Recent advances in our understanding of mast cell activation – or should it be mast cell mediator disorders?

ABSTRACT

Introduction: An increasing number of patients present with multiple symptoms affecting many organs including the brain due to multiple mediators released by mast cells. These unique tissue immune cells are critical for allergic reactions triggered by immunoglobulin E (IgE), but are also stimulated (not activated) by immune, drug, environmental, food, infectious, and stress triggers, leading to secretion of multiple mediators often without histamine and tryptase. The presentation, diagnosis, and management of the spectrum of mast cell disorders are very confusing. As a result, neuropsychiatric symptoms have been left out, and diagnostic criteria made stricter excluding most patients.

Areas covered: A literature search was performed on papers published between January 1990 and November 2018 using MEDLINE. Terms used were activation, antihistamines, atopy, autism, brain fog, heparin, KIT mutation, IgE, inflammation, IL-6, IL-31, IL-37, luteolin, mast cells, mastocytosis, mediators, mycotoxins, release, secretion, tetramethoxyluteolin, and tryptase.

Expert opinion: Conditions associated with elevated serum or urine levels of any mast cell mediator, in the absence of comorbidities that could explain elevated levels, should be considered ‘Mast Cell Mediator Disorders (MCMD).’ Emphasis should be placed on the identification of unique mast cell mediators, and development of drugs or supplements that inhibit their release.

KEYWORDS:

• Activation
• antihistamines
• autism spectrum disorder
• brain fog
• KIT mutation
• cytokines
• IgE
• inflammation
• IL-6
• IL-37
• luteolin
• mast cells
• mastocytosis
• mediators
• myalgic encephalomyelitis/chronic fatigue syndrome
• mycotoxins
• tetramethoxyluteolin
• tryptase

Article highlights

• The term MCMD should be used when specific criteria are met.

• Tryptase is specific for mast cells and is useful for diagnosis of SM, but is often not secreted and its function is still not known. Measurement of other serum mast cell mediators, especially IL-6 and IL-31, as well as CCL2 and CXCL8, and urine (24 h) histamine metabolites (methyl histamine, MIA), the PGD₂ metabolite (11β-PGF_2α), and LTE₄ should be considered in the absence of any other inflammatory conditions.

• Screening tissue sections for mast cells should combine immunohistochemistry for CD117 (identifies all mast cells) and tryptase (identifies degranulated mast cells).

• Single cell laser microcapture and qRT-PCR should be used to identify mast cell phenotype variability and mediator synthesis/release in situ.

• Special attention should be placed on the timing of measurement of mast cell mediators and patient symptoms as mast cells have been shown to be regulated by a circadian clock.

• There is no curative treatment for MCMDs at the present time. Prevention of stimulation of mast cells and reduction of the effects of their mediators are necessary. Step-wise increase in treatment is recommended as indicated and tolerated.

• Development of effective mast cell inhibitors should be a top priority. Recent promising results from the use of tetramethoxyluteolin and IL-37 should be expanded using appropriate mast cell-targeted formulations.

Declaration of interest

TC Theoharides is on the Scientific Advisory Board of The Mastocytosis Society (TMS, www.tmsforacure.org) TC Theoharides is the Scientific Director of Algonot, LLC, which has developed flavonoid containing dietary supplements. TC Theoharides is the inventor of US patent nos. 6,635,625; 6,641,806; 6,645,482; 6,689,748; 6,984,667; 7,906,153; 8,268,365; 9,050,275; and 9,76,146, as well as EPO 1365777 covering the use of proteoglycans and flavonoids for the treatment of mast cell-related and inflammatory diseases. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Aspects of the work discussed here were supported in part by US National Institutes of Health (NIH) grants NS055681; DK062861; AR47652; NS66205; NS71361, from Pfizer and the National Psoriasis Foundation and from Theta Biomedical Consulting and Development Co., Inc. (Brookline, MA).