atopy: the common and the rare-- allergies in the genomic era• why do we have them? • why are...

Atopy:theCommonandtheRare--AllergiesintheGenomicEra

Outline

•  Whatisanallergy?•  Howdotheyhappenandhowcanwetreatthem?

•  Whydowehavethem?•  Whyaretheyontheincrease?•  Howdogene9cscontributetoallergy?

– Examples:Eczema,monogenicdiseasesofallergy

Whatareallergies?Immediateallergies “chronic”allergies Notallergies

•  Anaphylaxis•  Breakingoutinto

hiveswithin4hoursoffoodordrug

•  HayFever(allergicrhiniconjunc9vi9s)

•  ManytypesofasthmaaJacks

•  Theoralallergysyndrome

•  Vomi9ngsoonaMerea9ngafood*

•  Eosinophilicesophagi9s

•  Proteinproc99s/proctocoli9s(bloodinthediaper)

•  Eczema•  Allergiccontact

derma99s*

•  Lung,esophagus,andnasalmucosalremodeling

•  Lactoseintolerance

•  Celiacdisease•  MostDrug

reac9ons•  Reflux/Heartburn•  Jointpain•  Overhalfof

reportedfoodallergies!!!

Othertypesofallergicsymptoms

•  Hives–triggeredornot•  Chronicitching•  Skinflushing(althoughallergiescancausealotoftheotherkindtoo)

•  Certaintypesofabdominalpain•  Dropinbloodpressure

What’sthebestwaytoknowI’mallergictosomething?

•  Ino9cehives,itching,throatclosureorlossofbloodpressurewithin4hoursofbeingexposed,usuallybyea9ngafoodordrug,orge\ngitbyIV

•  I get a runny nose and wheeze at the same time of year every year, or in the same house that I visit every time

(exception: in-laws’ place)

What’sthebestwaytogetmeskep9calaboutwhetherIhavean

allergy?•  AskinorbloodtestIreceivethatsomeonedrewalongwith300othertests“justtocheck”,saysI’mallergictomilk.Ireaditwhileea9ngpizzaandyogurt.

“AllergyTests”

•  Skinprickorpatch•  BloodIgE

– RAST– Validatedvs.unvalidated

•  Challenge•  Pulmonaryfunc9on

Outline




Howdoallergieshappen?

IgE–amajorplayerinacute“allergyaJacks”

IgM IgG IgA IgE

Mast cell

FcERI Hives Itchy skin Sneezing Wheezing Runny nose Vomiting Anaphylaxis

Leaky/dilated blood vessels

Anithistamines

Vasoconstrictors Mast cell stabilizers

IgE Blockade Antigenic tolerance

Corticosteroids

Acute Allergy vs. Allergic Inflammation

(Kay NEJM 2001)

GATA3

Atopicderma99s:anexampleofchronicallergicinflamma9on

TSLP

GATA3

ButI’vetakenan9histamines,steroidsandXolairandIs9llitch

•  Wedon’tknoweverything,regardlessofwhatwesay

Outline




Triggering“type2”responses

PulendranetalScience2012

Palm,Nature2012

Whydowehaveallergies?

Livefreelivenatural.com

Immunity 2013

Keepingbees9ngsatbay?

Outline




Whyareallergiesworsenowadays?

•  Thehygienehypothesis– Weavoidbugstoomuch

•  Delayedintroduc9onofsolidfoods– Weavoidfoodstoomuch

•  Westernlifestyle– Weareexposedtothewrongbugs,thewrongfoods,andthewrongchemicals

–  “Doctor,Xanaxisthemostwonderfulan9histamineIhaveevertaken.”

Allergicchild.com

X

Prior to speech, pretreatment with mast cell stabilizer (cromolyn)

Ge\nguphereandspeakingisworsethanelectricshock

Vanuytsel et al, Gut 2014

Themicrobiomeandallergy

Outline




Gene9csandallergy

•  Areallergiesgene9cdisorderswhosepenetranceincreaseover9me?

SkinBarrierDynamics

Cork, et al JACI 2006

• Elevated pH (from soap, detergents, etc.) increases protease activity

Filaggrin

Comel-NethertonSyndromeAphysicalbarrierdefect

•  Congenitalichthyosisandallergen-specificatopicdiathesis

•  Causedbymuta9onsinSPINK5—geneencodingLEKTIaproteaseinthecorneodesmosome

Pre-IvIg

Post-IvIg Renner et al JACI 2009

Copyright ©2009 BMJ Publishing Group Ltd.

van den Oord, R. A H M et al. BMJ 2009;339:b2433

Filaggrinmuta9onsincreaseriskfortypicalAD—importanceofbarrier

func9oninADpathogenesis

Protec9ngthebarrierwrapsGetSTpics

Tota

l SC

OR

AD

EczemaHerpe9cum

MonogenicdiseasesofatopyDisease Causa?veGene Primarypathologic

mechanism

IPEX FOXP3 Tregfailure

AD-HIES STAT3 Abnormalcytokinesignaling

WiskoJAldrichSyndrome WASP Cytoskeletaldysfunc9on.?Tregfailure

ADA-SCID ADA ?TCRrepertoire

Dock8deficiency DOCK8 Unknown

OmennSyndrome Various OligoclonalT-cellrepertoire

SAMSyndrome DSG1 Cell-celladhesion

Netherton’sSyndrome SPINK5 Skinbarrier

Loewys-DietzSyndrome TGFBR ?Tregfailure

PLAID PLCG2 Mastcellsignaling

PLAID •  PLCG2-associated •  Antibody deficiency •  Immune Dysregulation

Ombrello et al NEJM 2012

•  Evaporative cold urticaria from birth

•  Variable immune deficiency,

autoimmunity, granulomatous disease

•  Gain of function mutation in PLCG2

A novel monogenic allergic disease Clinical Features •  Severe atopic dermatitis,

elevated IgE, food allergy, asthma

•  Recurrent bacterial sinopulmonary infection, EBV viremia

•  Diffuse demyelination •  Myoclonus, delayed evoked

potential •  Neurocognitive delay •  Scoliosis, other bony/CT

abnormalities

Laboratory Features •  High IgG, IgA, IgE •  Low class-switched

memory B-cells •  Lymphopenia •  Autoantibodies

Family I Family II Zhang Et al; Sassi et al, JACI 2014

Phosphoglucomutase 3– an essential enzyme for glycosylation

GlcNAc-6p GlcNAc-1p

PGM3

Glucose Hexosamine Pathway GlcNAc

UDP-GlcNAc

Cytosol

Golgi/ER

N- and O- linked glycosylation UDP-GlcNAc

Atopic

Dermati

tis

Control

PGM3 Defi

ciency

0

25000

50000

PHA

-L M

FI

Naive CD4+ T Cells

**

Familial hypertryptasemia

•  Cutaneous –  Recurrent flushing, itching,

angioedema •  Connective Tissue

–  Hypermobile joints, retained dentition, scoliosis

•  Atopy –  Anaphylaxis, eczema, asthma, food/

drug allergy, rhinitis/conjunctivitis •  Gastrointestinal

–  Episodic pain, urgency, IBS, reflux, Neuropsychiatric, eosinophilic esophagitis, colitis

•  Neuropsychiatric –  tachycardia/dysautonomia, Anxiety/

Depression, pain, fatigue, “brain fog”

•  Normal bone marrow biopsy Lyons et al. J. Allergy Clin. Immunol. 2014!

ii." iii."i." v."iv."

vii."vi." viii." ix."

Hypertryptasemia: A dominantly inherited trait

Lyons et al. J. Allergy Clin. Immunol. 2014

x.! xiii.!xii.!

xi.!

?!

xvi.!

xv.!

xiv.!

Prevalenceofelevatedtryptaseinthegeneralpopula9on

n = 420

4.3% (n = 18): >11.4ug/L

Gonzalez-Quintela. Clin Chem Lab Med. 2010"

WilliamPaul,MD1936-2015

JEM 1982

FromBenchtoBedside:An9-IL-4R2therapy

THANKYOU!

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atopy: the common and the rare-- allergies in the genomic era• why do we have them? • why are...

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