Mast Cell Activation: Neurology, Mood, Stress & Mitochondria
Ann Haiden, DO Why Mast Cell Activation? It’s Personal What this looked like… • Some sort of neurologic problem • Atypical neuropathies / paresthesias / gait disturbance • Myopathies / myoclonus • Atypical MS • Some sort of atypical polycythemia • Chronic fatigue syndrome • Some sort of neuro / cardio syncope • Atypical stroke type migraine +/- aura • Stress / “Panic” reaction with anxiety & BP/HR lability • Severe IBS-C with episodes of D • Flushing of unknown reason • Atypical asthma • Sinus inflammation • Multiple chemical sensitivity • Breast implant reaction with severe cellulitis • Non-immune hypothyroidism – post radiation/chemo • Petechiae / scattered telagiectasias – often postprandial • Herpetiform rash • Chondritis (ear cartilage) • Visual blurring and focus problems • Cognitive fatigue • Episodic vertigo • Livido Reticularis with sun exposure • Arthropathy • Osteoporosis • Globus • Medication, food, and supplement sensitivities • Always cold (not remediable with thyroid hormone) • Insomnia What the problem really was
• Gut dysbiosis, SIBO - with multiple pathogens, fungi • Leaky gut • Mast Cell Activation • Neuroinflammation • Intolerance of environmental toxins • Stressed mitochondrial function • Sub-optimal nutrition Objectives
1) Participants will be able to identify neurologic, neurovascular, brain, and stress related symptoms which may potentially be mast cell activation symptoms.
2) Participants will be able to explain how mast cell activation causes mood, neurologic, and stress related symptoms, and the relationship to the gut.
3) Participants will be able to show how the mitochondria are involved with mast cells.
4) Participants will be able to implement a diagnostic plan.
5) Participants will be able to assemble the potential treatment options for mast cell activation syndrome.
Disclosures: None Up to 17% of people in western world estimated to have mast cell activation syndrome.
That doesn’t include those with only histamine intolerance or non-MCAS over active mast cells. Most Common Symptoms
• Fatigue 83% • Dyspnea 53% • Fibromyalgia type pain 75% • GERD 50% • Pre-syncope/syncope 71% • Cognitive Dysfunction 49% • Urticaria or pruritis 63% • Rashes 49% • Headache (incl migraine) 63% • Abdominal pain 48% • Paresthesias 58% • Throat irritation 48% • Nausea or vomiting 57% • Diarrhea or Constipation 39% • Chills 56% • Multiple drug reactions 23% • Migratory edema 56% • Anxiety or panic 16% • Eye Irritation 53%
Afrin,L.B,, et al. Characterization of Mast Cell Activation Syndrome. Am J Med Sci. 2017 Mar; 353(3); 207-215 Brief overview of Mast Cells
• Come from marrow CD34+ /CD117+ cells • Mature at destination • Found in all tissues, especially skin & barrier tissues • Often reside around blood vessels & nerves • Hold & release about 200 mediators • First line responders of immune system • Innate primarily, but also humoral • Mediators recruit other inflammation responders More mast cell facts
• Bind IgE via high-affinity surface receptors for IgE Fc region
• Binding not confined to IgE
• Allergic or non-allergic
• Activated by pro-inflammatory substance P
• Can activate locally or systemically
• Common cause of atopic disorders such as allergic rhinitis and allergic asthma (affects 30% of pop)
Akin, C. Mast Cell Activation Syndromes. J Allergy Clinical Immunology. August 2017; 140(2): 349-355 Mast Cell Disease Spectrum
Systemic Mastocytosis – Kit D816 mutation
Monoclonal Mast Cell Activation Syndrome – Kit mutation but does not meet SM criteria
Primary Mast Cell Activation Syndrome – Often somatic mutations in KIT mRNA (not D816)
Secondary Mast Cell Activation Syndrome – No mutations
Valent, P., Akin, C. Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome. J Allergy Clin Immunol Pract. April 2019; 7(4); 1126-1133 Histamine Intolerance vs. MCAS
• Histamine reactions predominantly • Absence of other MCAS mediator reactions • Does not meet criteria for MCAS • Could be histamine intolerance or MCA • DAO enzyme deficiency (innate or functional) • Histamine N-methyltransferase enzyme deficiency Fatigue, Malaise Constitutional/Skin Pruritis Neurologic Flushing, Plethora, Pallor Asthenia Chronic fatigue syndrome Hyperthermia (subj/object) Hypothermia (subj/object) Headache/Migraine Cold feeling Syncope/presyncope Sweats/diaphoresis Peripheral sensory neuropathy Appetite/weight change Motor neuropathy Chemical sensitivities Cardio-Vascular Paresthesias Physical sensitivities Tics Food, drug intolerances Tremors Urticaria, Rashes Inflammatory demyelinating Syncope/presyncope Polyneuropathy POTS Seizures Hypertension Pseudoseizures Depression Hypotention Dysautonomia Anxiety Palpitations Burning mouth Panic Dysrhythmias Bipolar disorder Chest pain / discomfort ADHD Hemorrhoids PTSD Hemangiomas / telangiectasias Anger Migratory edema Psychoses Coronary atherosclerosis Memory difficulties Peripheral a. atherosclerosis Word-finding difficulties Idiopathic heart failure Mood/Psychiatric Cognitive dysfunction Sleep disruptions
Afrin,L.B., Molderings,G.J. A concise, practical guide to diagnostic assessment of mast cell activation disease. World J Hematol. Feb 6, 2014; 3(1): 1-17 Mast Cell Mediators
• Bioactive amines - histamine, serotonin • Enzymes - tryptase, acid hydrolyzes, chymase, phospholipases • Lipid metabolites - prostaglandins, leukotrienes, platelet-activating factor • Cytokines - IL-1 to IL-6 • Chromogranin A • Heparin • Leukemia inhibitory factor • TNF (tumor necrosis factor alpha) • Interferon-y • Transforming growth factor-ß • Granulocyte-microphage colony-stimulating factor • ATP • Neuropeptides (vasoactive intestinal peptide (VIP) • Growth factors (nerve growth factor- nitric oxide) Brain Mast Cells
• Now known mast cells reside in the brain & CNS • Serve as sensors and effectors • Communicate between nerve, vascular, immune systems • Able to cross the blood brain barrier, especially when BBB is compromised • In the brain, they reside on the brain side of the BBB. • Communicate with the brain microglia, astrocytes, and blood vessels via their mediator chemicals
Dong, H., Zhang, X., Qian, Y. Mast Cells and Neuroinflammation. Med Sci Monit Basic Res. 2014;20; 200-206 Some areas of MC concentration
• Thalamus (relays motor & sensory to cortex) • Limbic system – Hypothalamus (releases hormones, temp control, etc), – Hippocampus (motivation, emotion, learning, memory) – Amygdala (emotion) • Leptomeninges (the inner 2 meningeal layers) • Choroidal plexus (produces CSF in ventricles) • Area postrema (brainstem, controls vomiting, autonomics) • Pineal (produces serotonin derived melatonin) • Infandibulum (connects hypothalamus & pituitary) • Substantia Nigra (reward, movement) • Dura mater (outer layer of spinal chord)
Hendriksen, et. al. Mast cells in neuroinflammation and brain disorders. Neuroscience & Behavioral Reviews. Dec 2017; 83: 774 Kempuraj D, et. al. Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer's Disease Pathogenesis. Front Neurosci 2017; 11: 703 Theoharides, TC, et. al. Mast Cells, Stress, Fear and Autism Spectrum Disorder. Int J Mol Sci. 2019 Aug; 20(15): 3611 Brain mast cells interact with the microglia and glia to cause neuroinflammation CNS Microglia
• Specialized monocytes • Constantly surveying • Phagocytize invaders • Infection, toxins, chemical irritants • Involved in neurodegenerative diseases • Triggered by mast cells & histamine • Involved in neuroinflammation Mast Cell Triggers
• IgE Allergy • Drugs, incipients • Stress • Infection – acute or chronic • Inflammatory or neoplastic disease • Exercise or physical stimuli • Heat or cold • Venum exposure • And more… Stabilize the mast cells and the microglial neuroinflammation is inhibited
Mast Cells & Mitochondria
• Mitochondria required for MC degranulation
• Mitochondrial DNA & ATP extruded from MC when MC degranulates
• Mt DNA then acts as an “autopathogen”
• Can travel to other areas of body
Zhang, B., Asadi, S., Weng, Z., Sismanopoulos, N., Theoharides, T.C. Stimulated Human Mast Cells Secrete itochondrial Components That Have Autocrine and Paracrine Inflammatory Actions. PLoS One. 2012;7(12): e49767
Theoharides TC, Asadi S, Panagiotidou S, Weng Z. The “missing link” in autoimmunity and autism: extracellular mitochondrial components secreted from activated live mast cells. Autoimmun Rev. 2013 Oct; 12(12): 1136-42 Mitochondrial STAT3 & Mast Cell Exocytosis
• OXPHOS • – related to MC exocytosis & translocation of mitochondria to exocytosis sites upon MC activation
• STAT3 • = mitochondrial signal transducer & activator of transcription 3 • - involved in OXPHOS / ATP production
IgE MC > MC exocytosis OXPHOS + Activation _ < MC exocytosis _ +
STAT3 – required for exocytosis
Erlick TH, et. al. Mitochondrial STAT3 plays a major role in IgE-antigen-mediated mast cell exocytosis. J Allergy Clinical Immunology. August 2014; 234(2): 460-469.e10 Mitochondrial DNA Stimulates Mast Cells and is Inhibited by Luteolin
IgE Mast Cell VEGF (vascular endothelial Growth factor) CRH Inhibited by luteolin
Extracellular Mitochondrial DNA
Asadi S, Theoharides TC. Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release, which is inhibited by luteolin. Journal of Neuroinflammation. 9, 85(2012) Migraine & Pain The MC Pain Connection
• MC mediators impact central, spinal and enteric neurons • Activated by stress • Sensitize nerve terminals • Many contributors & feedback loops • Tryptase, CGRP, PAR2, Substance P • Migraine, peripheral pain, fibromyalgia The Pain Stress Connection
Stress
HPA
Increased CRF
MC infiltration & activation
Sensitization of Nerve Terminals
Eller-Smith OC, etl al. Potential mechanisms underlying centralized pain and emerging therapeutic interventions. Front. Cell. Neurosci. 12:35. Migraine
Sensory nerves & meningeal mast Interact with cells communicate CNS & immune via “couplings” system Meningeal neuroinflammation (neuropeptide release, vasodilation, plasma Mast cells reside in the meninges (dura protein extravasation, mast mater) cell degranulation)
MC an intermediate between triggers & activation of meningeal nocioceptors Leads to Mast cells & sensory neurons – both the trigeminal source and target of neuropeptides nocioceptor sensitization
Irmak DK, Kilinc E, Tore F. Shared Fate of Meningeal Mast Cells and Sensory Neurons in Migraine. Front. Cell. Neurosci., 05 April 2019, https://doi.org/10.3389/fncel.2019.00136 Sensory Nerve Response to Noxious Stimuli
Cleavage & Activation by Tryptase Spinal Cord Peripheral Dorsal Root Ganglia Sensory Nerve Cells PAR2 Afferent Fibers Receptors + (Nocioceptors) (to brain ) for sensitization of TRPV1, TRPA1
Stimulus Active PAR2
Peripheral SP, CGRP & Neuroinflammation Similar process in (Pain, neuronal excitability, & visceral hyperalgesia) trigeminal sensory afferents
Kim YS, etl al. Expression of transient receptor potential ankyrin 1 (TRPA1) in the rat trigeminal sensory afferents and spinal dorsal horn. J. Comp. Neurol. 518, 687-698 Amadesi S, et. al. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase C epsilon and A-dependent mechanism in rats and mice. J. Physiol. 575(Pt 2), 555-571 Pain: Peripheral & Migraine
• CGRP & Substance P are adjacent to mast cells (central & peripheral) • Perpetuate neurogenic inflammation by further release of both
Release Meningial CGRP Nocioceptors (Calcitonin Gene-Related Peptide)
Activates Mast Cell Mechanosensitive Histamine Degranulation C-Fibers
Releases
CGRP & Substance P (Neurotransmitters)
Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 413, 203-210 Irmak DK, etl al. Shared fate of meningeal mast cells and sensory neuron in migraine. Front. Cell Neurosci. 13:136 Migraine & Flushing
• PACAP type migraine
• Pituitary adenylate cyclase activating peptide1-38 triggers migraine
• Flushing thought due to MC degranulation
• PACAP1-38 known to degranulate both peritoneal and dural mast cells
Jansen-Olesen I, Pedersen SH. PACAP and its receptors in crania arteries and mast cells. Journal of Headache and Pain 19, Article number: 16 (2018) Fibromyalgia Proposed Central Pain Path
• Muscle pain, cognitive dysfunction, fatigue, sleep disturbance • Reduced pain tolerance
Histamine HK-1 Subst P Thalamic Tryptase TNF CRH Mast Cells IL-6
Thalamic Microglia in Microglia Ascending Neurosensitization Direct Nocioceptive via either: mediation tracts in Spinal cord
Theoharides TC, et. al. Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome. Front Cell Neurosci. 2019; 13: 353
Mood & Psychologic Disorders Mast Cells & Neuro-Psychiatry
• MCAS (as opposed to mastocytosis)
• Neurologic and/or psychiatric symptoms
• No unifying underlying cause
• Can be multiple heterogenous symptoms
• Empiric therapy often unsatisfactory
• "Multisystem polymorbidity of generally inflammatory +/- allergic themes."
Afrin LB, et. al. Mast cell activation disease: An underappreciated cause of neurologic and psychiatric symptoms and diseases. Brain Behav Immun. 2015 Nov;50: 314-321 Common mastocytosis symptoms
• 33% of mastocytosis presented with neuropsychiatric symptoms
• Fatigue, musculoskeletal
• Chronic headache 35% (migraine 37.5%, aura 66%). Often with other symptoms: flushing, pruritis, etc.
• Depression-anxiety 40-60%
• Cognitive impairment 38.6%
• Syncope 5%, acute back pain 4%, MS findings on radiology 1%
Georgin-Lavialle S, et al. Mastocytosis in adulthood and neuropsychiatric disorders. Translational Resarch 2016; x:1-9. Depression, Anxiety, Fatigue
• Most work done in mastocytosis. 3 studies:
• Depression 64% (psychic anxiety, depressed mood/work/interests. Masitinib improved in 67% of those.
• Negative emotionality: depression (78.9%) & perceived stress (42.1%). Brain mast cells located in diencephalon (emotion).
• Fatigue in 7 patients. Triggers of heat/cold, exercise, food, ETOH, psychological stress. VAS 80 during attacks and 40 between attacks. Impacted social & recreational activities in 7/7 and occupational activity in 6/7.
Moura DS, et. al. Depression in Patients with Mastocytosis: Prevalence, Features and Effects of Masitinib Therapy. PLOS One. 2011, 6: e.26375. Georgin-Lavialle S, et al. Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress. Brain Behav Immun 2014; 35: 51-57 Viske J, Omdal R, Fatigue in Mastocytosis: A Case Series. Clinical Therapeutics. 2019 April; 41(4): 625-632) .
Neurologist Consults
• Presentation to Mayo Clinic neurology • Headache 35%, syncope, vertebral compression fracture (MC infiltration), multiple sclerosis (also with mastocytosis) • Actually mastocytosis • Mastocytosis may mimic neuro presentations, especially if flushing, abdominal cramping, diarrhea are present.
Smith JH, et al. Neurologic symptoms and diagnosis in adults with mast cell disease. Clin Neurol Neurosurg 2011, 113: 570-574. Stress Stress & mast cells
• Mast cells involved in a variety of neuroinflammatory diseases.
• Especially if those conditions already are potentially worsened by stress.
• Not activated by IgE at Fc receptors, but rather by other immunoglobulins, anaphylatoxins, neuropeptides and cytokines.
• Do not see allergic degranulation in these cases.
Theoharides TC. Critical role of mast cells in inflammatory diseases and the effect of acute stress. Journal of Neuroimmunology. January 2004; 146(1-2): 1-12 Stress, Mast Cells & BBB
• Usually stress activates HPA axis by release of corticotropin releasing hormone (CRH). Glucocorticoids then down-regulate immune responses.
• But, acute stress can be proinflammatory and mediated by activated mast cells.
• The BBB barrier sees increased permeability with stress and this is inhibited by giving disodium cromoglycate, a mast cell stabilitzer.
• After blocking the CRH-receptor with Antalarmin, less BBB permeability is seen.
• Injecting CRH into the hypothalamic paraventricular nucleus (PVN) mimics acute stress which is blocked by pretreatment with cromolyn.
• Also, in W/Wv mast cell-deficient mice, stress does not disrupt the BBB in the diencephalon and cerebellum.
• Therefore the BBB is regulated by CRH and mast cells, and possibly, brain inflammatory disorders exacerbated by acute stress as well.
Esposito P, et al. Corticotropin-Releasing Hormone and Brain Mast Cells Regulate Blood-Brain-Barrie Permeability Induced by Acute Stress. Journal of Pharmacology and Experimental Therapeutics. December 2002; 303(3): 1061-1066 Corticotropin Releasing Factor1 A CRF1-antagonist, antalarmin was receptor of the mast cell allows mast given in an IgE-mediated anaphylaxis cell degranulation by an unknown model. This stopped mast cell indirect mechanism. degranulation and hypothermia.
Reduced histamine, hypothermia, Also experienced less mast cell clinical scores, in Mast cell-deficient degranulation and intestinal mice engrafted with CRF1-/- bone permeability in response to acute marrow-derived mast cells. restraint stress.
Proposed that CRF1 is a modulator for both immunologic and psychologic stress
Ayyadurai S, et. Al. Frontline Science: Corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress- induced pathophysiology. J Leukoc Biol. 2017 Dec; 102(6): 1299-1312 Stress, neuroinflammation & neurodegeneration
• Stress induces release of CRH (corticotropin-releasing hormone) form paraventricular nucleus of hypothalamus.
• Activates glia and mast cells via CRH receptors.
• Releases neuroinflammatory mediators. Also induces proinflammatory mediator release in the periphery promoting neuroinflammation.
• Mast cell activation in brain injury, stress, PTSD may increase neuroinflammatory and neurodegenerative disease pathogenesis.
Kempuraj D, et al. Mast Cell Activation in Brain Injury, Stress, and Post Traumatic Stress Disorder and Alzheimers Disease Pathogenesis. Front Neurosci, 12 December 2017, https://doi.org/10.3389/fnins.2017.00703 Mast cells & gut permeability
• CRF causes Intestinal Epithelial Barrier Injury and increased permeability
• Response to MC proteases and TNF-alpha
• Multiple feedback loops with MC mediators
Overman EL, et. al. CRF Induces Intestinal Epithelial Barrier Injury via the Release of Mast Cell Proteases and TNF-a. Pone. June 29, 2012. https://doi.org/10.1371/journal.pone.0039935
Rodino-Janeiro BK, et. al. Role of Corticotropin-releasing Factor in Gastrointestinal Permeability. J Neurogastroenterol Motil. 2015 Jan; 21(1): 33-50 Many Types of Stressors
• Emotional • Physical • Chronic infection or illness • Environmental toxins • Oxidative stress Cognitive Impairment & Alzheimer’s Alzheimer’s
• Amyloid-ß protein accumulation promotes overactivation & recruitment of microglia, which penetrate plaques and leads to production of pro-inflammatory and cytotoxic molecules
• Both microglia & mast cells found surrounding amyloid plaques in AZ patients at autopsy
• Proposed that mast cells are either attracted to the sites by glia or are first responders
Shaik-Dasthagirisaheb YB, Conti P. The Role of Mast Cells in Alzheimer’s Disease. Adv Clin Exp Med. 2016 Jul-Aug;25(4): 781-7 Dong H, Zhang X, Qian Y. Mast Cells and Neuroinflammation. Med Sci Monit Basic Res. 2014;20: 200-206 Jones MK, Nair A, Gupta M. Mast Cells in Neurodegenerative Disease. Front Cell Neurosci, 30 April 2019, https://doi.org/10.3389/fncel.2019.00171 TBI
• TBI contributes to Alzheimer's disease by promoting chronic neuroinflammation and neuronal death.
• At the time of injury, mast cells recruit immune cells to the site via release of mediators across the BBB.
• In combination with risk factors, this leads to neurodegeneration and AD.
Kempuraj D, et al. Brain Injury-Mediated Neuroinflammatory Response and Alzheimer’s Disease. The Neuroscientist. May 16, 2019. https://doi.org/10.1177/1073858419848293
Multiple Sclerosis Multiple Sclerosis
• Mast cells at sites of inflammatory demyelination • Mast cell tryptase seen elevated in cerebrospinal fluid • Secreted histamine promotes edema • Secreted proteases cause demyelination • Theory that MS relapses and remits following mast cell degranulation and restoration of stored contents. • Theory that mast cells originally amplify in the brain during a remote or childhood infection
Dong H, Zhang X, Qian Y. Mast Cells and Neuroinflammation. Med Sci Mont Basic Res. 2014;20: 200-206 Experimental allergic encephalomyelitis (EAE) model with human counterpart as multiple sclerosis
Both EAE and MS considered CD4+ T cell-mediated autoimmune diseases affecth CNS
Shown that in EAE mast cell-deficient mice show significantly reduced disease incidence vs wild type.
Restoring mast cells in the deficient mice induces early severe disease.
Suggests mast cells are critical for full disease manifestation Stroke Stroke
• Cerebral ischemia brain injury triggers many types of inflammatory cell recruitement.
• Mast cells reside in the brain and meninges. Are first responders (even prior to microglia) to ischemia and hemorrhage.
• Act first to release vasoactive and neuroactive mediators from preformed cytoplasmic granules.
• Contribute to BBB damage, brain edema, prolonged extravasation, hemorrhage. Act on the basal membrane.
• Contribute to continued BBB damage > infiltration of other signals and blood-borne cells.
Parrella E, Porrini V, Benarese M, Pizzi M. The Role of Mast Cells in Stroke. Cells. 2019 May;8(5):437 Parkinson’s Parkinson’s
• Found that histamine triggers microglial phagocytosis via H1R histamine receptor activation and ROS production via both H1R and H4R activation.
• Performed in Substantia Nigra.
• Substantia nigra particularly susceptible to microglial activation, and histamine in particular.
• Others found that when the secretions of microglial cells were exposed to histamine, degeneration of the dopaminergic neurons was seen.
Rocha SM, et al. Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation. Journal of Neuroinflammation .04 June 2016. 13(137)
POTS & Ehlers Danlos
• Pilot study. Only 15 patients
• Ehlers Danlos Syndrome patients and 80% with known diagnosis of Postural Orthostatic Tachycardia Syndrome.
• Goal was to determine if patients with EDS and POTS also have mast cell activation as a phenotype
• 6 of the 9 (66%) patients with a dual diagnosis of EDS and POTS had validated symptoms of a mast cell disorder suggestive of MCAS
Cheung I, Vadas P. A New Disease Cluster: Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, and Ehlers-Danlos Syndrome. Allergy Clin Immunol, 2015; 135: AB65 Brain Mast Cell Vagus Mast Histamine & Cell & Mediators Other Systemic Neurons Mast Histamine, CRH Cell MC mediatiors, & HPA Microglia/Gl Cytokines, etc
ia Increased BBB Increased
Systemic Histamine, MC Mediators, cytokines, etc
Intestinal Permeability Gut
Tryptase, chymase Stress CRH & HPA Histamine
Histamine Leukotriene mediators MC otherand IgE Prostaglandin Non-IgE Cytokines, etc Toxins, drugs, heat, cold, etc Mast Cell Serotonin LPS Norepinephrine Gliadin Gut Lectins VEGF, VIP, MMP’s, ROS, etc, Microbiota Mitochondrial DNA & ATP (potential autoimmune antigen) For your reading pleasure…
Gut Brain:
• Mittal A, et. al. Mast Cell Neural Interactions in Health and Disease. Front Cell Neurosci. 20 March 2019. https://doi.org/10.3389/fncel.2019.00110 • Traina G. Mast Cells in Gut and Brain and Their Potential Role as an Emerging Therapeutic Target for Neural Diseases. Front Cell Neurosci. 30 July 2019. https://doi.org/10.3389/fncel.2019.00345 • Khalil M, et. al. Neuro-Immune Networks in Gastrointestinal Disorders. Visc Med. 2019; 35: 52-60 • Veiga-Fernandes H, Mucida D. Neuro-Immune Interactions at Barrier Surfaces. Cell. May 5, 2016; 165. http://dx.doi.org/10.1016/j.cell.2016.04.041
Permeability:
• Groschwitz K, et. al. Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism. PNAS. December 29, 2009; 106(52):22381-22386 • Jacob C, et. all. Mast Cell Tryptase Controls Paracellular Permeability of the intestine. Role of Protease-activated Receptor 2 and B-Arrestins. J Biolog Chem. July 18, 2005; 280: 31936-31948 • Forbes EE. IL-9 and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J Exp Med. 2008 Apr 14; 205(4): 897-913. • Lee H, et. al. Mucosal Mast Cell Count is Associated With Intestinal Permeability in Patients With Diarrhea Predominant Irritable Bowel Syndrome. J Neurogastroenterol Motil. 2013; 19(2): 244-250 • Groschwitz KR, et. al. Intestinal Expression of Interleukin 9 (IL-9) Induces Mast Cell-Mediated Intestinal Permeability. J All Clin Immunology. Jan 2007; 119(1):S313
Permeability bacterial transloaction / LPS endotoxemia
• Moriez R, et. al. Mucosal mast cell proteases are involved in colonic permeability alterations and subsequent bacterial translocation in endotoxemic rats. Shock. 2007 July, 28(1):118-124 • Dong H, et. al. Stabilization of Brain Mast Cells Alleviates LPS-Induced Neuroinflammation by Inhibiting Microglia Activation. Front Cell Neurosci. 03 May 2019. https://doi.org/10.3389/fncel.2019.00191
Celiac & Lectins:
• Frossi B, et. al. Mast cells are associated with the onset and progression of celiac disease. J All Clin Immunol. April 2017; 139(4):1266-1274 • Barbosa-Lorenzi VC, et. al. The lectin ArtinM binds to mast cells inducing cell activation and mediator release. Bioch Biophys Res Communications. 16 Dec 2011; 416(3-4): 318-324 • Pramod SN, et. al. Potato lectin activates basophils and mast cells of atopic subjects by its interaction with core chitobiose of cell-bound non-specific immunoglobulin E. Clin Exp Immunol. 2007; 148(3): 391-401. • Moreno AN, et. al. Mast cell degranulation induced by lectins: effect on neutrophil recruitment. Int Arch Allergy Immunol. 2003 Nov; 132(3): 221-30 • Lopes FC, et. al. Differential effect of plant lectins on mast cells of different origins. Braz J Med Biol Res. 2005 June; 38(6): 935-941 • Frigeri LG, Liu FT. Surface expression of functional IgE binding protein, and endogenous lectin, on mast cells and macrophages. J Immunol. Feb 1, 1992; 148(3): 861-867 Be looking for overlapping symptoms that could represent mast cell activation Systemic Mastocytosis diagnositic criteria
• Major + at least 1 minor, or only 3 minor criteria
• Major – Multifocal aggregates of ≥ 15 mast cells in a noncutaneous tissue biopsy specimen
• Minor – Aberrant mast cell morphology – Aberrant CD25 and/or CD2 expression – Codon 816 KIT mutation – Serum baseline tryptase >20 or 2x baseline +2
Akin, C. Mast Cell Activation Syndromes. J Allergy Clinical Immunology. August 2017; 140(2): 349-355 1º vs 2º vs Idopathic MCAS
• Primary (clonal MCAS) – KIT D816V. Usually CD25 in mast cells – A) with confirmed mastocytosis (CM or SM) – B) with just 2 minor SM criteria
• Secondary – No KIT D816V or neoplastic MC – IgE-mediated allergy, other hypersensitivity disease, or immunologic disease causing MCA
• Idiopathic – Meets MCAS criteria, but no related reactive disease, or IgE- dependent allergy, or neoplastic/monoclonal MC.
Valent, P., Akin, C. Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome. J Allergy Clin Immunol Pract. April 2019; 7(4); 1126-1133 MCAS Consensus Criteria
• Valent criteria. MCAS diagnosis requires all three
• Criterion A – Clinical signs of MCA that are severe and recurrent (ie, anaphylaxis, flushing, pruritis, urticaria, angioedema, nasal congestion or pruritis, wheezing, throat swelling, headache, hypotension, diarrhea, etc) in at least 2 organ systems
• Criterion B – Positive markers. Tryptase increase of 20% + 2 ng/mL
• Criterion C – Response to therapy with MC-stabilizing or MC-mediator inhibiting/blocking drugs.
Valent, P., Akin, C. Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome. J Allergy Clin Immunol Pract. April 2019; 7(4); 1126-1133 Workup
• Tryptase (best while flared) • Histamine, Heparin, Chromogranin A, Prostaglandin D2 (PGD2)
• CBC w/differential, serum chemistries • Quantitative immunoglobulins (if frequent/chronic infection or poor healing • PT/PTT if easy bruising/bleeding or thromboembolic events
• Spot urine PGD2 • 24 hr urine PGD2 or 2,3-dinor-11-ß-prostaglandin F2a • 24 hr urine N-methylhistamine • 24 hr urine LTE4
Valent, P., Akin, C. Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome. J Allergy Clin Immunol Pract. April 2019; 7(4); 1126-1133
Afrin,L.B., Molderings,G.J. A concise, practical guide to diagnostic assessment of mast cell activation disease. World J Hematol. Feb 6, 2014; 3(1): 1-17 Usefulness of markers
• sChromogranin A 49% • pHistamine 49% • pHeparin 48% • pPGD2 46% • 24u PGD2 44% • Ru PGD2 26% • 24u N-MH 11% • Ru N-MH 7%
Afrin,L.B,, et al. Characterization of Mast Cell Activation Syndrome. Am J Med Sci. 2017 Mar; 353(3); 207-215 Mast Cell activity can affect multiple systems whether it meets MCAS criteria or not.
And it’s modifiable. Drug Treatments
• H1 histamine receptor agonist (anti-histamines) • H2 histamine receptor agonist (acid blockers) • Leukotriene inhibitors • Cromolyn – Mast cell stabilizer – nasal, oral • Aspirin, NSAIDS – prostaglandin inhibitors • Glucocorticoids
• Omalizumab • Cytoreductive agents – IFN-a, cladribine • Multikinase inhibitor – Midostaurine • Tyrosine kinase inhibitor - Masitinib Potential Problems
• H1 Blocking Anti-histamine – Diphenhydramine (Benedryl) – anti-cholinergic dementia / Alzheimer’s risk – Less risk with non-sedating Loratadine, Cetirizine
• H2 Blocking Anti-histamine – Ranitidine, Famotidine – Acid inhibition and dysbiosis / SIBO
• Aspirin, NSAIDS – Bleeding, kidney Nutritional Supplements
• Quercetin – MC stabilizer • Luteolin (+/- with Rutin) – MC stabilizer • Butyrate – MC Stabilizer
• DAO enzyme – intestinal histamine degradation enzyme • Support Histamine N-methyltransferase methylation
Weng Z, et. al. Quercetin Is More Effective than Cromolyn in Blocking Human Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Photosensitivity in Humans. PLoS One. 2012; 7(3): d33805
Molderings GJ, et. al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebregs Arch Parmacol. 2016; 389: 671-694
Wang CC, et. al. Sodium butyrate enhances intestinal integrity, inhibits mast cell activation, inflammatory mediator production and JNK signaling pathway in weaned pigs. Innate Immunity. Nov 29, 2017.
Shaik, et. al. Impact of polyphenols on mast cells with special emphasis on the effect of quercetin and luteolin. Cent Eur J Immunol. 2018; 43(4): 476-481
Theoharides TC, Conti P, Economu M. Brain inflammation, neuropsychiatric disorders, and immunoendocrine effects of luteolin. J Clin Psychopahrmacol. 2014;34:187-189 Other Natural MC stabilizers & anti-histamines
• Flavonoids • Phenols – ie Curcumin • Theanine • Coumarins • Ellagic acid • Terpenoids • Vitamin C (DAO enzyme co-factor)
Kinner SR, et. al. Curcumin Ingestion Inhibits Mastocytosis and Suppresses Intestinal Anaphylaxis in a Murine Model of Food Allergy. PLoS One. 2015 Jul 6;10(7):e0132467
Maintz L, Novak N. Histamine and histamine intolerance. American J Clinical Nutrition. May 2007; 85(5): 1185-1196
Finn DF, Walsh JJ. Twenty-first century mast cell stabilizers. Br J Pharmacol. 2013 Sep; 170(1): 23-37 Histamine N-methyltransferase
• Systemic histamine degradation enzyme
• Methylates Histamine using SAMe to form N-methylhistamine
• Support methylation pathways, including with TMG (Betaine). Cheryl
• 51 y/o woman
• C/o bloating, constipation, slow digestion, heartburn
• High anxiety with depression many years, worsening
• Emotional lability, cognitive dysfunction/brain fog, severe social anxiety
• Multiple failed antidepressants, anxiolytics
• Flushing after eating: face & chest, for 1 year
• Tryptase 2x normal (20.1 ng/mL), Kit D816V negative
• Histamine borderline high
• Breath test – flat line H2 and low methane
• Stool tests – low bacteria except Bacteroidetes, low sIgA, high Beta-glucuronidase, low Akkermansia, low butyrate, neg mycology/parasites
• Quercetin, Luteolin, DAO enyzme, Butyrate, trial of Loratidine
• Nystatin, Intestinal motility agents
• Low histamine, anti-inflam, MC stabilizing diet
• N-acetylglucosamine, Ca D-glucarate, digestive enzymes
• Spore probiotic, B infantis / low histamine probiotics
• Gradual fiber and resistant starches as tolerated Avoid & Address Triggers
• Gut dysbiosis, SIBO, Parasites • Gut permeability • Stress • Chronic infections, Lyme • Environmental Triggers – chemicals, mold • Oxidative Stress • Mitochondrial dysfunction Let Food Be Your Medicine High Quercetin Foods (mg/100gm)
Dill weed 55.15 Chicory greens, raw 6.49 Onions, spring, red 30.60 Oregano, fresh 7.30 Chives, raw 4.77 Onions, red, raw 31.77 Oregano, Mexican, dried 42.00 Collards, raw 3.47 Peppers, hot chili 14.70 Terragon, fresh 10.00 Coriander (cilantro) leaves raw Peppers, long yellow 10.36 Apple skin 19.36 52.90 Peppers, sweet green 2.21 Blueberries 7.67 Fennel leaves, raw 48.80 Radicchio 31.51 Chokeberry 18.53 Hawthorn leaves, raw 24.10 Radish leaves, raw 70.37 Elderbrries 25.77 Kale, raw 22.58 Rocket, wild, raw 66.19 Goji berry, dried 13.60 Lettuce, romaine 3.06 Scallions 10.68 Juniper berries 46.61 Lettuce, green leaf 4.16 Sweet potato leaves 9.83 Lingonberries 13.30 Lovage leaves, raw 170.00 Tomato puree 4.12 Sea buckthorn berry 7.58 Lettuce, red leaf 11.90 Turmeric 4.92 Service berries 16.05 Mustard greens, raw 8.80 Watercress, raw 29.99 Asparagus, cooked 15.16 Spinach, raw 5.75 Chia seeds 18.42 Asparagus, raw 13.90 Okra, raw 20.97 Green tea, brewed 2.49 Broccoli, cooked 1.33 Spring onion leaves, red 12.60 Carob flour 38.78 Brussels sprouts, cooked 4.33 Onions, cooked 24.36 Bee pollen 20.95 Chinese cabbage, raw 2.12 Onions, raw 21.40 Cocoa, dry powder 3.37 Swiss chard, raw 2.63 Buckwheat, whole 15.38 High Luteolin Foods (mg/100gm)
Oregano (Mexican) dried 1028.75 Peppermint, fresh 11.3 Sage, fresh 16.70 Celery seed 811.41 Parsley, dried 19.75 Thyme, fresh 45.25 Juniper berries, ripe 69.05 Celery hearts, green 3.50 Chinese celery, raw 34.87 Chicory greens, raw 2.08 Lettuce red leaf 2.50 Radicchio 37.98 Nutrient Rich Diet • Plant rich • Includes greens, colors, sulfurs • Anti-oxidant rich • Anti-inflammatory • Olive oil • Fiber rich • Quality proteins • Supports mitochondria • Supports detoxification and hormonal systems • Consider gluten free and lower lectin
Penissi AB. Regulation of Immune and Nonimmune Mast Cell Activation by Phenols from Olive Oil. March 12, 2019, Technological Innnovation in the Olive Oil Production Chain. DOI: 10.5772/intechopen.84595
Folkerts J, et. al. Effect of Dietary Fiber and Metabolites on Mast Cell Activation and Mast Cell-Associated Diseases. Front Immuno. 2018; 9: 1067 Reduce High Histamine Foods
Aged cheese Fermented foods Fish or meat not Alcohol Fruits (dried) extremely fresh Beans Fruits Vegetables Cashews (avocado, citrus, (mushroom Chili powder pineapple, eggplant, Chocolates strawberry, tomato, Cinnamon papaya) spinach) Cloves Legumes Soy Sauce Cocoa Pickled foods Vinegar Eggplant Smoked or processed Walnuts meat DAO Reducers
Foods Gut Conditions Medications - Dysbiosis - NSAIDS - Alcohol - Leaky gut - Antidepressants - Raw egg white - Celiac - SSRIs - Tea (green, black, or - IBD - Cardiac rhythm mate) medications (ß- Genetic mutations blockers, calcium channel blockers) Histamine producing probiotics
• Lactobacillus acidophilus • Lactobacillus casei • Lactobacillus reuteri • Lactobacillus helveticus • Lactobacillus lactis • Lactobacillus delbrueckii • Lactobacillus bulgaricus Histamine Degrading Probiotics
• Lactobacillus rhamnosis • Lactobacillus salivarius • Lactobacillus gasseri • Lactobacillus plantarum • Bifidobacter infantis/longum • Bifidobacter lactis • Bifidobacter bifidum • Bacillus coagulans (Lactobacillus sporogenes) Provide Nutritional Support
• Methylation • Detoxification • Mitochondria • Hormonal • Microbiome Situations to be looking for Mast Cell Activation or Histamine Intolerance
• Mood disorders • Neurologic conditions • Cognitive decline • Neurodegenerative conditions • Stress & PTSD • Fatigue /chronic fatigue syndrome • IBS, gut dysbiosis/SIBO, GERD, Nausea