Elsevier

Clinical Therapeutics

Volume 37, Issue 5, 1 May 2015, Pages 941-953
Clinical Therapeutics

Review Article
Mast Cell Activation Disease and Microbiotic Interactions

https://doi.org/10.1016/j.clinthera.2015.02.008Get rights and content

Abstract

Purpose

This article reviews the diagnostically challenging presentation of mast cell activation disease (MCAD) and current thoughts regarding interactions between microbiota and MCs.

Methods

A search for all studies on interactions between mast cells, mast cell activation disease, and microbiota published on pubmed.gov and 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 by interlibrary loan.

Findings

Research increasingly is revealing essential involvement of MCs in normal human biology and in human disease. Via many methods, normal MCs—present sparsely in every tissue—sense their environment and reactively exert influences that, directly and indirectly, locally and remotely, improve health. The dysfunctional MCs of the “iceberg” of MCAD, on the other hand, sense abnormally, react abnormally, activate constitutively, and sometimes (in mastocytosis, the “tip” of the MCAD iceberg) even proliferate neoplastically. MCAD causes chronic multisystem illness generally, but not necessarily, of an inflammatory ± allergic theme and with great variability in behavior among patients and within any patient over time. Furthermore, the range of signals to which MCs respond and react include signals from the body’s microbiota, and regardless of whether an MCAD patient has clonal mastocytosis or the bulk of the iceberg now known as MC activation syndrome (also suspected to be clonal but without significant MC proliferation), dysfunctional MCs interact as dysfunctionally with those microbiota as they interact with other human tissues, potentially leading to many adverse consequences.

Implications

Interactions between microbiota and MCs are complex at baseline. The potential for both pathology and benefit may be amplified when compositionally variant microbiota interact with aberrant MCs in various types of MCAD. More research is needed to better understand and leverage these 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.

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