atopy: the common and the rare-- allergies in the genomic era• why do we have them? • why are...
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Atopy:theCommonandtheRare--AllergiesintheGenomicEra
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Outline
• Whatisanallergy?• Howdotheyhappenandhowcanwetreatthem?
• Whydowehavethem?• Whyaretheyontheincrease?• Howdogene9cscontributetoallergy?
– Examples:Eczema,monogenicdiseasesofallergy
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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!!!
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Othertypesofallergicsymptoms
• Hives–triggeredornot• Chronicitching• Skinflushing(althoughallergiescancausealotoftheotherkindtoo)
• Certaintypesofabdominalpain• Dropinbloodpressure
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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)
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What’sthebestwaytogetmeskep9calaboutwhetherIhavean
allergy?• AskinorbloodtestIreceivethatsomeonedrewalongwith300othertests“justtocheck”,saysI’mallergictomilk.Ireaditwhileea9ngpizzaandyogurt.
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“AllergyTests”
• Skinprickorpatch• BloodIgE
– RAST– Validatedvs.unvalidated
• Challenge• Pulmonaryfunc9on
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Outline
• Whatisanallergy?• Howdotheyhappenandhowcanwetreatthem?
• Whydowehavethem?• Whyaretheyontheincrease?• Howdogene9cscontributetoallergy?
– Examples:Eczema,monogenicdiseasesofallergy
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Howdoallergieshappen?
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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
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Corticosteroids
Acute Allergy vs. Allergic Inflammation
(Kay NEJM 2001)
GATA3
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Atopicderma99s:anexampleofchronicallergicinflamma9on
TSLP
GATA3
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ButI’vetakenan9histamines,steroidsandXolairandIs9llitch
• Wedon’tknoweverything,regardlessofwhatwesay
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Outline
• Whatisanallergy?• Howdotheyhappenandhowcanwetreatthem?
• Whydowehavethem?• Whyaretheyontheincrease?• Howdogene9cscontributetoallergy?
– Examples:Eczema,monogenicdiseasesofallergy
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Triggering“type2”responses
PulendranetalScience2012
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Palm,Nature2012
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Whydowehaveallergies?
Livefreelivenatural.com
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Immunity 2013
Keepingbees9ngsatbay?
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Outline
• Whatisanallergy?• Howdotheyhappenandhowcanwetreatthem?
• Whydowehavethem?• Whyaretheyontheincrease?• Howdogene9cscontributetoallergy?
– Examples:Eczema,monogenicdiseasesofallergy
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Whyareallergiesworsenowadays?
• Thehygienehypothesis– Weavoidbugstoomuch
• Delayedintroduc9onofsolidfoods– Weavoidfoodstoomuch
• Westernlifestyle– Weareexposedtothewrongbugs,thewrongfoods,andthewrongchemicals
– “Doctor,Xanaxisthemostwonderfulan9histamineIhaveevertaken.”
Allergicchild.com
X
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Prior to speech, pretreatment with mast cell stabilizer (cromolyn)
Ge\nguphereandspeakingisworsethanelectricshock
Vanuytsel et al, Gut 2014
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Themicrobiomeandallergy
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Outline
• Whatisanallergy?• Howdotheyhappenandhowcanwetreatthem?
• Whydowehavethem?• Whyaretheyontheincrease?• Howdogene9cscontributetoallergy?
– Examples:Eczema,monogenicdiseasesofallergy
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Gene9csandallergy
• Areallergiesgene9cdisorderswhosepenetranceincreaseover9me?
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SkinBarrierDynamics
Cork, et al JACI 2006
• Elevated pH (from soap, detergents, etc.) increases protease activity
Filaggrin
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Comel-NethertonSyndromeAphysicalbarrierdefect
• Congenitalichthyosisandallergen-specificatopicdiathesis
• Causedbymuta9onsinSPINK5—geneencodingLEKTIaproteaseinthecorneodesmosome
Pre-IvIg
Post-IvIg Renner et al JACI 2009
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Copyright ©2009 BMJ Publishing Group Ltd.
van den Oord, R. A H M et al. BMJ 2009;339:b2433
Filaggrinmuta9onsincreaseriskfortypicalAD—importanceofbarrier
func9oninADpathogenesis
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Protec9ngthebarrierwrapsGetSTpics
Tota
l SC
OR
AD
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EczemaHerpe9cum
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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
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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
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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
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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
**
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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!
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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.!
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Prevalenceofelevatedtryptaseinthegeneralpopula9on
n = 420
4.3% (n = 18): >11.4ug/L
Gonzalez-Quintela. Clin Chem Lab Med. 2010"
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WilliamPaul,MD1936-2015
JEM 1982
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FromBenchtoBedside:An9-IL-4R2therapy
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THANKYOU!
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Ques9ons?