many mutations in MC Kit mRNA in a cohort of patients with MCAS (findings later extended including healthy controls largely absent such mutations).9, 10 Multiple investigators soon reported that most mastocytosis cases, too, harbor multiple mutations across many MC regulatory genes, epigenes, and microRNAs.1
Expressed 10-fold brighter in MCs than any other human cells, transmembrane tyrosine kinase KIT is the dominant MC regulator.2 Binding of stem cell factor to homodimeric KIT conformationally changes the intracellular domains of KIT, effecting autoinhibition at the juxtamembrane domain and activation of kinase domains, consequently promoting MC survival, mediator production and release, and other functions. Thus, varied constitutively activating mutational patterns in MC KIT would be expected to produce varied clinical presentations. KITD816V is consistently found in SM (>90% of cases)2 and likely drives prominent pathologic features, including MC proliferation, aggregation, spindling, tryptase overexpression, and CD25 coexpression.2 However, repeated findings that patients with MCAS harbor multiple mutations in KIT, albeit in no yet-apparent recurrent patterns9, 10 (and almost never including KITD816V), together with similar mutational heterogeneity in KIT and other MC regulatory elements in patients with mastocytosis,11 align with observations of marked clinical heterogeneity in patients with MCAS and mastocytosis. Although MCAS appears usually clonal in the research laboratory, most commercial laboratories today assess MC clonality only by KIT mutation analysis at codon 816 (via polymerase chain reaction) or by MC CD25 or CD2 expression (by flow cytometry). As these signatures appear rare in MCAS, diagnosis presently rests on finding elevated MC mediator levels and excluding differential diagnoses.
Like most neoplasms, mastocytosis usually stems from somatic mutations; germ line mutations are rare.11 MCAS appears similar.11, 12 Yet, a familial predisposition for MC activation disease (MCAD) has been demonstrated.11, 13 Complexity multiplies on recognition that different affected members of an affected kindred usually bear disparate presentations and MC mutational profiles. Perhaps inheritable epigenetic mutations create genetic fragility states susceptible to specific stressors, inducing specific (and/or random?) stem cell or progenitor mutations principally operant in MCs. Evidence for epigenetic pathogenicity in MCAD is emerging; patients with MCAD bear abnormal epigenomes.11, 12, 14 However, lifestyle-influenced factors, such as diet; alcohol use; and, yes, microbiota,15, 16 may influence MCAD phenotype.
In 2010, the recognition that all MC disease manifests aberrant MC activation engendered new top-level designation of MCAD encompassing all pathologic MC states.1 Rare, proliferative CM and SM compose one element of MCAD, while forms of (relatively nonproliferative) MCAS compose other elements of MCAD. Except in aggressive mastocytoses, the distinctions between MCAS and mastocytosis are principally pathologic (eg, significantly elevated serum tryptase and gross MC proliferation present in mastocytosis but absent in MCAS) and appear clinically inconsequential. Two proposals, of varying strengths, for MCAS diagnostic criteria have emerged (Figure 1).17 The diagnosis and treatment of MCAD are complex; interested readers should consult recent reviews.1, 2, 17
Truly reactive/secondary MCAS is increasingly difficult to identify given rising recognition that diseases previously thought to provoke MC activation may actually be sparked by primary MCAS. It seems likely that given presentations of mastocytosis and primary MCAS result from specific mutation sets driving specific patterns of aberrant constitutive MC activation as well as aberrant MC reactivity, the effects of which may be direct and/or indirect as well as local and/or remote, ultimately affecting normal cells, other abnormal MCs, and other abnormal cells potentially harboring similar mutations. Effects in these other cells may “rebound,” too, to further activate the instigating abnormal MCs. Presently, commercial probing for MC mutations is very limited (essentially only KITD816V). Although some subclassify MCAS as primary (clonal), secondary (reactive), and idiopathic1 (or nonclonal18), perhaps subclassification as clonal and undetermined clonality is more accurate. When readily commercially available, whole genome/exome sequencing of isolated MCs may prove instructive.
Thus, after 150 years of orthodoxy that MC disease is principally allergic phenomena and neoplastic mastocytosis, it is now evident that such entities merely “cap” an MCAD “iceberg” (Figure 2), with non-neoplastic MCAS composing the largely unrecognized bulk of MCAD for reasons reviewed subsequently.
As recognition of MCAD/MCAS has expanded, so, too, has recognition of the importance of human microbiota to health and disease, including crucial interactions with MCs. Below we review highlights of MCAD and current thoughts regarding microbiotic interactions with MCs and MCAD.
Section snippets
Materials and Methods
A search for all studies on interactions between mast cells, mast cell activation disease, and microbiota published on pubmed.gov or scholar.google.com between 1960 and 2015 was conducted using the search terms mast cell, mastocyte, mastocytosis, mast cell activation, mast cell activation disease, mast cell activation syndrome, microbiome, microbiota. A manual review of the references from identified studies was also conducted. Studies were excluded if they were not accessible electronically or
Results
A total of 140 studies were identified and included in the present review. Studies not specifically cited were excluded due to redundancy of results and citation limits.
Conclusions
Conveying a new understanding that all MC disease features inappropriate MC activation, the new top-level designation MCAD encompasses various types of rare mastocytosis and likely prevalent MCAS. The apparent uniqueness in each patient with MCAD of constitutively activating mutational patterns in KIT and other MC regulatory elements likely is the principal driver of not only the specific clinical presentation, and therapeutic response profile, in each patient but also the great heterogeneity
Conflicts of Interest
The authors have indicated that they have no conflicts of interest with regard to the content of this article.
References (86)
- et al.
A novel cell-to-cell interaction between mast cells and other cell types
Exp Cell Res
(1983) - et al.
Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis
Blood
(2007) - et al.
Ethanol induces apoptosis in human mast cells
Life Sci
(2009) - et al.
Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes
Clin Ther
(2013) - et al.
Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors
Blood
(2009) - et al.
The Mastocytosis Society survey on mast cell disorders: patient experiences and perceptions
J Allergy Clin Immunol Pract
(2014) - et al.
Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients
J Allergy Clin Immunol
(2009) - et al.
Diagnostic criteria and classification of mastocytosis: a consensus proposal
Leuk Res
(2001) Epidemiology, prognosis, and risk factors in mastocytosis
Immunol Allergy Clin North Am
(2014)- et al.
n-Butyrate inhibits Jun NH(2)-terminal kinase activation and cytokine transcription in mast cells
Biochem Biophys Res Commun
(2006)
Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine
Gastroenterology
Urinary excretion of N-methylhistamine as a marker of disease activity in inflammatory bowel disease
Am J Gastroenterol
Impairment of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents
Am J Pathol
Effects of ethanol, acetaldehyde, and acetic acid on histamine secretion in guinea pig lung mast cells
Alcohol
Adverse reactions to alcohol and alcoholic beverages
Ann Allergy Asthma Immunol
Antibiotics, microbiota, and immune defense
Trends Immunol
Intestinal microbial diversity during early-life colonization shapes long-term IgE levels
Cell Host Microbe
Mast cells and cancer – no longer just basic science
Crit Rev Oncol Hematol
How I treat patients with advanced systemic mastocytosis
Blood
The absence of a microbiota enhances TSLP expression in mice with defective skin barrier but does not affect the severity of their allergic inflammation
J Invest Dermatol
KIT-D816V-independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib
Blood
The presentation, diagnosis and treatment of mast cell activation syndrome
Curr Allergy Clin Immunol
Presentation, diagnosis, and management of mast cell activation syndrome
The mast cell: an evolutionary perspective
Biol Rev Camb Philos Soc
Differential release of mast cell mediators and the pathogenesis of inflammation
Immunol Rev
Biochemical diagnosis of systemic mast cell disorders
J Invest Dermatol
Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: Monoclonal mast cell activation syndrome
Int Arch Allergy Immunol
Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder
Scand J Gastroenterol
Comparative analysis of mutation of tyrosine kinase Kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects
Immunogenetics
The genetic basis of mast cell activation disease—looking through a glass darkly
Crit Rev Oncol Hematol
Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics
Immunol
Familial occurrence of systemic mast cell activation disease
PLoS One
Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease
Immunogenetics
Commensal bacteria directly suppress in vitro degranulation of mast cells in a MyD88-independent manner
Biosci Biotechnol Biochem
A concise, practical guide to diagnostic assessment for mast cell activation disease
World J Hematol
Mastocytosis—An update
J Dtsch Dermatol Ges
Epidemiology of systemic mastocytosis in Denmark
Br J Haematol
Case-control cohort study of patients׳ perceptions of disability in mastocytosis
PLoS One
Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature
Curr Opin Hematol
Host-bacterial mutualism in the human intestine
Science
Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites
Proc Natl Acad Sci U S A
Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options
J Physiol Pharmacol
Activated mast cells infiltrate in close proximity to enteric nerves in diarrhea-predominant irritable bowel syndrome
J Korean Med Sci
Cited by (17)
Bidirectional communication between mast cells and the gut-brain axis in neurodegenerative diseases: Avenues for therapeutic intervention
2021, Brain Research BulletinCitation Excerpt :The intestinal mucosa contains numerous MCs, which serve both defense and immune-regulatory functions. The dysregulation of MC activation could affect the homeostasis of gut microbiota, which could in turn promote inflammation in the mucosa of patients with gastrointestinal (GI) complications and autoimmune diseases (Wu and Wu, 2012; Vieira et al., 2014; Mukhtar et al., 2019; Afrin and Khoruts, 2015). The GBA mainly consists of five signaling pathways: neural, immune, enteroendocrine, serotonin, and tryptophan (Fig. 1).
Alcoholic liver disease and mast cells: What's your gut got to do with it?
2019, Liver ResearchCitation Excerpt :As stated previously, MCs play a role in innate and acquired immunity, autoimmunity, as well as a modulator in bacterial infections.46–48 There are a range of signals to which MCs respond and react, which include signals from the body's microbiota.49 Alcohol suppresses one of the intestine's main lines of defense against harmful bacteria, such as Paneth cells, which secrete antibacterial compounds including α-defensins, lysozyme, secretory phospholipase A2 (sPLA2), angiogenin-4 (Ang4), RegIIIγ, and α1-antitrypsin.50
Immunoregulatory effect of mast cells influenced by microbes in neurodegenerative diseases
2017, Brain, Behavior, and ImmunityCitation Excerpt :Mycoplasma pneumoniae and Streptococcus pneumoniae induce MC degranulation, whereas probiotics inhibit degranulation in human and mouse MCs. In mice, Escherichia coli attenuates serotonin and β-hexosaminidase secretion through blocking of synaptosomal-associated protein 23 phosphorylation and soluble N-ethyl maleimide-sensitive fusion protein attachment protein receptor complex assembly, both of which are required for MC granule exocytosis (Afrin and Khoruts, 2015). MCs have an important role in disruption of the gut-blood barrier.
Skin microbiome and mast cells
2017, Translational ResearchCitation Excerpt :Under this paradigm, the role of MCs on the frontline of defense against pathogens suggests that they may also play an important role in fostering the host-microbiome relationship.3 Although roles of MCs in the host-microbiome relationship have been well described, mainly in gut microbiomes,10-13 in this review we focus on the role of MCs in the skin and microbiomes of the skin, which have unique and different characteristics and functions from gut microbiomes.14,15 MC phenotypes are different, not only in different species, but also in different organs or tissues within the same species.
Some Reflections on the Microbiome and Obesity
2015, Clinical Therapeutics