Mast Cell Ac+va+on Disorders

ANNE MAITLAND, MD, PHD Ass i s tant Professor , Department o f Medic ine , D iv i s ion o f C l in i ca l Immunology

I cahn Schoo l o f Medic ine a t Mount S ina i

Med ica l D i rector , Comprehens ive A l le rgy & Asthma Care , PLLC

Our Journey on mother Earth: “Life on the edge”

 (Our)immunesystems…(are)embodied

expecta6onsofinjuryandthecorresponding

programsofprotec6onandrepair.”  -PeterSloterdijk

The Great Wall of China… Protec+on along the Northern Border of China

 Afor0fica0on!  Builtfordefensivepurposesinthe3rdcentury  Itis  -1500milesalong-6meterswide

In imperial +mes, the Great Wall of China was easily breached and was not in itself a very effec+ve defense against resolute adversaries.

Rather, it was a communica+on route and housed, far from the imperial centre, a string of lonely guards who quickly engaged invaders and slowed their progress, while aler+ng and beckoning more substan+al back-up forces. -Christophe Benoist & Diane Mathis Mast cells in autoimmune disease Nature, 2002

InnateImmuneSystemComponentsAnatomicBarriers-  Skin-22squarefeet-  Mucosaofthe

-  Gastrointes6naltract,25feet,-  Respiratorytract,25sq.feet,-  Urogenitaltract,20sq.feet

PhysiologicBarriers-  Temperature,pH,Flow

-  InflammatoryMediators->redness,swelling,heat,pain

ImmuneCells-NKcells,DCs,Macrophages

An0microbialresponse

DefensinsCathelecidins/PsoriasinReac6veOxygenSpecies

Recrui0ngtheadap0veImmune

responseTcells,Bcells

InflammatoryresponseCytokines,ChemokinesNeuropep6desReac6veOxygenSpecies

Two important observa+ons are not captured in this common depic+on of our innate immune system…

Our Immune system = defense against dangers, such as infec+ous agents, toxins and trauma…

Wemeanyounoharm!

“Microbiome”

Port of Entry, “veZng” process– to allow entry to en++es that support and may enhance our existence, survival

MC

MC

MC

MastCells:BeyondAllergy?

Mast Cell Orders

MAST CELL BIOLOGY 101

Fat Cell

Lymphocyte

Macrophage

Capillary Blood Vessel

Melanocyte

Reticular Fibers

Mast Cell

Collagen Fibers

Elastic Fibers

MastCellOrders:Surveillance.Protec0on.CoordinateResponseandRepair.

Homeostasis: Keeping the Peace

Like a police officer,

who strives to serve and protect a neighborhood,

“rookie” Mast Cells arrive and learn to meet

the needs of local community of cells and

tissue.

Depending on the nature and severity of the

danger, the police officers will respond

with a defined, regulated series

of actions.

● Trained and prepared with different tools, each individual police officer must learn how to serve and protect his or her assigned, local neighborhood.

Depending on the nature and severity of the danger, the police officer will respond with a

defined, regulated series of actions.

Officer Sees This…

And then does this…

Armed with invariant sensors, Mast Cells

are hardwired to recognize and then react with a defined set of chemical and physical responses, in order to contain “usual suspects”, pathogens and

harmful substances.

TLR 3,7

CR 5a

CR 3,4

TLR 1,4,9

FcReI FcR

EnzymesChymaseTryptase Chemokines

Tumor Necrosis factor

HistamineHeparin

Leukotrienes

CytokinesNGF

MC

IgE IgG

mold

bacteria

parasites

wormsviruses

Mast Cells act as the local

Peace Keepers, maintaining

homeostasis in the surrounding

microenvironment.

Depending on the nature and severity of the danger, mast cells, will respond

with a defined set of mediators, calling for appropriate help.

911… what’s your

emergency?

parasite

Code

Blue

virusbacteria

Code R

ed Code

Orange

Insect sting

Vascular leakage -> Serum Proteins ->Swelling, Itch

MC

MASTCELL(MC)101▪  MCsarefoundinmostpartsofthebodyarewellknownforroleinallergic/anaphylac6creac6ons

▪  MCsarenowrecognizedtoplayaroleinanumberofinflammatorydiseasesintheskin,respiratorytract,joints,Gastrointes6naItract,nervoussystem,bladder

▪  MCscontain>500secretorygranulesandcandenovosynthesizeandreleasemediatorsfollowings6mula6on,viadegranula0onordifferen0al,piecemealrelease

arachidonicacidproducts,biogenicamines,chemo-a^ractants,cytokines,growthfactors,neuropep6des,proteoglycans,andproteoly6cenzymes

Theoharides,&Bielory,AnnalsAllergy,Asthma&Immunology,2003

Mast Cells=

Border Patrol, recognizing

and responding to

clear and present dangers

“usualsuspects”

(1) Infec0ous,nonselfthreats,thathaveaspa^ernrecogni6onreceptors(PRRs)andarerecognizedbyevolu6onarilyconservedmembrane-boundToll-likereceptors(TLRs),onMCs

(2)Endogenous,selfalarmsignals,indica0ngdanger:breakdownproductsofhyaluron(madewhenvesselsaredamaged).mammalianDNA,RNA,heatshockproteins(Hsps),interferona,(aninducibleproteinobenmadebyvirus-infectedcells),interleukin-1beta,CD40-L(asurfacemoleculeonac6vatedplateletsandac6vatedTcells),and

DangerSignals1

2

Dark Side of Mast Cell Ac+va+on Mast Cells are best known for “Allergies” Allergen-IGE-IgE Receptor Mast Cell Ac+va+on

IgE Allergens

FcεRI

Over Minutes Lipid mediators: Prostaglandins Leukotrienes

Wheezing Bronchoconstriction

Over Hours Cytokine production: Specifically IL-4, IL-13

Mucus production Eosinophil recruitment

Immediate Release Granule contents: Histamine, TNF-α, Proteases, Heparin

Sneezing Nasal congestion Itchy, runny nose Watery eyes

CMC Ac+va+on a_er Complement or IGG bound

pathogens,

MCrelease

➢ Tryptase(proteases)

➢ Histamine

MastCellresponsestopathogens.JeanMarshall,NatureReviewsImmunology,2004(4):787-799

IG-IGReceptoronMCs ComplementCoatedPathogen-C’Receptor

onMCs

Leukotrienes,Interleukin-1,Interleukin-6,CXCL8,GM-CSFTumorNecrosisFactor

TLR-pathogen mediated Mast Cell Ac+va+on

 TollLikeReceptorsonMastCellsbindpathogensPRRsforcomponentsofbacteriaandfungi➢ NoReleaseofProteases(tryptase)➢ NoHistamineRelease

MastCellresponsestopathogens.JeanMarshallNatureReviewsImmunology,2004(4):787-799

Leukotrienes,Interleukin-1,Interleukin-6,CXCL8,GM-CSFTumorNecrosisFactor

Mast Cells:

Defense and +ssue

repair

Mast Cells as “Local Peace

Keepers”

Mast Cell Disorders

MAST CELL ACTIVATION DISORDERS 101

0

25

50

75

100

125

1950 1960 1970 1980 1990 2000

Tuberculosis MeaslesMumps Hepa66sARheuma6cFever

Golden age of medicine = Age of immune dysregula+on?

The Increased Burden of Autoimmune and Allergic Disorders

Adapted from Bach, NEJM 2002

 Themiddleofthe20thcenturyhasobenbeendescribedasagoldenageof

medicine:scien6ficadvancementandmiraculousmedicalbreakthroughs:

▪  thebacteriologicalrevolu6on▪  thefloweringofscien6ficresearchandpharmaceu6caldevelopmentthatisassociatedwithWorldWarI

▪ changesinmedicaleduca6onandpublichealth

“SearchingforaGoldenAge”UniversityofPennsylvania

0

75

150

225

300

375

1950 1960 1970 1980 1990 2000

Crohn'sDiseaseMul6pleSclerosisType1DiabetesAsthma

Asthma

Orthostatic Intolerance

Dermatitis

Aut

o-im

mun

ity

MastCell

NeurocognitiveImpairment

Adapted from Theoharides, NEJM 2015

Epidemic of Hypersensi+vity Disorders:

Role of Mast Cell Dysregula+on?

Adapted from Bach, New Eng J Med 2002

Mast Cell Ac+va+on Syndrome (MCAS): a collec+on of disorders characterized by…

❖ Accumula6onofpathologicalmastcellsinpoten6allyanyorallorgansand6ssues

❖ Aberrantreleaseofvariablesubsetsofmastcellmediators,leadingtooneofmoresymptoms(sugges6veofsystemicmastcelldegranula6on)

ProposedDiagnos0cCriteriaforMastCellAc0va0onDisorders

(1)EpisodicSigns&SymptomsConsistentwithMastCell(MC)Ac6va6on,affec6ng2ormoreorgansystems

(2)Responsetotherapy–decreaseinfrequency,severityorresolu6onofsymptomswithan6-MCmediatortherapiesorMCstabilizers

(3)EvidenceofanincreaseinvalidatedurinaryorserummarkersofMCac6va6on;increasedburdenof6ssuemastcells(CD117)orchronicallyac6vatedmastcells(CD117+andCD25+/CD2+/CD30+)

ProposedCriteriaforMCASDiagnosis:RuleoutPrimaryMCASandSecondaryCausesofMCac6va6on,

clinicalen66esthatmimicMCac6va6on

Cardiaccondi0ons:Coronaryhypersensi6vity(theKounissyndrome)*Posturalorthosta6ctachycardiasyndromeEndocrinecondi0ons:FibromyalgiaParathyroidtumorPheochromocytomaCarcinoidsyndromeDiges0vecondi0onsAdversereac6ontofood*Eosinophilicesophagi6s*Eosinophilicgastroenteri6s*Gastroesophagealrefluxdisease;Glutenenteropathy;Irritablebowelsyndrome;Vasoac6veintes6nalpep6de–secre6ngtumorImmunologiccondi0ons:Autoinflammatorydisorderssuchasdeficiencyofinter-leukin-1–receptorantagonist*;Familialhyper-IgEsyndromeVasculi6s*Neurologicandpsychiatriccondi0onsAnxiety;Chronicfa6guesyndromeDepression;Headaches;Mixedorganicbrainsyndrome;Soma6za6ondisorder;Autonomicdysfunc6on;Mul6plesclerosisSkincondi0ons:Angioedema*Atopicderma66s*Chronicur6caria*Scleroderma*

Mast Cell Ac+va+on Disorder: Signs and Symptoms

MASTOCYTOSIS(ESCRIBANOETAL,JACI124:514)

SkinLesions 90%

Pruri6s 82%

Flushing 56%

Diarrhea 35%

AbdominalCramping 30%

NeuropsychiatricSymptoms 23%

Anaphylaxis 23%

Pep6cSymptoms 20%

Osteoporosis 18%

Hepatomegaly 12%

Splenomegaly 8%

NONCLONALMASTCELLACTIVATIONDISORDERSHAMILTON,JALLERGYCLINIMMUNOL128;147

AbdominalPain 94%Dermatographism 89%

Flushing 89%Headache 83%

Neuropsychiatric 67%Diarrhea 67%

Rhini6s(Naso-ocular) 39%Asthma 39%

Anaphylaxis 17%

SerotoninNerve Growth

Factor

EnzymesChymaseTryptase

ChemokinesTumor Necrosis

factor

Cytokines

HistamineHeparin

Leukotrienes

Interstitial Cystitis

HeadachesBRAIN

FOG

ASTHMA ANAPHYLAXIS

ARTHRITIS

HIVES

IRRITABLEBOWEL

SYNDROME

FOOD ALLERGY

RHINITIS

MastCell

▪  Mastcellsarefoundinmostpartsofthebody

▪  Mastcellshavearoleinallergic/anaphylac6creac6onsaswellasotherinflammatorydiseasesintheskin,respiratorytract,joints,gastrointes6naItract,nervoussystem,bladder

▪  Mastcellmediateddisordersworsenwithstress

Brain (> 20% reactions) Sense of uneasiness. angst

Headache, Dizziness Confusion, Tunnel Vision

Heart, Blood Pressure (10-45 % reactions)

Fainting, Chest Pain Fast Heart Rate, Palpitations

(pounding) Weak pulse, Dizziness

Joint and Muscle Pain

Airwayreac0ons,(70%reac6ons)Throat6ghtening,ThroatSwellingNasalconges6on,RhinorrheaWheezing,Dyspnea,ChestTightness

Skin (80-90% reactions) Hives (Urticaria), Itch Flushing, Swelling (Angioedema)

Gastrointestinal tract (30-45% reactions)

Nausea, Cramping Abdominal Pain

Vomiting, Diarrhea

Genito- Urinary tract (>10% reactions) Uterine Cramping Swelling -labia

Adapted from Theoharides et al., NEJM 2015

IgE Allergens

FcεRI

Over Minutes Lipid mediators: Prostaglandins Leukotrienes

Over Hours Cytokine production: IL-4, IL-6, IL-13

Immediate Release Granule contents: Histamine, TNF-α, Proteases, Heparin

CD2, CD25 Expression

Pathology- spindle MC, MC aggregates

Serum, Urine Histamine

Urine PGD2,

11-beta PGF2

Serum Tryptase

(2) Measuring Mast Cell Ac+va+on Markers, Inflammatory Mediators

(3) Response to Treatment: Targe+ng MC/MC Inflammatory Mediators

IgE Allergens

FcεRI

Over Minutes Lipid mediators: Prostaglandins Leukotrienes

Wheezing Bronchoconstriction

Over Hours Cytokine production: Specifically IL-4, IL-13

Mucus production Eosinophil recruitment

Immediate Release Granule contents: Histamine, TNF-α, Proteases, Heparin

Sneezing Nasal congestion Itchy, runny nose Watery eyes

Histamine Blockade Tricyclic Agents

Leukotriene Blockade

Anti-IGE mAb

Corticosteroids MC stabilizers

Traditional Chinese (TCM) Herbal Medicine Acupuncture

Spectrum of Mast Cell Disorders: clonal (c-kit pathway) vs nonclonal

adapted from Akin et al, JACI

1.  TypicalMCmediatedclinicalsymptoms

2.  Increase(transient/sustained)tryptase**

3.  Responsetoan6-MC/MC-mediatortreatment(s)

MASTCELLPROLIFERATION

Primary MCAS MMAS SM MCL

Secondary or Idiopathic MCAS

**Decreased likelihood MMAS, SM or MCL by bone marrow MC aggregates diminishes significantly in those with tryptase < 20 ng/mL

Classifica+on of MCAS - Associated Disorders

Primary(c-kitmuta0on)

SymptomsAssociatedwithmonoclonalmastcellpopula6onA. MastocytosisB.MonoclonalMastCellAc6va6onSyndrome(MMAS)

Secondary A.Allergic(IGEmediated)DisordersB.MCac6va6onassociatedwithchronicinflammatory/neoplas6cdisordersC.PhysicalUr6cariasD.ChronicAutoimmuneUr6cariaMastCellAc6va6onSyndrome(MCAS)

▪  Hyper-tryptasemia(tryptasemuta6on-autosomaldominant)

Idiopathic A. AnaphylaxisB.  AngioedemaC.  Ur6caria

Mast Cell Disorders

TREATMENT STRATEGIES

Mast Cell Ac+va+on Disorders Guidelines to Diagnosis and Treatment

1.  Accurate,“BestWorking”Diagnosis2.  Assessseverity3.  Educa6onforpartnershipinCare4.  Treatment/Management5.  Returntoreviewandreflecton

diagnosisandtreatment-areyouorareyounotbe^er

Who's Holding Up the Queue? Delay in diagnosis and treatment of MCAD HOMIK hlp://www.jrheum.org/content/38/7/1225 J Rheumatol 2011;38;1225-1227

Allergy(Immunemediated)

disordersnowcauseproblemsofincreasedcomplexityandcommonlyinvolvesseveralorgansystems,sopa6entsareobenreferredtoasuccessionofdifferentspecialists,resul6ngonlyinconfusion.

Allergy:theunmetneed,

RoyalCollegeofPhysicians,2006

PagingZocDocforthefutureofmedicineZocDoc,turninghealthcareintoaone-clickexperience,upendstradi6onalmedicalprac6ce.h^p://www.usatoday.com/story/money/business/2012/12/30/michael-wolfe-zocdoc-an-omen-of-big-changes-in-health-care/1799511/

Knowledge of good allergy management in prac+ce is therefore minimal or non-existent. Allergy: the unmet need, Royal College of Physicians, 2003

1.   Pa0entawareness“DoIhaveaproblemthatwarrantsmedical

care”

2.   GeneralPrac00onerAwarenessAllergybarelyfeaturesintheundergraduate

medicalcurriculum

“Doesthispa6enthaveaninflammatorydisorderthatwarrantsspecialista^en6on”

3.   SpecialistAwarenesslackofspecialistsinacademicmedicalcenters

andcommuni6esmeansvirtuallynoclinicaltrainingisavailable.

HOMIK,JRheumatol2011;38;1225-1227

Mast Cell Ac+va+on Disorders Guidelines to Diagnosis and Treatment

1.   Accurate,“BestWorking”Diagnosis

2.   Assessseverity3.   Educa0onforpartnershipin

Care4.  Treatment/Management5.  Returntoreviewandreflecton

diagnosisandtreatment-areyouorareyounotbe^er

❑ Symptoms?

❑ Becer with treatments that target MC or MC mediators?

❑ Test Results?

MoodDisorders

Anxiety ADHD

Depression

•  Sneezing,Itching:Nose,eyes,ears,palate•  Runnynose,Postnasaldrip,backdrip•  Conges6on,Headache,FacialPain,Dentalpain

•  Losesenseofsmell,taste•  Headache,Earache•  Tearing,Redeyes,Eyeswelling•  Fa6gue•  Snoring,Poorsleep,Drowsiness,Malaise•  Sorethroat,hoarseness.Mouthbreathing•  Acuteorchronicsinusi6s;O66smedia•  Sleepdisturbanceorapnea

Sinus Infections

Rhinitis

Cough Asthma

EarProblemsVertigo

Infections

Throat ProblemsHoarseness Infections

Fatigue

Common MC -Mediated Disorder: Rhini+s Sleep

Disorders Snoring Apnea

Mast Cell Ac+va+on Disorders Guidelines to Diagnosis and Treatment

1.  Accurate,“BestWorking”Diagnosis2.  Assessseverity3.  Educa6onforpartnershipinCare

4.   Treatment/Management

5.  Returntoreviewandreflectondiagnosisandtreatment-areyouorareyounotbe^er

MCAD/MCAS Treatment: Targe+ng MCs or

MC derived Inflammatory Mediators

IgE

FcεRI

Over Minutes Lipid mediators: Prostaglandins Leukotrienes

Over Hours Cytokine production: Specifically IL-4, IL-13

Immediate Release Granule contents: Histamine, TNF-α, Proteases, Heparin

Histamine Blockade Tricyclic Agents

Leukotriene Blockade Cyclooxygenase Inhibitors

Anti-IGE mAb

Corticosteroids MC stabilizers

Cytokine Antagonists

Nutraceu0calsDAOsupplementVitaminCQuerce6nS6ngingNe^leBu^erbur

Traditional Chinese (TCM) Herbal Medicine Acupuncture

Theoharidesetal,NEJM2015;Engleretal,JAllergyClinImmunol,2009;

heyarethemostreviledcellsinthebody.Theirmeddlingmakesourskinitch,oureyesswell,andournosesstream;thecellsevenprovokesuffoca6ngasthmaa^acksthatkillthousandsofpeopleeveryyear.Infact,thesevillains,knownasmastcells,areresponsibleforsomuchsufferingthatsomeresearchershaveproposederadica6ngthem.Thatcouldbeabigmistake.

Mast Cells: Defense and Wound Repair

Acupuncture & MCAS treatment: Role of mast cells in acupuncture effect: a pilot study Di Zhang, PhD et al, EXPLORE May/June 2008

 MCsarecommonatsitesthatareinclosecontactwiththeexternalenvironment(skin,gastrointes6naltractandairways),theyaredistributedinvirtuallyallorgansandvascularized6ssues  Mastcellsarefoundabundantatsitesofacupoints

Acupuncture & MCAS treatment: Role of mast cells in acupuncture effect: a pilot study Di Zhang, PhD et al, EXPLORE May/June 2008

Impactofmanuals6mula6onbyanacupunctureneedleonanesthesiaAcupuncture:•  Increasedthedensityofmastcells•  IncreaseinMCdegranula6on•  Pretreatmentoftheacupuncturepointwith

disodiumchromoglycatenotonlycounteractedthephenomenonofdegranula6onbutalsoreducedanalgesiceffectofacupuncture.

MCdegranula0on

ShamTreated

Beler Health = Mast Cell suppression ???

Treatment of Hypersensi+vity Disorders

 Likemostimmunologists,Ihadthoughtthatimmunityiscontrolledbythecellsofthe“adap6ve”immunesystem(lymphocytes)orthemoreancient“innate”immunesystem(suchasmacrophages,dendri6ccells,andthecomplementsystem).  -PollyMatzinger,Science2002

(1) Infec0ous,non-selfthreats,thathaveaspa^ernrecogni6onreceptors(PRRs)andarerecognizedbyevolu6onarilyconservedmembrane-boundToll-likereceptors(TLRs),onMCs

(2)Endogenous,selfalarmsignals,indica0ngdanger:breakdownproductsofhyaluron(madewhenvesselsaredamaged).mammalianDNA,RNA,heatshockproteins(Hsps),interferona,(aninducibleproteinobenmadebyvirus-infectedcells),interleukin-1beta,CD40-L(asurfacemoleculeonac6vatedplateletsandac6vatedTcells),and

DangerSignals1

2

Primary(c-kitmuta0on)

A. MastocytosisB.MonoclonalMastCellAc6va6onSyndrome(MMAS)

Secondary A.Allergic(IGEmediated)DisordersB.MCac0va0onassociatedwithchronicinflammatory/neoplas0cdisordersC.PhysicalUr0cariasD.ChronicAutoimmuneUr0cariaMastCellAc0va0onSyndrome(MCAS)

▪  Hyper-tryptasemia(tryptasemuta0on-autosomaldominant)

Idiopathic A. AnaphylaxisB.  AngioedemaC.  Ur6caria

 MastCellAc0va0onSyndrome(MCAS)

Endotypes:  from

 ClinicalPhenotypestoMolecularApproaches

Allergic Reac+ons

Allergen-IGE-IGEreceptor6rggeredMastCellAc6va6on

Firstexposuretoasensi0zingan0gencausesB-cellstomakelgEan0bodies

lgEbindstomastcells

An6gen Bcell

MastCell

Allergy:e.g.hives,hayfever,asthma,foodallergy

Subsequentexposuretoan0gencausesmastcellac0on,releasingallergenicmediators

 Whilethecauseofthecondi0onisn'tclear…"wehavesomecluesthatitmightbesomethingtodowiththesignalingthatgoesonatthemastcellsurface."-Dr.Ma^hewJ.HamiltonofBrighamandWomen'sHospital,Boston,2011

Primary(c-kitmuta0on)

A. MastocytosisB.MonoclonalMastCellAc6va6onSyndrome(MMAS)

Secondary A.Allergic(IGEmediated)DisordersB.MCac6va6onassociatedwithchronicinflammatory/neoplas6cdisordersC.PhysicalUr0cariasD.ChronicAutoimmuneUr6caria

MastCellAc0va0onSyndrome(MCAS)▪  Hyper-tryptasemia(tryptasemuta0on-autosomaldominant)

Idiopathic A. AnaphylaxisB.  AngioedemaC.  Ur6caria

 MastCellAc0va0onSyndrome(MCAS)

Endotypes:  from

 ClinicalPhenotypestoMolecularApproaches

elevensubjectswithMarfan'ssyndrome,neurofibromatosis,andfragilitasossiumweremorefrequentlyatopic

An early observa+on of a

possible rela+onship

between connec+ve +ssue

and mast cells

MCAS and EDS: Objec+ve Data  5pa6entsweretestedforobjec6veevidenceofmastcellac6va6on,including◦  serumtryptaselevelswerenormal◦  SerumIGE<20kiu/ml(3-20)◦  24hoururinehistaminecollec6onswereunremarkable.

 AllEhlersDanlosSyndromepa6entsappeartodisplaynon-IgEmediatedallergicdiseasecontrolledbyan6-mediatortherapyandavoidanceoftriggers.

One Gene Muta+on Links Three Mysterious, Debilita+ng Diseases: Hypertryptasemia, tryptase > 9 ng/ml

(personal communica+on with J. Milner, MD, PhD)

 “Onagoodday,myshoulders,knees,andhipswilldislocatetwotofive6mesapiece.Theslightestbumpintoatableordoorwillbloomnewbruisesonmyarmsandlegsortearagashinthethinskinonmyhands.Mybloodpressurewillplummeteach6meIstand,makingmefeelwoozy,nauseated,andweak.I’llhavetroublefocusingandrememberingwords.I’llrunmyerrandsfromunderneathanumbrellatopreventanallergicreac6ontotheSun.”

  -KateHorowitz,MentalFloss,October2016

 RHINITISSneezing*Conges6on*Stuffiness*ItchyEyes*Runnynose*PostNasalDrip*STINGINGINSECTALLERGY*Wheezing*ShortnessofBreath*ThroatTightness*Cough*HoarseVoice*ChestPain*ChestTightness*ANAPHYLAXISTroubleSwallowing*Itchymouth/throat*NasalStuffiness*Nasal/SinusConges6on*Circula6onProblems*Pale/Bluecolor*FOODALLERGYLowPulse*Dizziness*BreathingTroubles*Lightheadedness/PassingOut,LowBloodPressure*Shock*ASTHMALossofConsciousness*ItchySkin*Hives*Skinswelling*Warm,Red,Flee6ngRashes*StomachTroubles*Nausea*AbdominalPain/Cramps*Vomi6ng*URTICARIADiarrhea*Anxiety*FeelingofImpendingDoom,itchy/red/wateryeyes*ANGIOEDEMAHeadache*CrampingoftheUterus*FoodAllergy*Diarrhea*Wheezing*Mul6pleDRUGALLERGIES*FOODALLERGYLowPulse*Dizziness*BreathingTroubles*Lightheadedness/PassingOut,LowBloodPressure*Shock*ASTHMALossofConsciousness*ItchySkin*ALLERGICECZEMA*SinusHeadaches*Cough*FoodAllergy*Diarrhea/Vomi6ng*Bloa6ng*Shortnessofbreath*Wheezing*ChestTightness*Nasalconges6on*Runnynose*Itchyskin*Nosebleeds*PoorSenseofSmell*Itchynose*ASTHMANasalpolyps*ANGIOEDEMA*Nausea*AbdominalPain/Cramps*Vomi6ng*Headache*CrampingoftheUterus*FoodAllergy*Diarrhea*ANAPHYLAXISTroubleSwallowing*Itchymouth/throat*NasalStuffiness*Nasal/SinusConges6on*Circula6onProblems*Pale/Bluecolor*FOODALLERGYLowPulse*Dizziness*BreathingTroubles*Lightheadedness/PassingOut,LowBloodPressure*Shock*ASTHMALossofConsciousness*ItchySkin*Hives*Skinswelling*Warm,Red,Flee6ngRashes*StomachTroublesRHINITISSneezing*Conges6on*Stuffiness*ItchyEyes*Runnynose*PostNasalDrip*STINGINGINSECTALLERGY*Wheezing*ShortnessofBreath*ThroatTightness*Cough*HoarseVoice*ChestPain*ChestTightness*DrugAllergies*Headache*ANAPHYLAXISANGIOEDEMA**TroubleSwallowing*Itchymouth/throat*NasalStuffiness*Nasal/SinusConges6on*Circula6onProblems*ASTHMA*fa6gue*PainwhenUrina0ng*BrainFog*diarrhea*RHINITISSneezing*Conges6on*Stuffiness*

TryptaseChymaseCor0solReleasingHormone

Mast Cell Derived Enzyme Muta+on and EDS/JHS?

 “Ourfindingslinkfindings(germline)duplica6oninTPSAB1(thealpha-tryptasegene)with

◦  Irritablebowelsyndrome◦  Cutaneouscomplaints◦  Connec6veTissueAbnormali6es

◦  Dysautonomia

Mast Cell

Reticular Fibers

Elastic Fibers

Collagen FibersCapillary Blood Vessel

Fat Cell

Macrophage

Melanocyte

Mast Cell Ac+va+on Syndrome

(MCAS) Endotypes

 An‘‘endotype’’isasubtypeofacondi6ondefinedbyadis6nctpathophysiologicalmechanism.

 CriteriafordefiningMCASendotypesonthebasisoftheirphenotypesandputa6vepathophysiology.

 Usingthesecriteriawillhelpiden6fyMCASendotypes,whichcanthenbeusedtodesignandtailorexis6ngandnoveltherapiestopa6ents,thatwouldmostlikelytobenefit.

SerotoninNerve Growth

Factor

EnzymesChymaseTryptase

ChemokinesTumor Necrosis

factor

HistamineHeparin

Leukotrienes

Interstitial Cystitis

HeadachesBRAIN

FOG

ASTHMA ANAPHYLAXIS

ARTHRITIS

HIVES

IRRITABLEBOWEL

SYNDROME

FOOD ALLERGY

RHINITISMastCell

Mastcells▪  arefoundinmostpartsofthebody

▪  havearoleinallergic/anaphylac6creac6onsandotherinflammatorydiseasesintheskin,respiratorytract,joints,gastrointes6naItract,nervoussystem,bladder

▪  worsenwithstress

MCADDiagnosis:(1)Symptoms,(2)Data,(3)ResponsetoMCmedica0ons

Key to MCAD treatment: Early Diagnosis, Educa+on

to reduce stress

Stress Reduc+on & Regain Tolerance

 Inowbelievethattheul6matepowerlieswiththe6ssues.Whenhealthy,6ssuesinducetolerance.Whendistressed,theys6mulateimmunity,and(con6nuingdownthispath)theymayalsodeterminetheeffectorclassofaresponse.◦  PollyMatzinger,Reflec6onsonself:Immunityandbeyond.Viewpoint:TheDangerModel:ARenewedSenseofSelf,Sciencevol296,2002

MastCells