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

https://doi.org/10.1080/1744666X.2019.1596800

Comment; Excellent overview of the evolving state of understanding of Mast Cell Disorders as well as lists of the Symptoms divided by Organ Systems, Co-Morbid conditions involving mast cells, Triggers of Mast Cells with and without full degranulation, Mediators contained in mast cells, Diagnostic Criteria for mast cell disorders and most importantly, treatment options.

Theoharis C. Theoharides, Irene Tsilioni & Huali Ren

Expert Review of Clinical Immunology, DOI: 10.1080/1744666X.2019.1596800

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 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 is very confusing. As a result, specialists have recently excluded neuropsychiatric symptoms, and made the diagnostic criteria stricter, at the expense of 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, myalgic encephalomyelitis/chronic fatigue syndrome, mycotoxins, release, secretion, tetramethoxyluteolin, tryptase.

Expert commentary: Conditions associated with elevated serum or urine levels of any mast cell mediator, in the absence of any comorbidity that could otherwise explain such increases, should be considered mast cell activation disorders, or better yet be collectively termed “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.

Common Symptoms in Patients With Mast Cell Mediator Disorders   

• Cardiovascular: chest pain, hypotension, hypotensive syncope, tachycardia

• Dermatologic: angioedema, dermatographism, flushing, pruritus, urticaria pigmentosa

• Gastrointestinal: abdominal crumping/pain, bloating, diarrhea, esophagitis, nausea, vomiting 

• Musculoskeletal: bone/muscle pain, degenerative disc disease, osteoporosis/ osteopenia

• Naso-ocular: nasal congestion, pruritus, tearing

• Neurologic: headache, memory and concentration difficulties (brain fog), paresthesias, peripheral neuropathy 

• Respiratory: hoarseness, sore throat, stridor, throat swelling, wheezing

• Systemic: anaphylaxis, fatigue

Conditions Often Comorbid With Mast Cell Diseases

• Chronic inflammatory response syndrome (CIRS)

• Fibromyalgia syndrome (FMS)

• Ehlers-Danlos Syndrome (EDS)

• Gulf War Illness (GWI)

• Interstitial cystitis/bladder pain syndrome (IC/BPS)

• Irritable bowel syndrome (IBS)

• Kounis syndrome

• Multiple chemical sensitivity syndrome (MCSS)

• Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

• Post-Lyme syndrome

• Postural orthostatic tachycardia syndrome (POTS)

• Post-traumatic stress disorder (PTSD)

Cell Triggers of Mast Cell Degranulation

Acetylcholine

Complement fragments 

– C3α, C4α, C5α

Drugs

– Local anesthetics

– Lactam antibiotics

– Neuromuscular junction blockers

– Vancomycin

IgE

IgG1

IgG4

Lysophosphatidylserine

Peptides

– Adrenomedullin

– CGRP

– Endorphin

– Endothelin

– Eosinophil granule proteins

– Hemokinin-1

– Leptin

– Mastoparan

– Neurotensin

– NGF

– PTH

– Somatostatin

– SP

– Thrombin

– VIP

Physical conditions

– Cold

– Heat

– Pressure

– Stress

– Vibration

Triggers of Mast Cells Without Degranulation

Triggers	Mediator
Peptides
CRH	VEGF
SCF	IL-6
Cytokines
IL-1β	IL-6
IL-33	IL-31
IL-33	CX CL8 (IL-8)
IL-33 + SP	TNF, VEGF
Heavy metals
Aluminum
Cadmium
Mercury
Herbicides
Atrazine
Glyphosate
Pathogens
Borrelia (Lyme disease) *	TNF
LPS	TNF
Poly (I:C) (viruses)	IL-6, TNF
Sporothrix (mold)*	IL-6, TNF
*Mycotoxins

Mediators found in Mast Cells

Prestored	De novo synthesized
Biogenic Amines	Chemokines
Dopamine	IL-8 (CXCL8), MCP-1 (CCL2), MCP-3 (CCL7),
Histamine	MCP-4, RANTES (CCL5), Eotaxin (CCL11)
5-Hydroxytryptamine (5-HT, serotonin)	Cytokines
Polyamines	IL-1β, IL-4, IL-5, IL-6, IL-15, IL-17, IL-31, IL-33, TNF
Spermidine, spermine	Growth Factors
Cytokines	SCF, β-FGF, neurotrophin 3, NGF,
TNF	PDGF, TGFβ, VEGF
Enzymes	Nitric oxide
Arylsulfatases A	Phospholipid metabolites
Beta-hexosaminidase	Leukotriene B4
Beta-glucuronidase	Leukotriene C4
Beta-glucosaminidase	Platelet activating factor
Beta-D-galactosidase	Prostaglandin D2
Carboxypeptidase A
Cathepsins B, C, D, E, L
Chymase
Garnzyme B
Kinogenases
Phospholipases
Renin
Tryptase
Metalloproteinases
(CPA3, MMP9, ADAMTSS)
Growth factors
FGF
NGF
SCF
TGFβ
VEGF
Peptides
ACTH
Angiogenin
Angiopoietin
Calcitonin gene-related peptide
Corticotropin-releasing hormone
Endorphins
Endothelin
Hemokinin-1
Kinins (bradykinin)
Leptin
Melatonin
Neurotensin
RANKL
Somatostatin
Substance P
Urocortin
Vasoactive intestinal peptide
Proteoglycans
Chondroitin sulfate
Heparan sulfate
Heparin
Hyaluronic acid
Serglin

Diagnostic Criteria for Systemic Mastocytosis

Major criterion

a. Multifocal, dense infiltrates of mast cells (≥ 15 mast cells in aggregates) detected in intramedullary biopsy sections and/or extramedullary organ(s).

Minor criteria

a. In intramedullary biopsy sections or other extramedullary ones >25% of the mast cells in the infiltrate are spindle shaped or have atypical morphology, or of all mast cells in bone marrow aspirate smears >25% are immature or atypical

b. Gain of function point mutation of KIT at codon 816 (usually KIT D816V) in bone marrow, blood or other extracutaneous organ

c. Aberrant immunophenotype of mast cells of CD2 and/or CD25 in bone marrow, blood or other extracutaneous organ (in addition to normal mast cell markers)

d. Persistently elevated baseline serum total tryptase (>20 ng/ml).

Treatment Approach for Mast Cell Mediator Disorders

1. Antihistamines (cetirizine, diphenhydramine, hydroxyzine)

2. Antihistamines with anti-eosinophilic action (ketotifen, rupatadine)

3. Antihistamine with anti-serotonin action (cyproheptadine)

4. Tricyclic antidepressants with combined antihistamine action (doxepin)

5. Flavonoids (luteolin, quercetin of high purity and increased absorption)

6. Antileukotrienes (montelukast)

7. Cromolyn sodium

8. Steroids (methylprednisolone)

9. Epinephrine (EpiPen, AnaPen)

10. Anti-IgE (omalizumab)

11. TK inhibitor (imatinib)

12. Kinase inhibitors for mast cells expressing mutant KIT (mitostaurine, avapritinib)

*Patients with migraine headaches could be helped prophylactically with cyproheptadine or with prochlorperazine, both of which also inhibit human mast cells [285].