Celiac disease : how complicated can it get?

Celiac disease : how complicated can it get?

Tjon, J.M.L.

Citation

Tjon, J. M. L. (2011, November 30). Celiac disease : how complicated can it get?. Retrieved from https://hdl.handle.net/1887/18156

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/18156

Note: To cite this publication please use the final published version (if

applicable).

Jennifer M-L. Tjon

C ^ELIAC D ^ISEASE

How complicated can it get?

J.M-L . Tjon

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Scope of this Thesis

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ĞůŝĂĐ ĚŝƐĞĂƐĞ ;Ϳ ŝƐ Ă ĐŽŵŵŽŶ ŝŶŇĂŵŵĂƚŽƌLJ ĚŝƐŽƌĚĞƌ ŽĨ ƚŚĞ ƐŵĂůů ŝŶƚĞƐƟŶĞ͕ ǁŚŝĐŚ

ŝƐƚƌŝŐŐĞƌĞĚďLJŝŶŐĞƐƚĞĚŐůƵƚĞŶƉƌŽƚĞŝŶƐ͘WƌĞǀŝŽƵƐƐƚƵĚŝĞƐŝĚĞŶƟĮĞĚĐƌƵĐŝĂůƐƚĞƉƐŝŶƚŚĞ

ĚĞǀĞůŽƉŵĞŶƚŽĨĐĞůŝĂĐĚŝƐĞĂƐĞĂŶĚďĂƐĞĚŽŶƚŚŝƐŬŶŽǁůĞĚŐĞ͕ǁĞƉƌŽƉŽƐĞĂƚŚƌĞƐŚŽůĚ

ŵŽĚĞů ĨŽƌ ƚŚĞ ĚĞǀĞůŽƉŵĞŶƚ ŽĨ ĐĞůŝĂĐ ĚŝƐĞĂƐĞ͕ ǁŚŝĐŚ ŝƐ ĚĞƐĐƌŝďĞĚ ŝŶ ĐŚĂƉƚĞƌ ϭ͘ /ƚ ŚĂƐ

ĂůƐŽďĞĐŽŵĞĐůĞĂƌƚŚĂƚĂĚƵůƚͲŽŶƐĞƚĐĞůŝĂĐĚŝƐĞĂƐĞŚĂƐĂŚŝŐŚĞƌĨƌĞƋƵĞŶĐLJŽĨĚĞǀĞůŽƉŝŶŐ

ĐŽŵƉůŝĐĂƟŽŶƐ͗ ƌĞĨƌĂĐƚŽƌLJ ĐĞůŝĂĐ ĚŝƐĞĂƐĞ ;ZͿ ĂŶĚ ĞŶƚĞƌŽƉĂƚŚLJ ĂƐƐŽĐŝĂƚĞĚ d ĐĞůů

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ƚLJƉĞ//͘dŚŝƐĚŝǀŝƐŝŽŶǁĂƐďĂƐĞĚŽŶƚŚĞƌĞƐƉĞĐƟǀĞĂďƐĞŶĐĞŽƌƉƌĞƐĞŶĐĞŽĨĂŶĂďĞƌƌĂŶƚ

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ĐĞůůƐĂŶĚǁĞƌĞŝĚĞŶƟĮĞĚĂƐƚŚĞŵŝƐƐŝŶŐ

ůŝŶŬďĞƚǁĞĞŶƌĞŐƵůĂƌ/>ƐŝŶƵŶĐŽŵƉůŝĐĂƚĞĚĐĞůŝĂĐĚŝƐĞĂƐĞĂŶĚůLJŵƉŚŽŵĂĐĞůůƐŝŶd>͘

dŚĞĨƵŶĐƟŽŶĂŶĚĐĞůůƵůĂƌŽƌŝŐŝŶŽĨƚŚĞĂďĞƌƌĂŶƚ/>Ɛ͕ŚŽǁĞǀĞƌ͕ƌĞŵĂŝŶĞĚƵŶĐůĞĂƌ͘dŚĞ

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ĐŚĂƌĂĐƚĞƌŝƐƟĐƐŽĨĂďĞƌƌĂŶƚ/>ƐĂƐƚŚŝƐŵŝŐŚƚŚĞůƉƚŽƵŶĚĞƌƐƚĂŶĚƚŚĞĞǀĞŶƚƐůĞĂĚŝŶŐĨƌŽŵ

ƵŶĐŽŵƉůŝĐĂƚĞĚƚŽZ//ĂŶĚŐĂƐƚƌŽŝŶƚĞƐƟŶĂůůLJŵƉŚŽŵĂ͘

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ŝŶǀŽůǀĞŵĞŶƚŽĨ ƚŚĞĚŝƐĞĂƐĞ ƉƌĞĚŝƐƉŽƐŝŶŐ ,>ͲYϮ ĂŶĚ ,>ͲYϴ ŵŽůĞĐƵůĞƐ ĂŶĚ ƚŚĞŝƌ

ƌŽůĞ ŝŶ ƚŚĞ ƉƌĞƐĞŶƚĂƟŽŶ ŽĨ ŐůƵƚĞŶ ĚĞƌŝǀĞĚ ƉĞƉƟĚĞƐ͘ ĂƐĞĚ ŽŶ ƚŚĞ ĂǀĂŝůĂďůĞ ĚĂƚĂ ǁĞ

ƉƌŽƉŽƐĞĂƚŚƌĞƐŚŽůĚŵŽĚĞůŝŶǁŚŝĐŚƚŚĞĞĸĐŝĞŶĐLJŽĨŐůƵƚĞŶƉƌĞƐĞŶƚĂƟŽŶƚŽϰ

$5$/"661$

ĚĞƚĞƌŵŝŶĞƐƚŚĞůŝŬĞůŝŚŽŽĚŽĨĚĞǀĞůŽƉŝŶŐĂŶĚŝƚƐĐŽŵƉůŝĐĂƟŽŶƐ͘

hŶƟů ƌĞĐĞŶƚůLJ͕ ĂďĞƌƌĂŶƚ />Ɛ ǁĞƌĞ ŵĂŝŶůLJ ŝŶǀĞƐƟŐĂƚĞĚ ŝŶ ƐŝƚƵ ĚƵĞ ƚŽ ůĂĐŬ ŽĨ ŵŽĚĞů

ƐLJƐƚĞŵƐ͘dŚŝƐůŝŵŝƚĞĚƚŚĞƚLJƉĞĂŶĚĞdžƚĞŶƚŽĨĞdžƉĞƌŝŵĞŶƚƐƚŽŝŶǀĞƐƟŐĂƚĞŵŽůĞĐƵůĂƌĞǀĞŶƚƐ

ůŝŶŬĞĚƚŽƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨZ//ĂŶĚd>͘/Ŷ><;(%+".?ǁĞĚĞƐĐƌŝďĞƚŚĞŝƐŽůĂƟŽŶĂŶĚ

ƉƌŽƉĂŐĂƟŽŶŽĨƚŚƌĞĞĐĞůůůŝŶĞƐĨƌŽŵĚƵŽĚĞŶĂůďŝŽƉƐŝĞƐŽĨƚŚƌĞĞŝŶĚŝǀŝĚƵĂůZ//ƉĂƟĞŶƚƐ

ƚŚĂƚĚŝƐƉůĂLJĂƐƵƌĨĂĐĞdZͲϯ

ϰ

ϴ

ϳ

ϭϬϯ

͕ŝŶƚƌĂĐĞůůƵůĂƌϯ

ƉŚĞŶŽƚLJƉĞƚŚĂƚ

ŝƐĐŚĂƌĂĐƚĞƌŝƐƟĐĨŽƌƚŚĞĂďĞƌƌĂŶƚĐĞůůƐĨŽƵŶĚŝŶƉĂƟĞŶƚƐǁŝƚŚZ//͘tĞƵƐĞĚƚŚĞƐĞĐĞůů

ůŝŶĞƐĂƐĂŵŽĚĞůĨŽƌĂďĞƌƌĂŶƚ/>ƐŝŶĂůůƚŚĞƐƚƵĚŝĞƐĚĞƐĐƌŝďĞĚŝŶƚŚŝƐƚŚĞƐŝƐ͘/Ŷ><;(%+".?$

ǁĞƐƚƵĚŝĞĚƚŚĞƉƌĞƐĞŶĐĞĂŶĚĨƵŶĐƟŽŶĂůŝƚLJŽĨƚŚĞŝŶĚŝǀŝĚƵĂůdZĂŶĚϯĐŚĂŝŶƐ͘

/ŶĂĐƟǀĞĐĞůŝĂĐĚŝƐĞĂƐĞ͕ƌĞŐƵůĂƌdZ

/>ƐĂĐƋƵŝƌĞĂŶE<ĐĞůůƌĞĐĞƉƚŽƌƌĞƉĞƌƚŽŝƌĞƚŚƌŽƵŐŚ

ǁŚŝĐŚ ƚŚĞLJ ĐĂŶ ůLJƐĞ ĞƉŝƚŚĞůŝĂů ĐĞůůƐ͘ DƵĐŚ ůĞƐƐ ŝƐ ŬŶŽǁŶ ĂďŽƵƚ ƚŚĞ ĐŽŶƚƌŝďƵƟŽŶ ŽĨ

ĂďĞƌƌĂŶƚ/>ƐƚŽƟƐƐƵĞĚĂŵĂŐĞŝŶZ//ĂŶĚd>͘/Ŷ><;(%+".@ǁĞƵƐĞĚƚŚĞZĐĞůůůŝŶĞƐ

ƚŽŝŶǀĞƐƟŐĂƚĞƚŚĞƐƉĞĐŝĮĐŝƚLJŽĨĐLJƚŽƚŽdžŝĐŝƚLJŽĨĂďĞƌƌĂŶƚ/>ƐĂŶĚƚŚĞƌĞĐĞƉƚŽƌƐŝŶǀŽůǀĞĚ͘

/Ŷ><;(%+".AǁĞƐƚƵĚŝĞĚƚŚĞĂďŝůŝƚLJŽĨƚŚĞZĐĞůůůŝŶĞƐƚŽƐĞĐƌĞƚĞĐLJƚŽŬŝŶĞƐĂŌĞƌƚƌŝŐŐĞƌŝŶŐ

ǁŝƚŚĂŶĂƌƌĂLJŽĨƐƟŵƵůŝ͘dŚŝƐĐŚĂƉƚĞƌĂůƐŽƐƵŐŐĞƐƚƐĂŶŽǀĞůƌŽůĞĨŽƌƚŚĞĂĐƟǀĂƟŽŶŵĂƌŬĞƌ

ϯϬŽŶ;ƉƌĞͿŵĂůŝŐŶĂŶƚ/>ƐŝŶZ//ĂŶĚd>͘

dŚĞĞdžĂĐƚĐĞůůƵůĂƌŽƌŝŐŝŶŽĨĂďĞƌƌĂŶƚ/>ƐŝƐƐƟůůƵŶĐůĞĂƌ͘&ƌŽŵ><;(%+".?ǁĞůĞĂƌŶĞĚƚŚĂƚ

ŝŶƚƌĂĐĞůůƵůĂƌ͕ Ăůů ϯ ĐŚĂŝŶƐ ǁĞƌĞ ƉƌĞƐĞŶƚ͕ ǁŚĞƌĞĂƐ ƚŚĞ dZ ĐŚĂŝŶƐ ǁĞƌĞ ŶŽƚ ĂůǁĂLJƐ

ƉƌĞƐĞŶƚ͘&ƵƌƚŚĞƌŵŽƌĞ͕ƚŚĞϯĐŽŵƉůĞdžǁĂƐĨƵŶĐƟŽŶĂů ĂƐŝŶƚƌŽĚƵĐƟŽŶ ŽĨĞdžŽŐĞŶŽƵƐ

dZĐŚĂŝŶƐƌĞƐƵůƚĞĚŝŶƐƵƌĨĂĐĞdZͲϯĞdžƉƌĞƐƐŝŽŶ͘/Ŷ><;(%+".BǁĞƉĞƌĨŽƌŵĞĚŐĞŶŽŵŝĐ͕

ϭϬ

ƚƌĂŶƐĐƌŝƉƚŽŵŝĐĂŶĚŇŽǁĐLJƚƌŽŵĞƚƌŝĐĂŶĂůLJƐŝƐŽĨƚŚĞZĐĞůůůŝŶĞƐĂƐĂĨƵƌƚŚĞƌƐƚĞƉƚŽ

ĚĞƚĞƌŵŝŶĞ ƚŚĞ ĐĞůůƵůĂƌ ŽƌŝŐŝŶ ŽĨ ĂďĞƌƌĂŶƚ />Ɛ͘ tĞ ĚĞŵŽŶƐƚƌĂƚĞ ƚŚĂƚ ĐĞůůƐ ǁŝƚŚ ĂŶ

͞ĂďĞƌƌĂŶƚ͟ƉŚĞŶŽƚLJƉĞĂƌĞƉƌĞƐĞŶƚŝŶƚŚĞŝŶƚĞƐƟŶĂůĞƉŝƚŚĞůŝƵŵŽĨŚĞĂůƚŚLJŝŶĚŝǀŝĚƵĂůƐĂƐ

ǁĞůů͘dŚŝƐůĞĚƵƐƚŽƉƌŽƉŽƐĞƚŚĂƚƐƵĐŚĐĞůůƐĂƌĞƉĂƌƚŽĨƚŚĞŶŽƌŵĂůůLJŵƉŚŽĐLJƚĞƌĞƉĞƌƚŽŝƌĞ

ĂŶĚ ŵŽƐƚ ůŝŬĞůLJ ƚŚĞ ƉƌĞĐƵƌƐŽƌƐ ŽĨ ƚŚĞ ŵŽŶŽĐůŽŶĂů ĂďĞƌƌĂŶƚ ĐĞůů ƉŽƉƵůĂƟŽŶƐ ĨŽƵŶĚ ŝŶ

ƉĂƟĞŶƚƐǁŝƚŚZ//ĂŶĚd>͘DŽƌĞŽǀĞƌ͕ƚŚĞƐĞĚĂƚĂŝŶĚŝĐĂƚĞƚŚĂƚĂďĞƌƌĂŶƚ/>ƐĂƌĞŶŽƚ

ĚĞƌŝǀĞĚĨƌŽŵŵĂƚƵƌĞdĐĞůůƐ͘

/Ŷ><;(%+".CƚŚĞƌĞůĞǀĂŶĐĞŽĨƚŚŝƐƚŚĞƐŝƐĂŶĚĚŝƌĞĐƟŽŶƐĨŽƌĨƵƌƚŚĞƌƌĞƐĞĂƌĐŚĂŶĚĨƵƚƵƌĞ

ƚŚĞƌĂƉĞƵƟĐƉŽƐƐŝďŝůŝƟĞƐĂƌĞĚŝƐĐƵƐƐĞĚ͘

ϭϭ

Scope of this Thesis

C ^HAPTER 1

G ENERAL I NTRODUCTION

C ELIAC D ISEASE : H OW C OMPLICATED C AN I T G ET ?

Jennifer M-L. Tjon

, Jeroen van Bergen

and Frits Koning

1

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.

Immunogenetics. 2010 Oct; 62(10): 641-651

ϭϰ

«ƒÖã›Ù

=

Chapter 1

Ýãك‘ã

/ŶƚŚĞƐŵĂůůŝŶƚĞƐƟŶĞŽĨĐĞůŝĂĐĚŝƐĞĂƐĞƉĂƟĞŶƚƐ͕ĚŝĞƚĂƌLJǁŚĞĂƚŐůƵƚĞŶĂŶĚƐŝŵŝůĂƌƉƌŽƚĞŝŶƐ

ŝŶďĂƌůĞLJĂŶĚƌLJĞƚƌŝŐŐĞƌĂŶŝŶŇĂŵŵĂƚŽƌLJƌĞƐƉŽŶƐĞ͘tŚŝůĞƐƚƌŝĐƚĂĚŚĞƌĞŶĐĞƚŽĂŐůƵƚĞŶͲ ĨƌĞĞĚŝĞƚŝŶĚƵĐĞƐĨƵůůƌĞĐŽǀĞƌLJŝŶŵŽƐƚƉĂƟĞŶƚƐ͕ĂƐŵĂůůƉĞƌĐĞŶƚĂŐĞŽĨƉĂƟĞŶƚƐĨĂŝůƚŽ

ƌĞĐŽǀĞƌ͘/ŶĂƐƵďƐĞƚŽĨƚŚĞƐĞƌĞĨƌĂĐƚŽƌLJĐĞůŝĂĐĚŝƐĞĂƐĞƉĂƟĞŶƚƐĂŶ;ĂďĞƌƌĂŶƚͿŽůŝŐŽĐůŽŶĂů

ŝŶƚƌĂĞƉŝƚŚĞůŝĂů ůLJŵƉŚŽĐLJƚĞ ƉŽƉƵůĂƟŽŶ ĚĞǀĞůŽƉƐ ŝŶƚŽ ŽǀĞƌƚ ůLJŵƉŚŽŵĂ͘ ĞůŝĂĐ ĚŝƐĞĂƐĞ

ŝƐ ƐƚƌŽŶŐůLJ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ,>ͲYϮ ĂŶĚͬŽƌ ,>ͲYϴ ĂƐ ďŽƚŚ ŐĞŶŽƚLJƉĞƐ ƉƌĞĚŝƐƉŽƐĞ

ĨŽƌ ĚŝƐĞĂƐĞ ĚĞǀĞůŽƉŵĞŶƚ͘ dŚŝƐ ĂƐƐŽĐŝĂƟŽŶ ĐĂŶ ďĞ ĞdžƉůĂŝŶĞĚ ďLJ ƚŚĞ ĨĂĐƚ ƚŚĂƚ ŐůƵƚĞŶ

ƉĞƉƟĚĞƐĐĂŶďĞƉƌĞƐĞŶƚĞĚŝŶ,>ͲYϮĂŶĚ,>ͲYϴŵŽůĞĐƵůĞƐŽŶĂŶƟŐĞŶƉƌĞƐĞŶƟŶŐ

ĐĞůůƐ͘'ůƵƚĞŶͲƐƉĞĐŝĮĐϰ

dĐĞůůƐŝŶƚŚĞůĂŵŝŶĂƉƌŽƉƌŝĂƌĞƐƉŽŶĚƚŽƚŚĞƐĞƉĞƉƟĚĞƐĂŶĚ

ƚŚŝƐ ůŝŬĞůLJ ĞŶŚĂŶĐĞƐ ĐLJƚŽƚŽdžŝĐŝƚLJ ŽĨ ŝŶƚƌĂĞƉŝƚŚĞůŝĂů ůLJŵƉŚŽĐLJƚĞƐ ĂŐĂŝŶƐƚ ƚŚĞ ŝŶƚĞƐƟŶĂů

ĞƉŝƚŚĞůŝƵŵ͘ tĞ ƉƌŽƉŽƐĞ Ă ƚŚƌĞƐŚŽůĚ ŵŽĚĞů ĨŽƌ ƚŚĞ ĚĞǀĞůŽƉŵĞŶƚ ŽĨ ĐĞůŝĂĐ ĚŝƐĞĂƐĞ ŝŶ

ǁŚŝĐŚƚŚĞĞĸĐŝĞŶĐLJŽĨŐůƵƚĞŶƉƌĞƐĞŶƚĂƟŽŶƚŽϰ

dĐĞůůƐĚĞƚĞƌŵŝŶĞƐƚŚĞůŝŬĞůŝŚŽŽĚŽĨ

ĚĞǀĞůŽƉŝŶŐĐĞůŝĂĐĚŝƐĞĂƐĞĂŶĚŝƚƐĐŽŵƉůŝĐĂƟŽŶƐ͘<ĞLJĨĂĐƚŽƌƐƚŚĂƚŝŶŇƵĞŶĐĞƚŚĞĞĸĐŝĞŶĐLJ

ŽĨ ŐůƵƚĞŶ ƉƌĞƐĞŶƚĂƟŽŶ ŝŶĐůƵĚĞ͗ ;ϭͿ ƚŚĞ ůĞǀĞů ŽĨ ŐůƵƚĞŶ ŝŶƚĂŬĞ͕ ;ϮͿ ƚŚĞ ĞŶnjLJŵĞ ƟƐƐƵĞ

ƚƌĂŶƐŐůƵƚĂŵŝŶĂƐĞϮǁŚŝĐŚŵŽĚŝĮĞƐŐůƵƚĞŶŝŶƚŽŚŝŐŚĂĸŶŝƚLJďŝŶĚŝŶŐƉĞƉƟĚĞƐĨŽƌ,>ͲYϮ

ĂŶĚ,>ͲYϴ͕;ϯͿƚŚĞ,>ͲYͲƚLJƉĞĂƐ,>ͲYϮďŝŶĚƐĂǁŝĚĞƌƌĂŶŐĞŽĨŐůƵƚĞŶƉĞƉƟĚĞƐ

ƚŚĂŶ,>ͲYϴ͕;ϰͿƚŚĞŐĞŶĞĚŽƐĞŽĨ,>ͲYϮĂŶĚ,>ͲYϴĂŶĚĮŶĂůůLJ͕;ϱͿĂĚĚŝƟŽŶĂů

ŐĞŶĞƟĐƉŽůLJŵŽƌƉŚŝƐŵƐƚŚĂƚŵĂLJŝŶŇƵĞŶĐĞdĐĞůůƌĞĂĐƟǀŝƚLJ͘dŚŝƐƚŚƌĞƐŚŽůĚŵŽĚĞůŵŝŐŚƚ

ĂůƐŽŚĞůƉƚŽƵŶĚĞƌƐƚĂŶĚƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨƌĞĨƌĂĐƚŽƌLJĐĞůŝĂĐĚŝƐĞĂƐĞĂŶĚůLJŵƉŚŽŵĂ͘

ϭϱ

«ƒÖã›Ù

=

General Introduction

/ÄãÙʗç‘ã®ÊÄ

tŝƚŚĂƉƌĞǀĂůĞŶĐĞŽĨϭйŝŶǁĞƐƚĞƌŶƉŽƉƵůĂƟŽŶƐ͕ĐĞůŝĂĐĚŝƐĞĂƐĞ;ͿŝƐŽŶĞŽĨƚŚĞŵŽƐƚ

ĐŽŵŵŽŶŝŶŇĂŵŵĂƚŽƌLJĚŝƐŽƌĚĞƌƐŽĨƚŚĞƐŵĂůůŝŶƚĞƐƟŶĞ

͘ŝƐŽŌĞŶĂƐƐƵŵĞĚƚŽŚĂǀĞŝƚƐ

ŽŶƐĞƚŝŶĐŚŝůĚŚŽŽĚďƵƚŝƚŚĂƐƌĞĐĞŶƚůLJďĞĞŶƐƵŐŐĞƐƚĞĚƚŚĂƚĂĚƵůƚƐĐĂŶĂůƐŽĚĞǀĞůŽƉ

͘

ůŝŶŝĐĂůŵĂŶŝĨĞƐƚĂƟŽŶƐǀĂƌLJĂĐĐŽƌĚŝŶŐƚŽĂŐĞŐƌŽƵƉ͗ŝŶĨĂŶƚƐĂŶĚLJŽƵŶŐĐŚŝůĚƌĞŶƉƌĞƐĞŶƚ

ǁŝƚŚĚŝĂƌƌŚĞĂ͕ĂďĚŽŵŝŶĂůĚŝƐƚĞŶƟŽŶĂŶĚĨĂŝůƵƌĞƚŽƚŚƌŝǀĞ͕ǁŚĞƌĞĂƐĂĚƵůƚƐƚŚĂƚĚĞǀĞůŽƉ

ŶŽƚŽŶůLJƉƌĞƐĞŶƚǁŝƚŚĚŝĂƌƌŚĞĂďƵƚĂůƐŽǁŝƚŚƐŝůĞŶƚŵĂŶŝĨĞƐƚĂƟŽŶƐƐƵĐŚĂƐĂŶĞŵŝĂ͕

ŽƐƚĞŽƉŽƌŽƐŝƐŽƌŶĞƵƌŽůŽŐŝĐĂůƐLJŵƉƚŽŵƐ

͘/ŵŵƵŶŽŚŝƐƚŽĐŚĞŵŝƐƚƌLJŽĨƚŚĞƐŵĂůůŝŶƚĞƐƟŶĞ

ŽĨƉĂƟĞŶƚƐƐŚŽǁƐǀŝůůŽƵƐĂƚƌŽƉŚLJ͕ĐƌLJƉƚŚLJƉĞƌƉůĂƐŝĂĂŶĚĞůĞǀĂƚĞĚůĞǀĞůƐŽĨŝŶƚƌĂĞƉŝƚŚĞůŝĂů

ůLJŵƉŚŽĐLJƚĞƐ;/>ƐͿ͘dŚĞŽŶůLJƚŚĞƌĂƉLJƵŶƟůŶŽǁŝƐĂŐůƵƚĞŶͲĨƌĞĞĚŝĞƚ͕ǁŚŝĐŚǁŝůůŶŽƌŵĂůŝnjĞ

ƚŚĞĐůŝŶŝĐĂůĂŶĚŚŝƐƚŽůŽŐŝĐĂůŵĂŶŝĨĞƐƚĂƟŽŶƐĂŶĚĂůůŽǁƐƚŚĞƉĂƟĞŶƚƐƚŽůŝǀĞĂŶŽƚŚĞƌǁŝƐĞ

ŶŽƌŵĂůůŝĨĞ͘

ƐŵĂůůƉĞƌĐĞŶƚĂŐĞŽĨĂĚƵůƚͲŽŶƐĞƚƉĂƟĞŶƚƐĚĞǀĞůŽƉĂƉƌŝŵĂƌLJŽƌƐĞĐŽŶĚĂƌLJƌĞƐŝƐƚĂŶĐĞ

ƚŽĂŐůƵƚĞŶͲĨƌĞĞĚŝĞƚ;&ŝŐƵƌĞϭͿ͘dŚŝƐĐŽŶĚŝƟŽŶŝƐĐĂůůĞĚƌĞĨƌĂĐƚŽƌLJĐĞůŝĂĐĚŝƐĞĂƐĞ;ZͿ

ĂŶĚŝƐĐŚĂƌĂĐƚĞƌŝnjĞĚďLJƉĞƌƐŝƐƟŶŐǀŝůůŽƵƐĂƚƌŽƉŚLJĂŶĚĞůĞǀĂƚĞĚůĞǀĞůƐŽĨ/>Ɛ͘ƵƌƌĞŶƚůLJ͕

ZŝƐƐƵďĚŝǀŝĚĞĚŝŶƚŽƚǁŽƐƵďƚLJƉĞƐ͗ZƚLJƉĞ/;Z/ͿĂŶĚZƚLJƉĞ//;Z//ͿƚŚĂƚ

ďŽƚŚĚŝƐƉůĂLJĐůŝŶŝĐĂůĂŶĚŚŝƐƚŽůŽŐŝĐĂůƌĞƐŝƐƚĂŶĐĞƚŽĂŐůƵƚĞŶͲĨƌĞĞĚŝĞƚ

͘Z//͕ŚŽǁĞǀĞƌ͕

ŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚƚŚĞƉƌĞƐĞŶĐĞŽĨĂŶĂďĞƌƌĂŶƚ/>ƉŽƉƵůĂƟŽŶƚŚĂƚůĂĐŬƐƐƵƌĨĂĐĞdĐĞůů

ƌĞĐĞƉƚŽƌ;dZͿͲϯĞdžƉƌĞƐƐŝŽŶďƵƚĐŽŶƚĂŝŶƐŝŶƚƌĂĐĞůůƵůĂƌϯɸĂŶĚŚĂƐĐůŽŶĂůdZɶͲŐĞŶĞ

ƌĞĂƌƌĂŶŐĞŵĞŶƚƐ

͘dŚĞƐĞĂďĞƌƌĂŶƚ/>ƐĐĂŶŐĂŝŶĐŚƌŽŵŽƐŽŵĂůĂďŶŽƌŵĂůŝƟĞƐĂŶĚĚĞǀĞůŽƉ

ŝŶƚŽƐƵƌĨĂĐĞdZͲϯ

ůLJŵƉŚŽŵĂĐĞůůƐ

͘Z//ŝƐƚŚĞƌĞĨŽƌĞĐŽŶƐŝĚĞƌĞĚĂƉƌĞŵĂůŝŐŶĂŶƚ

ĐŽŶĚŝƟŽŶĂŶĚƌŽƵŐŚůLJϱϬйŽĨƚŚĞZ//ƉĂƟĞŶƚƐĚĞǀĞůŽƉŽǀĞƌƚůLJŵƉŚŽŵĂǁŝƚŚŝŶϱLJĞĂƌƐ

ŽĨĚŝĂŐŶŽƐŝƐ

͘/ŶƐƵŵŵĂƌLJ͕ƚŚĞŵĂũŽƌŝƚLJŽĨƉĂƟĞŶƚƐŚĂƐĂŶƵŶĐŽŵƉůŝĐĂƚĞĚĚŝƐĞĂƐĞ

ĐŽƵƌƐĞĂŶĚĐĂŶďĞƚƌĞĂƚĞĚǁŝƚŚĂŐůƵƚĞŶͲĨƌĞĞĚŝĞƚ;&ŝŐƵƌĞϭͿ͘Z//ĂŶĚZͲĂƐƐŽĐŝĂƚĞĚ

ůLJŵƉŚŽŵĂ͕ŚŽǁĞǀĞƌ͕ĂƌĞĚŝĸĐƵůƚƚŽƚƌĞĂƚĂŶĚŚĂǀĞƚŚĞƌĞĨŽƌĞƉŽŽƌϱͲLJĞĂƌƐƵƌǀŝǀĂůƌĂƚĞƐ

ŽĨфϰϰйĂŶĚфϮϬйƌĞƐƉĞĐƟǀĞůLJ

͘

dŚĞĚĞǀĞůŽƉŵĞŶƚŽĨŝƐĚĞƚĞƌŵŝŶĞĚďLJďŽƚŚĞŶǀŝƌŽŶŵĞŶƚĂůĂŶĚŐĞŶĞƟĐĨĂĐƚŽƌƐ͘/ŶƚŚĞ

ϭϵϱϬƐŝŶŐĞƐƟŽŶŽĨǁŚĞĂƚƉƌŽĚƵĐƚƐǁĂƐĚĞƐĐƌŝďĞĚƚŽĐĂƵƐĞŵĂůĂďƐŽƌƉƟŽŶƐLJŵƉƚŽŵƐŝŶ

ƉĂƟĞŶƚƐ

͘>ĂƚĞƌŽŶŝƚǁĂƐĞƐƚĂďůŝƐŚĞĚƚŚĂƚŐůƵƚĞŶ͕ƚŚĞƐƚŽƌĂŐĞƉƌŽƚĞŝŶƐŝŶǁŚĞĂƚ͕ďĂƌůĞLJ

ĂŶĚƌLJĞ͕ĐĂƵƐĞĚĂĐĞůůͲŵĞĚŝĂƚĞĚŝŵŵƵŶĞƌĞƐƉŽŶƐĞŝŶƚŚĞƐŵĂůůŝŶƚĞƐƟŶĞ

͘/ŶĂĚĚŝƟŽŶƚŽ

&®¦çٛ ϭ͘ Wٛòƒ½›Ä‘› Ê¥  ƒÄ— ‘ÊÃÖ½®‘ƒã›—  ®Ä 㫛 ƒç‘ƒÝ®ƒÄ ÖÊÖ罃ã®ÊÄ͘ ƉƉƌŽdžŝŵĂƚĞůLJ Ϯϱй

ŽĨ ƚŚĞ ŐĞŶĞƌĂů ĂƵĐĂƐŝĂŶ ƉŽƉƵůĂƟŽŶ ŝƐ ,>ͲYϮ⁴͘ &ƌŽŵ ƚŚĞƐĞ ŐĞŶĞƟĐĂůůLJ ƐƵƐĐĞƉƟďůĞ ŝŶĚŝǀŝĚƵĂůƐ ŽŶůLJ

ϰй ĚĞǀĞůŽƉƐ ͘ /Ŷ ƚŚĞ ŵĂũŽƌŝƚLJ ŽĨ ƚŚĞ  ƉĂƟĞŶƚƐ ƚŚĞ ĚŝƐĞĂƐĞ ĐŽƵƌƐĞ ŝƐ ƵŶĐŽŵƉůŝĐĂƚĞĚ͘ ZŽƵŐŚůLJ ϯй

ŽĨ ƚŚĞ  ƉĂƟĞŶƚƐ ǁŝůů ŶŽƚ ƌĞƐƉŽŶĚ ƚŽ Ă ŐůƵƚĞŶͲĨƌĞĞ ĚŝĞƚ ĂŶĚ ĚĞǀĞůŽƉ Z͘  ƐƵďƐĞƚ ŽĨ Z ƉĂƟĞŶƚƐ

ĚĞǀĞůŽƉ Z // ŽĨ ǁŚŝĐŚ ĂƉƉƌŽdžŝŵĂƚĞůLJ ϱϬй ĚĞǀĞůŽƉƐ ZͲĂƐƐŽĐŝĂƚĞĚ ůLJŵƉŚŽŵĂ ;ŶŽƚ ƐŚŽǁŶͿ͘

ϭϲ

«ƒÖã›Ù

=

Chapter 1

ƚŚŝƐĞŶǀŝƌŽŶŵĞŶƚĂůĨĂĐƚŽƌ͕ĚĞǀĞůŽƉŵĞŶƚŝŶǀŽůǀĞƐŐĞŶĞƟĐƉƌĞĚŝƐƉŽƐŝƟŽŶĂƐƚŚĞǀĂƐƚ

ŵĂũŽƌŝƚLJŽĨƚŚĞƉĂƟĞŶƚƐƉŽƐƐĞƐƐ,>ͲYϮĂŶĚͬŽƌ,>ͲYϴ

͘,>ͲYϮŝƐĂŐĞŶŽƚLJƉĞ

ƚŚĂƚŝƐƉƌĞƐĞŶƚŝŶƌŽƵŐŚůLJϮϱйŽĨƚŚĞƵƌŽƉĞĂŶƉŽƉƵůĂƟŽŶ

;&ŝŐƵƌĞϭͿ͘zĞƚŽŶůLJΕϰй

ŽĨĂůů,>ͲYϮ

ŝŶĚŝǀŝĚƵĂůƐĚĞǀĞůŽƉ;&ŝŐƵƌĞϭͿ

͘ĚĞǀĞůŽƉŵĞŶƚŝŶ,>ͲYϮͲĂŶĚ

,>ͲYϴͲŶĞŐĂƟǀĞ ŝŶĚŝǀŝĚƵĂůƐ ŝƐ ĞdžƚƌĞŵĞůLJ ƌĂƌĞ

͘ dŚĞƐĞ ĮŶĚŝŶŐƐ ĐĂŵĞ ƚŽŐĞƚŚĞƌ ǁŝƚŚ

ƚŚĞŽďƐĞƌǀĂƟŽŶƚŚĂƚϰ

dĐĞůůůŝŶĞƐĨƌŽŵĚƵŽĚĞŶĂůďŝŽƉƐŝĞƐŽĨƉĂƟĞŶƚƐƐƉĞĐŝĮĐĂůůLJ

ƌĞƐƉŽŶĚƚŽŐůƵƚĞŶƉĞƉƟĚĞƐƉƌĞƐĞŶƚĞĚďLJ,>ͲYϮĂŶĚͬŽƌ,>ͲYϴ

͘dŚĞĞƟŽůŽŐLJŽĨ

ZŝƐŵƵĐŚůĞƐƐĐůĞĂƌ͕ďƵƚƐĞĞŵƐƚŽďĞĂƐƐŽĐŝĂƚĞĚǁŝƚŚ,>ͲYϮ

͘

/Ŷ ƐŚŽƌƚ͕ ƚŚĞ ĐŽŵƉůĞdž ŝŶƚĞƌƉůĂLJ ŽĨ ŵƵůƟƉůĞ ŐĞŶĞƟĐ ĂŶĚ ĞŶǀŝƌŽŶŵĞŶƚĂů ĨĂĐƚŽƌƐ ǁŝůů

ĚĞƚĞƌŵŝŶĞƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨĂŶĚŝƚƐĐŽŵƉůŝĐĂƟŽŶƐ͘dŚŝƐƌĞǀŝĞǁĚĞƐĐƌŝďĞƐĐƵƌƌĞŶƚ

ŬŶŽǁůĞĚŐĞŽŶŐůƵƚĞŶ͕,>ͲYĂŶĚƚŚĞŝŵŵƵŶŽƉĂƚŚŽŐĞŶĞƐŝƐŽĨĂŶĚŝƚƐĐŽŵƉůŝĐĂƟŽŶƐ͘

/ŶĂĚĚŝƟŽŶ͕ǁĞƉƌĞƐĞŶƚĂůŝŬĞůLJƐĞƋƵĞŶĐĞŽĨĞǀĞŶƚƐŝŶƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨĂŶĚĚŝƐĐƵƐƐ

ƚŚĞĨĂĐƚŽƌƐƚŚĂƚŵĂLJŝŶŇƵĞŶĐĞƚŚĞƌŝƐŬŽĨĚĞǀĞůŽƉŵĞŶƚ͘

'½çã›Ä͗㫛—®Ý›ƒÝ›®Ä—瑮Ħ›Äò®ÙÊÄÛÄヽãÙ®¦¦›Ù

dŚĞǀŝƐĐŽͲĞůĂƐƟĐƉƌŽƉĞƌƟĞƐŽĨŐůƵƚĞŶĂƌĞĞƐƐĞŶƟĂůĨŽƌĚŽƵŐŚĨŽƌŵĂƟŽŶŽĨǁŚĞĂƚŇŽƵƌ

ĂŶĚŐŝǀĞďƌĞĂĚŝƚƐƵŶŝƋƵĞƚĞdžƚƵƌĞĂŶĚƚĂƐƚĞ͘ĞĐĂƵƐĞŽĨŝƚƐƵŶŝƋƵĞƉƌŽƉĞƌƟĞƐŐůƵƚĞŶŝƐ

ǁŝĚĞůLJƵƐĞĚŝŶƚŚĞĨŽŽĚŝŶĚƵƐƚƌLJ͗ŶŽƚŽŶůLJŝŶƉƌŽĚƵĐƚƐƚŚĂƚĂƌĞƌĞĂĚŝůLJĂƐƐŽĐŝĂƚĞĚǁŝƚŚ

ǁŚĞĂƚ͕ůŝŬĞďƌĞĂĚ͕ĐŽŽŬŝĞƐĂŶĚƉĂƐƚĂ͕ďƵƚĂůƐŽĂƐĂŚŝĚĚĞŶŝŶŐƌĞĚŝĞŶƚŝŶƐĂƵĐĞƐ͕ŝŶƐƚĂŶƚ

ƐŽƵƉƐĂŶĚĞǀĞŶŵĞĚŝĐĂƟŽŶ͘ŽŶƐĞƋƵĞŶƚůLJ͕ƚŚĞĚĂŝůLJŐůƵƚĞŶŝŶƚĂŬĞŽŶĂŐůƵƚĞŶͲĐŽŶƚĂŝŶŝŶŐ

ĚŝĞƚŝŶtĞƐƚĞƌŶͲƵƌŽƉĞĂŶĚƚŚĞhŶŝƚĞĚ^ƚĂƚĞƐŝƐŚŝŐŚ͕ďĞƚǁĞĞŶϭϱĂŶĚϮϬŐƌĂŵƉĞƌĚĂLJ͘

dŚĞŽŵŶŝƉƌĞƐĞŶĐĞŽĨŐůƵƚĞŶŵĂŬĞƐĂĚŚĞƌĞŶĐĞƚŽĂŐůƵƚĞŶͲĨƌĞĞĚŝĞƚĐŚĂůůĞŶŐŝŶŐĨŽƌ

ƉĂƟĞŶƚƐ͘

'ůƵƚĞŶŝƐĂŚĞƚĞƌŽŐĞŶĞŽƵƐŵŝdžƚƵƌĞŽĨŐůŝĂĚŝŶƐĂŶĚŐůƵƚĞŶŝŶƐŝŶǁŚĞĂƚŽƌƐŝŵŝůĂƌƉƌŽƚĞŝŶƐ

ŝŶďĂƌůĞLJĂŶĚƌLJĞ͘ĂĐŚǁŚĞĂƚǀĂƌŝĞƚLJĞdžƉƌĞƐƐĞƐŵƵůƟƉůĞɲͲ͕ɶͲĂŶĚʘͲŐůŝĂĚŝŶƐŝŶĂĚĚŝƟŽŶ

ƚŽůŽǁĂŶĚŚŝŐŚŵŽůĞĐƵůĂƌǁĞŝŐŚƚŐůƵƚĞŶŝŶƐ͘'ůƵƚĞŶŚĂƐĂǀĞƌLJŚŝŐŚĐŽŶƚĞŶƚŽĨƚŚĞĂŵŝŶŽͲ ĂĐŝĚƐŐůƵƚĂŵŝŶĞ;ϯϬйͿĂŶĚƉƌŽůŝŶĞ;ϭϱйͿ͘LJǀŝƌƚƵĞŽĨŝƚƐŚŝŐŚŐůƵƚĂŵŝŶĞĐŽŶƚĞŶƚŐůƵƚĞŶŝƐ

ƌŝĐŚŝŶŶŝƚƌŽŐĞŶ͕ĂŶĞƐƐĞŶƟĂůĨĂĐƚŽƌĨŽƌƐĞĞĚŐĞƌŵŝŶĂƟŽŶ͘dŚĞŚŝŐŚƉƌŽůŝŶĞĐŽŶƚĞŶƚƌĞŶĚĞƌƐ

ŐůƵƚĞŶŚŝŐŚůLJƌĞƐŝƐƚĂŶƚƚŽĚĞŐƌĂĚĂƟŽŶďLJŐĂƐƚƌŽŝŶƚĞƐƟŶĂůĞŶnjLJŵĞƐ͕ŵĂŬŝŶŐŝƚƉŽƐƐŝďůĞĨŽƌ

ůĂƌŐĞŝŵŵƵŶŽŐĞŶŝĐŐůƵƚĞŶƉĞƉƟĚĞƐƚŽƌĞĂĐŚƚŚĞŵƵĐŽƐĂůƐƵƌĨĂĐĞ

͘ƐŵŽĚĞƌŶǁŚĞĂƚ

ǀĂƌŝĞƟĞƐĐŽŶƚĂŝŶƚŚƌĞĞĐŽŵƉůĞƚĞŐĞŶŽŵĞƐĞŶĐŽĚŝŶŐŐůŝĂĚŝŶƐĂŶĚŐůƵƚĞŶŝŶƐ͕ƵƉƚŽϭϬϬ

ĚŝīĞƌĞŶƚŐůƵƚĞŶƉƌŽƚĞŝŶƐŵĂLJďĞƉƌĞƐĞŶƚŝŶĂƐŝŶŐůĞǁŚĞĂƚǀĂƌŝĞƚLJĂŶĚŵĂŶLJŽĨƚŚĞƐĞĂƌĞ

ŝŵƉůŝĐĂƚĞĚŝŶƚŚĞƉĂƚŚŽŐĞŶĞƐŝƐŽĨ͘

,>ͲY͗㫛ÝãÙÊĦ›Ý㗮ݛƒÝ›ͲƒÝÝʑ®ƒã›—¦›Ä›½Ê‘çݐù¥ƒÙ

dŚĞƐƚƌŽŶŐŐĞŶĞƟĐŝŶŇƵĞŶĐĞŝŶŝƐĂƉƉĂƌĞŶƚĂƐƚŚĞĐŽŶĐŽƌĚĂŶĐĞďĞƚǁĞĞŶŵŽŶŽnjLJŐŽƟĐ

ƚǁŝŶƐŝƐϴϬй͕ǁŚĞƌĞĂƐŝŶĚŝnjLJŐŽƟĐƚǁŝŶƐƚŚŝƐŝƐŽŶůLJϭϭй

͕ǁŚŝĐŚŝƐĂƉƉƌŽdžŝŵĂƚĞůLJƚŚĞ

ƐĂŵĞĂƐƚŚĞƌŝƐŬĨŽƌĮƌƐƚͲĚĞŐƌĞĞƌĞůĂƟǀĞƐ

͘dŚĞŵĂŝŶŐĞŶĞƟĐŝŶŇƵĞŶĐĞŝŶŝƐ,>͕

ǁŚŝĐŚǁĂƐĮƌƐƚŝŶĚŝĐĂƚĞĚďLJƐƚƵĚŝĞƐĚĞƐĐƌŝďŝŶŐƚŚĞƉƌĞĚŽŵŝŶĂŶĐĞŽĨ,>ͲϴĂŶĚ,>ͲZϯ

ƐĞƌŽƚLJƉĞƐŝŶƉĂƟĞŶƚƐ

͘>ĂƚĞƌƐƚƵĚŝĞƐĞƐƚĂďůŝƐŚĞĚƚŚĂƚƚŚĞƐƚƌŽŶŐĞƐƚĂƐƐŽĐŝĂƟŽŶŝƐ

ǁŝƚŚ,>ͲYϮ;YΎϬϱϬϭ͕YΎϬϮϬϭ͕ƚĞƌŵĞĚ,>ͲYϮ͘ϱŚĞƌĞĂŌĞƌͿ

͕ǁŚŝĐŚŝƐĞŶĐŽĚĞĚ

ƚŽŐĞƚŚĞƌǁŝƚŚ,>ͲϴĂŶĚ,>ͲZϯŽŶƚŚĞŚŝŐŚůLJĐŽŶƐĞƌǀĞĚĂŶĐĞƐƚƌĂůŚĂƉůŽƚLJƉĞϴ͘ϭ

͘

ŝƐĂƐƐŽĐŝĂƚĞĚƚŽĂůĞƐƐĞƌĞdžƚĞŶƚǁŝƚŚ,>ͲYϴ;YΎϬϯ͕YΎϬϯϬϮͿ

͘dŚĞƐƚƌŽŶŐ

ĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶ,>ͲYϮ͘ϱĂŶĚŝƐĨƵƌƚŚĞƌŝůůƵƐƚƌĂƚĞĚďLJƚŚĞŽďƐĞƌǀĂƟŽŶƚŚĂƚ

ϭϳ

«ƒÖã›Ù

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General Introduction ŝŶĚŝǀŝĚƵĂůƐŚŽŵŽnjLJŐŽƵƐĨŽƌ,>ͲYϮ͘ϱŚĂǀĞĂĮǀĞͲĨŽůĚŝŶĐƌĞĂƐĞĚƌŝƐŬĨŽƌĚĞǀĞůŽƉŵĞŶƚ

ŽĨ  ĐŽŵƉĂƌĞĚ ƚŽ ŝŶĚŝǀŝĚƵĂůƐ ŚĞƚĞƌŽnjLJŐŽƵƐ ĨŽƌ ,>ͲYϮ͘ϱ

͘ ^ŝŵŝůĂƌůLJ͕ ,>ͲY Ϯ͘ϱ

ŚŽŵŽnjLJŐŽƐŝƚLJ ŝƐ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ƚŚĞ ĚĞǀĞůŽƉŵĞŶƚ ŽĨ Z // ĂŶĚ ZͲĂƐƐŽĐŝĂƚĞĚ

ůLJŵƉŚŽŵĂ͕ǁŚĞƌĞĂƐƚŚŝƐĂƐƐŽĐŝĂƟŽŶŝƐůĞƐƐĐůĞĂƌĨŽƌ,>ͲYϮ͘ϱŚĞƚĞƌŽnjLJŐŽƐŝƚLJĂŶĚ,>Ͳ

Yϴ

͘ŶŽƚŚĞƌ,>ͲYϮǀĂƌŝĂŶƚĞdžŝƐƚƐ͗,>ͲYϮ͘Ϯ;YΎϬϮϬϭ͕YΎϬϮϬϮͿǁŚŝĐŚŚĂƐ

ĂƉĞƉƟĚĞͲďŝŶĚŝŶŐŵŽƟĨƚŚĂƚŝƐĂůŵŽƐƚŝĚĞŶƟĐĂůƚŽƚŚĂƚŽĨ,>ͲYϮ͘ϱ

͘tŚĞƌĞĂƐ,>Ͳ

YϮ͘ϱƉƌĞĚŝƐƉŽƐĞƐƚŽ͕,>ͲYϮ͘ϮĚŽĞƐŶŽƚ͘dŚŝƐĚŝīĞƌĞŶĐĞŝƐƌĞůĂƚĞĚƚŽƚŚĞƉĞƉƟĚĞͲ ďŝŶĚŝŶŐƉƌŽƉĞƌƟĞƐŽĨƚŚĞƐĞ,>ͲYϮǀĂƌŝĂŶƚƐ͘dŚĞĞƐƟŵĂƚĞĚƌŝƐŬĞīĞĐƚŽĨ,>ͲYϮĂŶĚ

,>ͲYϴŽŶĚĞǀĞůŽƉŵĞŶƚŝƐĞƐƟŵĂƚĞĚƚŽďĞΕϯϱй

͘

EŽƚ Ăůů ,>ͲYϮ͘ϱ

 ĂŶĚ ,>ͲYϴ

 ŝŶĚŝǀŝĚƵĂůƐ ĚĞǀĞůŽƉ ͕ ŝŶĚŝĐĂƟŶŐ ƚŚĂƚ ƚŚĞƐĞ ,>Ͳ ŐĞŶŽƚLJƉĞƐ ĂƌĞ ŶĞĐĞƐƐĂƌLJ ďƵƚ ŶŽƚ ƐƵĸĐŝĞŶƚ ĨŽƌ  ĚĞǀĞůŽƉŵĞŶƚ͘ ZĞĐĞŶƚ ůĂƌŐĞͲƐĐĂůĞ

ŐĞŶĞƟĐĂƐƐŽĐŝĂƟŽŶƐƚƵĚŝĞƐŝĚĞŶƟĮĞĚŵĂŶLJĂĚĚŝƟŽŶĂůŐĞŶĞƟĐůŽĐŝƚŚĂƚĂůůŵĂŬĞĂƐŵĂůů

ĐŽŶƚƌŝďƵƟŽŶƚŽƚŚĞƌŝƐŬƚŽĚĞǀĞůŽƉ;ŽdžϭĂŶĚdĂďůĞϭͿ͘/ŵƉŽƌƚĂŶƚůLJ͕ŵŽƐƚŽĨƚŚĞƐĞ

ŐĞŶĞƐĞŶĐŽĚĞƉƌŽƚĞŝŶƐŝŶǀŽůǀĞĚŝŶŝŵŵƵŶŝƚLJǁŚŝĐŚƐƵƉƉŽƌƚƐƚŚĞŶŽƟŽŶƚŚĂƚŝƐĂŶ

ŝŵŵƵŶĞƌĞůĂƚĞĚĚŝƐŽƌĚĞƌĂŶĚƉŽƐƐŝďůLJƉƌŽǀŝĚĞƐĐůƵĞƐŽŶƚŚĞŝŵŵƵŶŽƉĂƚŚŽŐĞŶĞƐŝƐŽĨ͘

dƒ½›ϭ͘>ʑ®ƒÝÝʑ®ƒã›—ó®ã«—›ò›½ÊÖÛÄã͘ΎKĚĚƐƌĂƟŽƐĨƌŽŵƵďŽŝƐĞƚĂů͘^ϲϬ

ϭϴ

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Chapter 1

d«›ƒ—ƒÖã®ò›®ÃÃçěٛÝÖÊÄݛ͗¦½çã›Ä͕,>ͲYƒÄ—ϰ

d‘›½½Ý

ƐŶŽƚĞĚĂďŽǀĞ͕ĚĞǀĞůŽƉƐĂůŵŽƐƚĞdžĐůƵƐŝǀĞůLJŝŶ,>ͲYϮ͘ϱ

Žƌ,>ͲYϴ

ŝŶĚŝǀŝĚƵĂůƐ͘

/ƚŝƐĂůƐŽǁĞůůĞƐƚĂďůŝƐŚĞĚƚŚĂƚŝŶƉĂƟĞŶƚƐ͕ŐůƵƚĞŶͲĚĞƌŝǀĞĚƉĞƉƟĚĞƐƉƌĞƐĞŶƚĞĚďLJĞŝƚŚĞƌ

,>ͲYϮ͘ϱŽƌ,>ͲYϴŝŶĚƵĐĞĂϰ

dĐĞůůƌĞƐƉŽŶƐĞ͘ŽƚŚ,>ͲYϮ͘ϱĂŶĚ,>ͲYϴ

ƉƌĞĨĞƌƚŽďŝŶĚƉĞƉƟĚĞƐǁŝƚŚŶĞŐĂƟǀĞůLJĐŚĂƌŐĞĚĂŵŝŶŽĂĐŝĚƐĂƚĂŶĐŚŽƌƌĞƐŝĚƵĞƐ͘'ůƵƚĞŶ

ƉĞƉƟĚĞƐ͕ŚŽǁĞǀĞƌ͕ĂƌĞǀŝƌƚƵĂůůLJĚĞǀŽŝĚŽĨŶĞŐĂƟǀĞĐŚĂƌŐĞƐĂŶĚŶĂƟǀĞŐůƵƚĞŶƉĞƉƟĚĞƐ

ƚŚƵƐďŝŶĚƉŽŽƌůLJƚŽ,>ͲYϮ͘ϱŽƌ,>ͲYϴ͘ŽŶƐĞƋƵĞŶƚůLJ͕ϰ

dĐĞůůƐƐƉĞĐŝĮĐĨŽƌŶĂƟǀĞ

ŐůƵƚĞŶƉĞƉƟĚĞƐĂƌĞƌĂƌĞ͘/ƚŚĂƐďĞĐŽŵĞĐůĞĂƌƚŚĂƚƚŚĞĞŶnjLJŵĞƟƐƐƵĞƚƌĂŶƐŐůƵƚĂŵŝŶĂƐĞ

Ϯ ;d'ϮͿ ĐĂŶ ŵŽĚŝĨLJ ŐůƵƚĞŶ ƉĞƉƟĚĞƐ ƚŽ Įƚ ƚŚĞ ƌĞƋƵŝƌĞŵĞŶƚƐ ĨŽƌ ŚŝŐŚ ĂĸŶŝƚLJ ďŝŶĚŝŶŐ

ƚŽ ,>ͲYϮ ĂŶ ,>ͲYϴ

͘ d'Ϯ ĐĂŶ ĐŽŶǀĞƌƚ ŶŽŶͲĐŚĂƌŐĞĚ ŐůƵƚĂŵŝŶĞ ŝŶƚŽ ŶĞŐĂƟǀĞůLJ

ĐŚĂƌŐĞĚŐůƵƚĂŵŝĐĂĐŝĚ͕ĂƉƌŽĐĞƐƐĐĂůůĞĚĚĞĂŵŝĚĂƟŽŶ͘ĞĐĂƵƐĞŐůƵƚĞŶŚĂƐĂŚŝŐŚĐŽŶƚĞŶƚ

ŽĨ ŐůƵƚĂŵŝŶĞ ;YͿ ĂŶĚ ƉƌŽůŝŶĞ ;WͿ͕ ƚŚĞ ƐĞƋƵĞŶĐĞƐ YW͕ YyW ĂŶĚ YyyW ;ŝŶ ǁŚŝĐŚ y ĐĂŶ

ƌĞƉƌĞƐĞŶƚĂŶLJĂŵŝŶŽĂĐŝĚͿĂƌĞĨƌĞƋƵĞŶƚůLJĨŽƵŶĚŝŶŐůƵƚĞŶƉĞƉƟĚĞƐ͘^ƚƌŝŬŝŶŐůLJ͕ŽŶůLJŝŶƚŚĞ

ƐĞƋƵĞŶĐĞYyWƚŚĞŐůƵƚĂŵŝŶĞŝƐĐŽŶǀĞƌƚĞĚ͕ǁŚŝĐŚƌĞƐƵůƚƐŝŶŚŝŐŚůLJƐĞůĞĐƟǀĞŝŶƚƌŽĚƵĐƟŽŶ

ŽĨŶĞŐĂƟǀĞĐŚĂƌŐĞƐŝŶŐůƵƚĞŶƉĞƉƟĚĞƐ

͘dŚŝƐƐƉĞĐŝĮĐĚĞĂŵŝĚĂƟŽŶƉƌŽĐĞƐƐŝŶƚƌŽĚƵĐĞƐƚŚĞ

ŶĞŐĂƟǀĞĐŚĂƌŐĞƐĂƚƚŚĞƉŽƐŝƟŽŶƐĨĂǀŽƌĞĚďLJ,>ͲYϮĂŶĚ,>ͲYϴ͕ƚŚĞƌĞďLJĞdžƉĂŶĚŝŶŐ

ƚŚĞƉƌĞƐĞŶƚĂďůĞŐůƵƚĞŶƉĞƉƟĚĞƌĞƉĞƌƚŽŝƌĞ;&ŝŐƵƌĞϮͿ͘ƐĂƌĞƐƵůƚ͕ƚŚĞŐůƵƚĞŶͲƐƉĞĐŝĮĐϰ

$ dĐĞůůƌĞƉĞƌƚŽŝƌĞŝƐƐƵďƐƚĂŶƟĂůůLJĞdžƉĂŶĚĞĚǁŚŝĐŚĞŶŚĂŶĐĞƐƚŚĞŝŶŇĂŵŵĂƟŽŶĂŶĚĚŝƐĞĂƐĞ

ĚĞǀĞůŽƉŵĞŶƚ;&ŝŐƵƌĞϮͿ͘

d'ϮŝƐŵŽƐƚůLJƌĞƚĂŝŶĞĚŝŶƚƌĂĐĞůůƵůĂƌůLJŝŶĂŶŝŶĂĐƟǀĞĨŽƌŵĂŶĚŝƐĂĐƟǀĂƚĞĚƵƉŽŶŝƚƐƌĞůĞĂƐĞ

ĚƵƌŝŶŐ ƟƐƐƵĞ ĚĂŵĂŐĞ

͘ dŚĞƌĞĨŽƌĞ͕ ƐŽŵĞƚŚŝŶŐ ƐŚŽƵůĚ ƚƌŝŐŐĞƌ ƟƐƐƵĞ ĚĂŵĂŐĞ ǁŚŝĐŚ

ŝŶŝƟĂƚĞƐd'ϮƌĞůĞĂƐĞ͕ĂůůŽǁŝŶŐƚŚĞŵŽĚŝĮĐĂƟŽŶŽĨŐůƵƚĞŶƉĞƉƟĚĞƐ͘tŚĞƌĞĂƐϰ

$5$/"66$

ƌĞƐƉŽŶƐĞƐĂŐĂŝŶƐƚŶĂƟǀĞŐůƵƚĞŶƉĞƉƟĚĞƐĂƌĞƌĞůĂƟǀĞůLJƌĂƌĞ͕ƚŚĞLJĐŽƵůĚƌĞƉƌĞƐĞŶƚƚŚĞ

ĮƌƐƚďƌĞĂĐŚŝŶŽƌĂůƚŽůĞƌĂŶĐĞƚŽŐůƵƚĞŶ͘dŚĞƉƌĞƐĞŶƚĂƟŽŶŽĨŶĂƟǀĞŐůƵƚĞŶƉĞƉƟĚĞƐďLJ

,>ͲYϮŽƌ,>ͲYϴƚŽϰ

dĐĞůůƐǁŝůůůĞĂĚƚŽƚŚĞƉƌŽĚƵĐƟŽŶŽĨ/&EͲɶ;&ŝŐƵƌĞϮͿ͘/&EͲɶ

ǁŝůůŝŶƚƵƌŶůĞĂĚƚŽŚŝŐŚĞƌĞdžƉƌĞƐƐŝŽŶŽĨƚŚĞ,>ͲYŵŽůĞĐƵůĞƐĂŶĚƚŚĞƌĞďLJƚŽŝŶĐƌĞĂƐĞĚ

ŐůƵƚĞŶƉĞƉƟĚĞƉƌĞƐĞŶƚĂƟŽŶ;&ŝŐƵƌĞϮͿ͘/ŶƚŚĞƉƌĞƐĞŶĐĞŽĨŐůƵƚĞŶ͕ƚŚŝƐĐŽƵůĚďĞĐŽŵĞĂ

ƐĞůĨͲĂŵƉůŝĨLJŝŶŐůŽŽƉƚŚĂƚĐŽƵůĚĐĂƵƐĞůŝŵŝƚĞĚƟƐƐƵĞĚĂŵĂŐĞůŽĐĂůůLJ͘dŚŝƐƟƐƐƵĞĚĂŵĂŐĞ

ǁŽƵůĚůĞĂĚƚŽƚŚĞƌĞůĞĂƐĞŽĨd'ϮƚŚĂƚǁŝůůŵŽĚŝĨLJŶĂƟǀĞŐůƵƚĞŶƉĞƉƟĚĞƐŝŶƚŽŚŝŐŚĂĸŶŝƚLJ

ůŝŐĂŶĚƐ ĨŽƌ ,>ͲYϮ ĂŶĚͬŽƌ ,>ͲYϴ͕ ƚŚĞƌĞďLJ ĞdžƉĂŶĚŝŶŐ ƚŚĞ ŐůƵƚĞŶͲƐƉĞĐŝĮĐ ϰ

$ 5$

Box 1. Non-HLA genes associated with CD

Candidate gene association study: Candidate genes, selected on the basis of current understanding of CD immunopathology, were tested for association with CD. Genes studied with this approach include, among others, IFN-γ, FAS, TCR, and TG2⁵⁵. No convincing association with CD was found.

Genetic linkage study: This approach is aimed at the identification of chromosomal regions that likely contain disease-causing genes in families with a high prevalence of CD. The genomic region 2q33 showed linkage to CD in multiple populations. This region contains the genes CD28, CTLA4 and ICOS which all control different aspects of the T cell response⁵⁵. Linkage was also found for chromosome 5q31-33⁵⁶ and chromosome 19p13.1⁵⁷. Linkage to these regions, however, could not always be replicated in other populations.

Genome-wide association study (GWAS): In recent years it has become possible to perform large-scale case control-based association studies using single nucleotide polymorphisms (SNPs). With this approach it is possible to identify common variants in the genome that predispose to disease. Until now, 10 non-HLA loci associated with CD have been identified and linkage to 2q33 has been confirmed (Table 1)^28;58;59. Recently, 13 additional true risk variants and 13 suggestive risk variants were identified⁶⁰. Although causality has only been proven for the risk allele SH2B3⁶¹, it is clear that nearly all associated regions contain genes involved in immune response.

ϭϵ

«ƒÖã›Ù

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General Introduction

&®¦çٛϮ͘^›½¥ƒÃÖ½®¥ù®Ä¦½ÊÊÖÝ®Ä㫛—›ò›½ÊÖÛÄãÊ¥͘,>ͲYϮ⁴Žƌ,>Yϴ⁴ŝŶĚŝǀŝĚƵĂůƐĐĂŶƉƌĞƐĞŶƚŶĂͲ ƟǀĞŐůƵƚĞŶƉĞƉƟĚĞƐŽŶƚŚĞŝƌWƚŽϰ⁴dĐĞůůƐ͘dŚĞ/&EͲɶƌĞůĞĂƐĞĚŝŶƚŚŝƐƉƌŽĐĞƐƐĐĂŶŝŶƚƵƌŶƐƚ,>ͲYϮͬϴ

ĞdžƉƌĞƐƐŝŽŶ͘dŚŝƐůŽǁͲŐƌĂĚĞŝŶŇĂŵŵĂƟŽŶŵŝŐŚƚĞǀĞŶƚƵĂůůLJůĞĂĚƚŽƟƐƐƵĞĚĂŵĂŐĞǁŝƚŚd'ϮƌĞůĞĂƐĞ͘d'ϮŝƐĂďůĞƚŽ

ĞdžƉĂŶĚƚŚĞƉƌĞƐĞŶƚĂďůĞŐůƵƚĞŶƉĞƉƟĚĞƌĞƉĞƌƚŽŝƌĞďLJĚĞĂŵŝĚĂƟŽŶ͘ƐĂƌĞƐƵůƚƚŚĞϰ⁴dĐĞůůƌĞƐƉŽŶƐĞŝƐƐƚƌŽŶŐůLJ

ĞŶŚĂŶĐĞĚ͕ůĞĂĚŝŶŐƚŽŵŽƌĞ/&EͲɶ͕ƟƐƐƵĞĚĂŵĂŐĞĂŶĚŝŶĐƌĞĂƐĞĚƌĞůĞĂƐĞŽĨd'Ϯ͘dŚĞĞŶĚƌĞƐƵůƚŝƐĨƵůůͲďůŽǁŶ͘

ĐĞůůƌĞƐƉŽŶƐĞƐĂŶĚůĞĂĚŝŶŐƚŽĂĚĚŝƟŽŶĂůƟƐƐƵĞĚĂŵĂŐĞ͗ƚŚĞŝŶŝƟĂƟŽŶŽĨĂƐĞĐŽŶĚƐĞůĨͲ ĂŵƉůŝĨLJŝŶŐ ůŽŽƉ ;&ŝŐƵƌĞ ϮͿ͘ ůƚĞƌŶĂƟǀĞůLJ͕ ŝŶĨĞĐƟŽŶƐ ŽĐĐƵƌƌŝŶŐ ŝŶ ƚŚĞ ŐĂƐƚƌŽŝŶƚĞƐƟŶĂů

ƚƌĂĐƚǁŽƵůĚŐĞŶĞƌĂƚĞĂƉƌŽͲŝŶŇĂŵŵĂƚŽƌLJŵŝůŝĞƵƚŚĂƚŵŝŐŚƚůĞĂĚƚŽůŽƐƐŽĨƚŽůĞƌĂŶĐĞƚŽ

ŶĂƟǀĞ ŐůƵƚĞŶ ƉĞƉƟĚĞƐ ĂŶĚ ŐĞŶĞƌĂƚĞ ƟƐƐƵĞ ĚĂŵĂŐĞ ƐŝŵƵůƚĂŶĞŽƵƐůLJ ĂŶĚ ƚŚƵƐ ŝŶŝƟĂƚĞ

ĚĞĂŵŝĚĂƟŽŶďLJd'Ϯ͘

‘ã®òƒã›— ®Äãك›Ö®ã«›½®ƒ½ ½ùÃ֫ʑùã›Ý —ƒÃƒ¦› 㫛 ®Äã›Ýã®Äƒ½

›Ö®ã«›½®çÃ

/ŶƚƌĂĞƉŝƚŚĞůŝĂů ůLJŵƉŚŽĐLJƚĞƐ ĂƌĞ ůŽĐĂůŝnjĞĚ ďĞƚǁĞĞŶ ŝŶƚĞƐƟŶĂů ĞƉŝƚŚĞůŝĂů ĐĞůůƐ Ăƚ ƚŚĞ

ďĂƐŽůĂƚĞƌĂů ƐŝĚĞ ŽĨ ƚŚĞ ĞƉŝƚŚĞůŝƵŵ ĂŶĚ ĂƌĞ ƚŚŽƵŐŚƚ ƚŽ ƉůĂLJ ĂŶ ŝŵƉŽƌƚĂŶƚ ƌŽůĞ ŝŶ

ŝŵŵƵŶŽƐƵƌǀĞŝůůĂŶĐĞ ŽĨ ƚŚĞ ĞƉŝƚŚĞůŝƵŵ͘ dŚĞ /> ƉŽƉƵůĂƟŽŶ ŝŶ ƚŚĞ ƐŵĂůů ŝŶƚĞƐƟŶĞ ŝƐ

Ă ŵŝdžĞĚ ƉŽƉƵůĂƟŽŶ ŽĨ dZɲɴ

 d ĐĞůůƐ͕ dZɶɷ

 d ĐĞůůƐ ĂŶĚ E< ĐĞůůƐ͕ ĂůƚŚŽƵŐŚ ƚŚĞ ǀĂƐƚ

ŵĂũŽƌŝƚLJ ŽĨ ƚŚĞ />Ɛ ĂƌĞ ϴ

 dZɲɴ

$ 5$ /"661

͘ &ƵƌƚŚĞƌŵŽƌĞ͕ ŵŽƐƚ ŽĨ ƚŚĞƐĞ dZ

 />Ɛ

ĞdžƉƌĞƐƐĂǀĂƌŝĞƚLJŽĨE<ĐĞůůƌĞĐĞƉƚŽƌƐƚŚĂƚŝƐĚŝƐƟŶĐƚĨƌŽŵƚŚĞE<ĐĞůůƌĞĐĞƉƚŽƌƐĞdžƉƌĞƐƐĞĚ

.*$86..,$5$/"661

͘dŚĞE<ĐĞůůƌĞĐĞƉƚŽƌƐĂƌĞƚŚŽƵŐŚƚƚŽĂĐƚŵĂŝŶůLJĂƐdĐĞůůĐŽͲƐƟŵƵůĂƚŽƌƐ͕

ůŽǁĞƌŝŶŐƚŚĞƚŚƌĞƐŚŽůĚĨŽƌdĐĞůůĂĐƟǀĂƟŽŶŝŶƐƚƌĞƐƐĨƵůƟŵĞƐ

͘

/ŶĂĐƟǀĞƚŚĞŶƵŵďĞƌŽĨϴ

dZɲɴ

ĂŶĚdZɶɷ

/>ƐŝƐŵĂƌŬĞĚůLJŝŶĐƌĞĂƐĞĚ͘/ƚŝƐ

ƵŶĐůĞĂƌǁŚĞƚŚĞƌƚŚŝƐŝƐĂƌĞƐƉŽŶƐĞƚŽĐŚĂŶŐĞƐŝŶƚŚĞŚŽŵĞŽƐƚĂƐŝƐŽĨƚŚĞĞƉŝƚŚĞůŝƵŵŽƌĂ

ĐŽŶƐĞƋƵĞŶĐĞŽĨƚŚĞƉƌŽͲŝŶŇĂŵŵĂƚŽƌLJŵŝůŝĞƵĐƌĞĂƚĞĚďLJƚŚĞϰ

dĐĞůůƌĞƐƉŽŶƐĞŝŶƚŚĞ

ůĂŵŝŶĂƉƌŽƉƌŝĂ;&ŝŐƵƌĞϯͿ͘^ŝŵŝůĂƌƚŽ/>ƐŽĨŶŽƌŵĂůĐŽŶƚƌŽůƐ͕/>ƐĨƌŽŵĂĐƟǀĞĞdžƉƌĞƐƐ

E<ĐĞůůƌĞĐĞƉƚŽƌƐ͘tŚĞŶĐŽŵƉĂƌĞĚƚŽŶŽƌŵĂůĐŽŶƚƌŽůƐ͕ŚŽǁĞǀĞƌ͕/>ƐĨƌŽŵƉĂƟĞŶƚƐ

ŚĂǀĞ ĂĐƋƵŝƌĞĚ Ă ŵŽƌĞ ĂĐƟǀĂƟŶŐ E< ĐĞůů ƌĞĐĞƉƚŽƌ ƌĞƉĞƌƚŽŝƌĞ

͘ /Ŷ ƚŚĞ ŚĞĂůƚŚLJ ƐŵĂůů

ŝŶƚĞƐƟŶĞ͕/>ƐƉƌĞĚŽŵŝŶĂŶƚůLJĞdžƉƌĞƐƐƚŚĞŝŶŚŝďŝƚŽƌLJϵϰͬE<'ϮƌĞĐĞƉƚŽƌ͘/ŶĐŽŶƚƌĂƐƚ͕

ϮϬ

«ƒÖã›Ù

=

Chapter 1

/>ƐŝŶĞdžƉƌĞƐƐŚŝŐŚůĞǀĞůƐŽĨĂĐƟǀĂƟŶŐƌĞĐĞƉƚŽƌƐůŝŬĞϵϰͬE<'ϮĂŶĚE<'Ϯ

͘

^ŝŵƵůƚĂŶĞŽƵƐůLJ͕ŝŶƚĞƐƟŶĂůĞƉŝƚŚĞůŝĂůĐĞůůƐŝŶƵƉƌĞŐƵůĂƚĞD/ĂŶĚ,>Ͳ͕ƚŚĞůŝŐĂŶĚƐĨŽƌ

E<'ϮĂŶĚϵϰͬE<'Ϯ͕ƌĞƐƉĞĐƟǀĞůLJ͘/ŶƚĞƌĂĐƟŽŶŽĨE<'ϮĂŶĚϵϰͬE<'ϮǁŝƚŚƚŚĞŝƌ

ůŝŐĂŶĚƐǁŝůůĞŶŚĂŶĐĞ/&EͲɶͲƉƌŽĚƵĐƟŽŶĂŶĚĐLJƚŽůLJƐŝƐ͕ůĞĂĚŝŶŐƚŽƟƐƐƵĞĚĂŵĂŐĞ;&ŝŐƵƌĞϯͿ͘

ŶŝŵƉŽƌƚĂŶƚĨĂĐƚŽƌŝŶĂĐƋƵŝƌŝŶŐĂŶĂĐƟǀĂƟŶŐE<ĐĞůůƌĞĐĞƉƚŽƌƌĞƉĞƌƚŽŝƌĞŝƐŝŶƚĞƌůĞƵŬŝŶ

ϭϱ;/>Ͳϭϱ͖ŽdžϮͿ͕ǁŚŝĐŚŚĂƐďĞĞŶƐŚŽǁŶƚŽƵƉƌĞŐƵůĂƚĞďŽƚŚE<'ϮĂŶĚϵϰͬE<'ϮŽŶ

/>ƐŽĨĂĐƟǀĞƉĂƟĞŶƚƐĂŶĚƐƚƚŚĞŝƌĂďŝůŝƚLJƚŽůLJƐĞĞŶƚĞƌŽĐLJƚĞƐ

͘/ŶĂĚĚŝƟŽŶ͕/>Ͳϭϱ

ĐĂŶĂůƚĞƌƚŚĞE<ĐĞůůƌĞĐĞƉƚŽƌĨƵŶĐƟŽŶ͕ůĞĂĚŝŶŐƚŽE<ĐĞůůƌĞĐĞƉƚŽƌŵĞĚŝĂƚĞĚĐLJƚŽƚŽdžŝĐŝƚLJ

ŝŶĚĞƉĞŶĚĞŶƚŽĨdZƐƉĞĐŝĮĐŝƚLJ

͘/ŶĐŽŶĐůƵƐŝŽŶ͕ǁŚŝůĞŐůƵƚĞŶͲƐƉĞĐŝĮĐϰ

$5$/"661$"6'/'!$

ĂŶŝŶŇĂŵŵĂƚŽƌLJƌĞƐƉŽŶƐĞŝŶƚŚĞůĂŵŝŶĂƉƌŽƉƌŝĂ͕/>ƐŝŶƚŚĞĞƉŝƚŚĞůŝƵŵĂĐƋƵŝƌĞĂĐƟǀĂƟŶŐ

E<ƌĞĐĞƉƚŽƌƐĂŶĚƚŚĞĂďŝůŝƚLJƚŽůLJƐĞƐƚƌĞƐƐĞĚĞƉŝƚŚĞůŝĂůĐĞůůƐŝŶĚĞƉĞŶĚĞŶƚŽĨdĐĞůůƌĞĐĞƉƚŽƌ

ƐŝŐŶĂůŝŶŐ͕ǁŚŝĐŚůŝŬĞůLJĐŽŶƚƌŝďƵƚĞƐƚŽƚŚĞƚLJƉŝĐĂůƟƐƐƵĞĚĂŵĂŐĞŝŶ͘

/ŶZ͕ƚŚĞƐƵƌǀŝǀĂů͕ĞdžƉĂŶƐŝŽŶĂŶĚĂĐƋƵŝƐŝƟŽŶŽĨĂŶE<ĐĞůůͲůŝŬĞƉŚĞŶŽƚLJƉĞďLJ/>ƐŝƐ

ĞǀĞŶŵŽƌĞƉƌŽŶŽƵŶĐĞĚƚŚĂŶŝŶ͕ƉŽƐƐŝďůLJĂƐĂƌĞƐƵůƚŽĨƚŚĞƉƌĞƐĞŶĐĞŽĨůĂƌŐĞƌĂŵŽƵŶƚƐ

ŽĨ/>Ͳϭϱ͘Z//ƉĂƟĞŶƚƐŚĂǀĞĂŶĂďĞƌƌĂŶƚĐůŽŶĂů/>ƉŽƉƵůĂƟŽŶƚŚĂƚůĂĐŬƐƐƵƌĨĂĐĞdZͲ

ϯĞdžƉƌĞƐƐŝŽŶ͘^ƚƵĚŝĞƐŽŶĂďĞƌƌĂŶƚdZͲϯ

/>ůŝŶĞƐĨƌŽŵZ//ƉĂƟĞŶƚƐƐŚŽǁĞĚƚŚĂƚ͕

ƵƉŽŶƐƟŵƵůĂƟŽŶǁŝƚŚ/>Ͳϭϱ͕ƚŚĞƐĞĐĞůůůŝŶĞƐĞdžƉƌĞƐƐŐƌĂŶnjLJŵĞĂŶĚůLJƐĞƚŚĞŝŶƚĞƐƟŶĂů

ĞƉŝƚŚĞůŝĂůĐĞůůůŝŶĞ,dϮϵ͕ƐƵŐŐĞƐƟŶŐĂƌŽůĞĨŽƌĂďĞƌƌĂŶƚ/>ƐŝŶƉĞƌƉĞƚƵĂƟŶŐĞƉŝƚŚĞůŝĂů

ĚĂŵĂŐĞŝŶZ//

͘dŚĞƌĞĨŽƌĞ͕/>ͲϭϱĚĞƉĞŶĚĞŶƚE<ĐĞůůͲůŝŬĞƚƌĂŶƐĨŽƌŵĂƟŽŶŽĨ/>ƐŵĂLJ

ďĞĂŶĞƐƐĞŶƟĂůƐƚĞƉŝŶƚŚĞŝŵŵƵŶŽƉĂƚŚŽůŽŐLJŽĨZ͘

&®¦çٛ ϯ͘ ÙÊÝÝヽ» ›ãó››Ä 㫛 ϰ¹ d ‘›½½ ٛÝÖÊÄݛ ƒÄ— /> ‘ùãÊãÊø®‘®ãù͘ dŚĞ ϰ⁴$ 5$ /"66$

ƌĞƐƉŽŶƐĞ ƚŽ ŐůƵƚĞŶ ŵĂLJ ůĞĂĚ ƚŽ /&EͲɶ ƉƌŽĚƵĐƟŽŶ ĂŶĚ ƉŽƚĞŶƟĂůůLJ ƚŽ ƵƉƌĞŐƵůĂƟŽŶ ŽĨ />Ͳϭϱ͕ ǁŚŝĐŚ ŝŶ

ƚƵƌŶ ƐƚƐ />ͲŵĞĚŝĂƚĞĚ ĐLJƚŽƚŽdžŝĐŝƚLJ͘ ĐƟǀĂƚĞĚ />Ɛ ůLJƐĞ ƚŚĞ ĞƉŝƚŚĞůŝƵŵ͕ ǁŚŝĐŚ ůĞĂĚƐ ƚŽ d'Ϯ ƌĞůĞĂƐĞ

ĂŶĚ ƐƵďƐĞƋƵĞŶƚ ĚĞĂŵŝĚĂƟŽŶ ŽĨ ŐůƵƚĞŶ ƉĞƉƟĚĞƐ͘ dŚŝƐ ŵĂLJ ĐŽŶƐƟƚƵƚĞ LJĞƚ ĂŶŽƚŚĞƌ ƐĞůĨͲĂŵƉůŝĨLJŝŶŐ

ĨĞĞĚďĂĐŬ ůŽŽƉ͕ ĂƐ ĚĞĂŵŝĚĂƟŽŶ ŽĨ ŐůƵƚĞŶ ƉĞƉƟĚĞƐ ǁŝůů ĞŶŚĂŶĐĞ ƚŚĞ ϰ⁴ d ĐĞůů ƌĞƐƉŽŶƐĞ ;ƐĞĞ &ŝŐƵƌĞ ϮͿ͘

Ϯϭ

«ƒÖã›Ù

=

General Introduction

Box 2. IL-15

IL-15 is a cytokine that, just as IL-2, is able to induce T cell proliferation, IFN-γ production and cytotoxicity. Furthermore, IL- 15 is known to play an important role in NK cell development and activation⁶². Under normal circumstances, IL-15 expression is strictly regulated at the level of transcription, translation and secretion⁶³. In CD this regulation is disrupted, which results in massive upregulation of IL-15 in the epithelium and lamina propria. The abnormal availability of IL-15 results in chronic inflammation by survival, proliferation and activation of IELs^64;65. Furthermore, IL-15 can exert an inhibitory effect on TGF-β, a negative regulator of the immune response⁶⁶. Recently it has been shown that IL-15 can synergize with IL-21, a cytokine expressed on CD4+ T cells and a stimulator of IFN-γ production and cytolytic activity of CD8+ T cells and NK cells^67;68.

ã«Ù›Ý«Ê½—Ãʗ›½¥ÊÙ㫛ٮݻÊ¥—›ò›½ÊÖÛÄã

dŚĞ ĞdžƉĂŶƐŝŽŶ ŽĨ ƚŚĞ ƉƌĞƐĞŶƚĂďůĞ ŐůƵƚĞŶ ƉĞƉƟĚĞ ƌĞƉĞƌƚŽŝƌĞ ĚƵĞ ƚŽ ƚŚĞ ƌĞůĞĂƐĞ ĂŶĚ

ĂĐƟǀŝƚLJŽĨd'ϮŝƐĂĐƌŝƟĐĂůƐƚĞƉŝŶƚŚĞƉĂƚŚŽŐĞŶĞƐŝƐŽĨĨƵůůͲďůŽǁŶ͘^ĞǀĞƌĂůůŝŶĞƐŽĨ

ĞǀŝĚĞŶĐĞ ƐƵƉƉŽƌƚ ƚŚĞ ŶŽƟŽŶ ƚŚĂƚ ƚŚĞ ůĞǀĞů ŽĨ ŐůƵƚĞŶ ƉƌĞƐĞŶƚĂƟŽŶ ƚŽ d ĐĞůůƐ ĐƌŝƟĐĂůůLJ

ŝŶŇƵĞŶĐĞƐƚŚĞƌŝƐŬŽĨĚŝƐĞĂƐĞĚĞǀĞůŽƉŵĞŶƚ͘

&ŝƌƐƚ͕,>ͲYϮ͘ϱŚŽŵŽnjLJŐŽƵƐŝŶĚŝǀŝĚƵĂůƐŚĂǀĞĂĮǀĞͲĨŽůĚŚŝŐŚĞƌƌŝƐŬŽĨĚĞǀĞůŽƉŵĞŶƚ

ƚŚĂŶ ,>ͲYϮ͘ϱ ŚĞƚĞƌŽnjLJŐŽƵƐ ŝŶĚŝǀŝĚƵĂůƐ

͘ dŚŝƐ ŐĞŶĞ ĚŽƐĞ ĞīĞĐƚ ĚŝƌĞĐƚůLJ ĐŽƌƌĞůĂƚĞƐ

ǁŝƚŚ ƚŚĞ ŵĂŐŶŝƚƵĚĞ ŽĨ ƚŚĞ ϰ

 d ĐĞůů ƌĞƐƉŽŶƐĞ͗ ĂŶƟŐĞŶ ƉƌĞƐĞŶƟŶŐ ĐĞůůƐ ;WͿ ĨƌŽŵ

,>ͲYϮ͘ϱ ŚŽŵŽnjLJŐŽƵƐ ŝŶĚŝǀŝĚƵĂůƐ ŝŶĚƵĐĞ ǀĞƌLJ ƐƚƌŽŶŐ ƉƌŽůŝĨĞƌĂƟǀĞ d ĐĞůů ƌĞƐƉŽŶƐĞƐ

ĂŶĚ/&EɶƉƌŽĚƵĐƟŽŶ͕ǁŚŝůĞWĨƌŽŵ,>ͲYϮ͘ϱͬYyŚĞƚĞƌŽnjLJŐŽƵƐŝŶĚŝǀŝĚƵĂůƐŝŶĚƵĐĞ

ŵƵĐŚǁĞĂŬĞƌƌĞƐƉŽŶƐĞƐ

͘dŚĞƐĞĚĂƚĂŝŶĚŝĐĂƚĞƚŚĂƚƚŚĞŶƵŵďĞƌŽĨ,>ͲYϮ͘ϱŵŽůĞĐƵůĞƐ

ĐĂƉĂďůĞŽĨƉƌĞƐĞŶƟŶŐŐůƵƚĞŶƉĞƉƟĚĞƐŽŶƚŚĞƐƵƌĨĂĐĞŽĨWǁŝůůĚĞĮŶĞƚŚĞŵĂŐŶŝƚƵĚĞ

ŽĨƚŚĞϰ

dĐĞůůƌĞƐƉŽŶƐĞ͘

^ĞĐŽŶĚ͕ǁŚĞƌĞĂƐ,>ͲYϮ͘ϱŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĚĞǀĞůŽƉŵĞŶƚ͕ƚŚĞŚŽŵŽůŽŐŽƵƐ,>Ͳ

YϮ͘ϮŝƐŶŽƚ͘ůƚŚŽƵŐŚƚŚĞƐĞƚǁŽǀĂƌŝĂŶƚƐŚĂǀĞĂůŵŽƐƚŝĚĞŶƟĐĂůƉĞƉƟĚĞďŝŶĚŝŶŐŵŽƟĨƐ͕

,>ͲYϮ͘ϮĐĂŶŽŶůLJďŝŶĚĂƐƵďƐĞƚŽĨƚŚĞŐůƵƚĞŶƉĞƉƟĚĞƐƚŚĂƚĐĂŶďŝŶĚƚŽ,>ͲYϮ͘ϱ͘

dŚŝƐĚŝīĞƌĞŶĐĞŝƐĞdžƉůĂŝŶĞĚďLJƚŚĞĨĂĐƚƚŚĂƚĂƉƌŽůŝŶĞĂƚƉŽƐŝƟŽŶϯŝŶƉĞƉƟĚĞƐŚĂǀĞĂŶ

ĂĚǀĞƌƐĞĞīĞĐƚŽŶƉĞƉƟĚĞďŝŶĚŝŶŐƚŽ,>ͲYϮ͘Ϯ

͘ƐŐůƵƚĞŶĞƉŝƚŽƉĞƐĐůƵƐƚĞƌŝŶƉƌŽůŝŶĞͲ ƌŝĐŚ ƌĞŐŝŽŶƐ

͕ ŵĂŶLJ ŐůƵƚĞŶ ƉĞƉƟĚĞƐ ŚĂǀĞ Ă ƉƌŽůŝŶĞ Ăƚ ƉŽƐŝƟŽŶ ϯ ĂŶĚ ĚŽ ŶŽƚ ďŝŶĚ ƚŽ

,>ͲYϮ͘Ϯ

͘ ŽŶƐĞƋƵĞŶƚůLJ͕ ,>ͲYϮ͘ϱ ŝƐ ĂďůĞ ƚŽ ƉƌĞƐĞŶƚ Ă ŵƵĐŚ ďƌŽĂĚĞƌ ƌĞƉĞƌƚŽŝƌĞ

ŽĨŐůƵƚĞŶƉĞƉƟĚĞƐƚŚĂŶ,>ͲYϮ͘Ϯ͘/ŶĂĚĚŝƟŽŶ͕,>ͲYϮ͘ϱŝƐďĞƩĞƌĂƚƌĞƚĂŝŶŝŶŐŐůƵƚĞŶ

ƉĞƉƟĚĞƐ ŝŶ ŝƚƐ ďŝŶĚŝŶŐ ŐƌŽŽǀĞ ĐŽŵƉĂƌĞĚ ƚŽ ,>ͲYϮ͘Ϯ

͘ Ɛ Ă ƌĞƐƵůƚ͕ ŐůƵƚĞŶ ƉĞƉƟĚĞ

ƉƌĞƐĞŶƚĂƟŽŶďLJ,>ͲYϮ͘ϱŝƐƉƌŽƚƌĂĐƚĞĚĐŽŵƉĂƌĞĚƚŽƉƌĞƐĞŶƚĂƟŽŶďLJ,>ͲYϮ͘ϮǁŚŝĐŚ

ǁŝůůŝŶĐƌĞĂƐĞƚŚĞĐŚĂŶĐĞĨŽƌƉƌŽĚƵĐƟǀĞϰ

dĐĞůůƐƟŵƵůĂƟŽŶ͘

dŚŝƌĚ͕ŝƐĂƐƐŽĐŝĂƚĞĚŵĂŝŶůLJǁŝƚŚ,>ͲYϮ͘ϱĂŶĚƚŽĂůĞƐƐĞƌĞdžƚĞŶƚǁŝƚŚ,>ͲYϴ͘

ůƚŚŽƵŐŚĂǀĂƌŝĞƚLJŽĨŐůƵƚĞŶƉĞƉƟĚĞƐŚĂƐďĞĞŶŝĚĞŶƟĮĞĚƚŚĂƚĐĂŶƐƟŵƵůĂƚĞ,>ͲYϴ

ƌĞƐƚƌŝĐƚĞĚ d ĐĞůůƐ ĨƌŽŵ  ƉĂƟĞŶƚƐ͕ ŽŶĞ ɲͲŐůŝĂĚŝŶ ƉĞƉƟĚĞ ŝŶ ƉĂƌƟĐƵůĂƌ ĂƉƉĞĂƌƐ ƚŽ ďĞ

ŝŵŵƵŶŽĚŽŵŝŶĂŶƚ ĂƐ ƚŚŝƐ ƉĞƉƟĚĞ ŝŶǀĂƌŝĂďůLJ ŝŶĚƵĐĞƐ ƐƉĞĐŝĮĐ d ĐĞůů ƌĞƐƉŽŶƐĞƐ ŝŶ ,>Ͳ

Yϴ

  ƉĂƟĞŶƚƐ

;<ŽŽLJ Ğƚ Ăů͘ ƵŶƉƵďůŝƐŚĞĚ ĚĂƚĂͿ͘ /Ŷ ĐŽŶƚƌĂƐƚ ƚŽ ƚŚĞ ,>ͲYϮ͘ϱ

ƌĞƐƚƌŝĐƚĞĚɲͲŐůŝĂĚŝŶƉĞƉƟĚĞƐ͕ƚŚĞ,>ͲYϴƉĞƉƟĚĞŝƐŶŽƚĚĞƌŝǀĞĚĨƌŽŵĂƉƌŽůŝŶĞͲƌŝĐŚ

ƌĞŐŝŽŶ ŽĨ ƚŚĞ ɲͲŐůŝĂĚŝŶ ƉƌŽƚĞŝŶ ĂŶĚ ƚŚĞƌĞĨŽƌĞ ůŝŬĞůLJ ƐƵƐĐĞƉƟďůĞ ƚŽ ĚĞŐƌĂĚĂƟŽŶ ŝŶ ƚŚĞ

ŐĂƐƚƌŽŝŶƚĞƐƟŶĂů ƚƌĂĐƚ͘ &ƵƌƚŚĞƌŵŽƌĞ͕ ǁŚĞƌĞĂƐ ĨŽƌ ,>ͲYϮ Ă ƐŝŶŐůĞ ĚĞĂŵŝĚĂƟŽŶ ŝŶ Ă

ŐůƵƚĞŶƉĞƉƟĚĞŝƐƐƵĸĐŝĞŶƚƚŽĞǀŽŬĞĂϰ

dĐĞůůƌĞƐƉŽŶƐĞ͕ĨŽƌ,>ͲYϴĚĞĂŵŝĚĂƟŽŶĂƚ

ƚǁŽƉŽƐŝƟŽŶƐŝƐƉƌĞĨĞƌƌĞĚ

͕ǁŚŝĐŚŵĂLJůŝŵŝƚƚŚĞŐĞŶĞƌĂƟŽŶŽĨƐƚƌŽŶŐĂŶƟŐĞŶŝĐŐůƵƚĞŶ

ƉĞƉƟĚĞƐ͘dŚĞĨĂĐƚƚŚĂƚƚŚĞŝŵŵƵŶŽĚŽŵŝŶĂŶƚ,>ͲYϴƉĞƉƟĚĞŝƐŵŽƌĞƌĞĂĚŝůLJĚĞŐƌĂĚĞĚ

ϮϮ

«ƒÖã›Ù

=

Chapter 1

ĂŶĚƌĞƋƵŝƌĞƐŵŽƌĞĚĞĂŵŝĚĂƟŽŶƐƚĞƉƐ͕ůŝŵŝƚƐƚŚĞĂǀĂŝůĂďŝůŝƚLJĨŽƌĂŶƟŐĞŶƉƌĞƐĞŶƚĂƟŽŶĂŶĚ

ŵĂLJƚŚĞƌĞĨŽƌĞůŝŵŝƚƚŚĞƌŝƐŬƚŽĚĞǀĞůŽƉ͘

&ŽƵƌƚŚ͕ ĨƵƌƚŚĞƌ ĞǀŝĚĞŶĐĞ ƚŚĂƚ ƚŚĞ ůĞǀĞů ŽĨ ŐůƵƚĞŶ ƉƌĞƐĞŶƚĂƟŽŶ ŝƐ Ă ĐƌŝƟĐĂů ƉĂƌĂŵĞƚĞƌ

ĐŽŵĞƐĨƌŽŵĂƚŽƚĂůůLJĚŝīĞƌĞŶƚĂŶŐůĞ͗ŵŽƐƚƉĂƟĞŶƚƐƚŽůĞƌĂƚĞŽĂƚĞǀĞŶƚŚŽƵŐŚŝƚŚĂƐ

ďĞĞŶƐŚŽǁŶƚŚĂƚƚŚĞŐůƵƚĞŶͲůŝŬĞŵŽůĞĐƵůĞƐŝŶŽĂƚĐĂŶĞůŝĐŝƚϰ

dĐĞůůƌĞƐƉŽŶƐĞƐŝŶ

ƉĂƟĞŶƚƐ

dŚĞƌĞĂƌĞƚǁŽƐƚƌŝŬŝŶŐĚŝīĞƌĞŶĐĞƐďĞƚǁĞĞŶƚŚĞƌĞůĂƟǀĞůLJƐĂĨĞŽĂƚĂŶĚƚŚĞ

ĚŝƐĞĂƐĞŝŶĚƵĐŝŶŐĐĞƌĞĂůƐǁŚĞĂƚ͕ďĂƌůĞLJĂŶĚƌLJĞ͗;ϭͿǁŚŝůĞƚŚĞŐůƵƚĞŶͲůŝŬĞŵŽůĞĐƵůĞƐŝŶ

ŽĂƚĐŽŶƚĂŝŶŽŶůLJƚǁŽĂŶƟŐĞŶŝĐƐĞƋƵĞŶĐĞƐ͕ĚŽnjĞŶƐĂƌĞĨŽƵŶĚŝŶŐůƵƚĞŶĂŶĚƚŚĞŐůƵƚĞŶͲůŝŬĞ

ŵŽůĞĐƵůĞƐŽĨďĂƌůĞLJĂŶĚƌLJĞ͕;ϮͿƚŚĞ͞ŐůƵƚĞŶ͟ĐŽŶƚĞŶƚŽĨŽĂƚŝƐŵƵĐŚůŽǁĞƌĐŽŵƉĂƌĞĚƚŽ

ƚŚĞŽƚŚĞƌĐĞƌĞĂůƐ͘ŽŶƐƵŵƉƟŽŶŽĨŽĂƚƚŚƵƐƌĞƐƵůƚƐŝŶĂŵƵĐŚůŽǁĞƌĞdžƉŽƐƵƌĞƚŽĂŶƟŐĞŶŝĐ

ƉĞƉƟĚĞƐŝŶĐŽŵƉĂƌŝƐŽŶǁŝƚŚƚŚĞŽƚŚĞƌĐĞƌĞĂůƐĂŶĚƚŚŝƐŝƐĂƉƉĂƌĞŶƚůLJƚŽůĞƌĂƚĞĚĂƐŝƚĚŽĞƐ

ŶŽƚůĞĂĚƚŽĚŝƐĞĂƐĞŝŶƚŚĞŵĂũŽƌŝƚLJŽĨƉĂƟĞŶƚƐ͘

ŽůůĞĐƟǀĞůLJ͕ƚŚĞƐĞĚĂƚĂŝŶĚŝĐĂƚĞƚŚĞƉƌĞƐĞŶĐĞŽĨĂƚŚƌĞƐŚŽůĚƚŽĚĞǀĞůŽƉ͘/ŶŝƟĂƟŽŶŽĨ

ďĞĐŽŵĞƐŵŽƌĞůŝŬĞůLJǁŝƚŚŝŶĐƌĞĂƐĞĚdĐĞůůĞdžƉŽƐƵƌĞƚŽŐůƵƚĞŶĂŶƟŐĞŶƐ͘dŚŝƐĞdžƉŽƐƵƌĞ

ŝƐŝŶŇƵĞŶĐĞĚďLJƚŚĞƚLJƉĞĂŶĚĂŵŽƵŶƚŽĨ,>ͲYĂƐƚŚŝƐĚĞƚĞƌŵŝŶĞƐƚŚĞĞĸĐŝĞŶĐLJŽĨ

ŐůƵƚĞŶƉĞƉƟĚĞƉƌĞƐĞŶƚĂƟŽŶƚŽϰ

dĐĞůůƐ͘&Žƌ,>ͲYϮ͘ϱŚŽŵŽnjLJŐŽƵƐŝŶĚŝǀŝĚƵĂůƐ͕ƚŚĞ

ƚŚƌĞƐŚŽůĚƚŽĚĞǀĞůŽƉŝƐŵŽƐƚĞĂƐŝůLJĞdžĐĞĞĚĞĚ͕ǁŚĞƌĞĂƐĨŽƌ,>ͲYϮ͘Ϯ

ĂŶĚ,>ͲYϴ

ŝŶĚŝǀŝĚƵĂůƐƚŚĞƚŚƌĞƐŚŽůĚŝƐŵƵĐŚŚŝŐŚĞƌ͘

—›ò›½ÊÖÛÄã͗ƒݛٮ›ÝÊ¥çÄ¥ÊÙãçăã››ò›ÄãÝ

dŚĞƉĂƐƚƚǁŽĚĞĐĂĚĞƐŚĂǀĞǁŝƚŶĞƐƐĞĚƚŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨƐĞǀĞƌĂůĐƌŝƟĐĂůŝŵŵƵŶŽůŽŐŝĐĂů

ĨĂĐƚŽƌƐŝŶ͕ĨƌŽŵǁŚŝĐŚĂůŝŬĞůLJƐĞƋƵĞŶĐĞŽĨĞǀĞŶƚƐŝŶƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨƚŚŝƐĚŝƐĞĂƐĞ

ĐĂŶďĞĚĞĚƵĐĞĚ͘/ƚŝƐǁĞůůŬŶŽǁŶƚŚĂƚŚĞĂůƚŚLJŝŶĚŝǀŝĚƵĂůƐĐĂŶŚĂǀĞĂŶƟďŽĚŝĞƐĂŐĂŝŶƐƚ

ŶĂƟǀĞŐůƵƚĞŶƉĞƉƟĚĞƐ͘ƐĂŶĂŶƟďŽĚLJƌĞƐƉŽŶƐĞŝƐĐŽŶƚƌŽůůĞĚďLJϰ

dĐĞůůŚĞůƉ͕ƐƵĐŚ

ŝŶĚŝǀŝĚƵĂůƐŵŽƐƚůŝŬĞůLJŚĂǀĞϰ

dĐĞůůƐƐƉĞĐŝĮĐĨŽƌŶĂƟǀĞŐůƵƚĞŶƉĞƉƟĚĞƐ͕ŝŶĚŝĐĂƟŶŐƚŚĂƚ

ƚŚĞŵĞƌĞƉƌĞƐĞŶĐĞŽĨƐƵĐŚdĐĞůůƐŝƐ͕ŝŶŐĞŶĞƌĂů͕ŶŽƚƐƵĸĐŝĞŶƚƚŽĞdžĐĞĞĚƚŚĞƚŚƌĞƐŚŽůĚƚŽ

ĚĞǀĞůŽƉ;&ŝŐƵƌĞϰͿ͘dŚŝƐŝŶĚŝĐĂƚĞƐƚŚĂƚŝŶƚŚĞŵĂũŽƌŝƚLJŽĨŝŶĚŝǀŝĚƵĂůƐ͕ƚŽůĞƌŽŐĞŶŝĐĂŶĚ

ƌĞŐƵůĂƚŽƌLJƉƌŽĐĞƐƐĞƐŝŶƚŚĞŝŶƚĞƐƟŶĞŬĞĞƉŐůƵƚĞŶͲƐƉĞĐŝĮĐdĐĞůůƌĞƐƉŽŶƐĞƐŝŶĐŚĞĐŬ͘dŚŝƐ

ƐƚĞĂĚLJƐƚĂƚĞĐĂŶďĞďƌĞĂĐŚĞĚďLJĨƌĞƋƵĞŶƚĞƉŝƐŽĚĞƐŽĨĞŶƚĞƌŽǀŝƌĂůŝŶĨĞĐƟŽŶƐĂƐƚŚŝƐůĞĂĚƐ

ƚŽ ƚŚĞ ƐĞĐƌĞƟŽŶ ŽĨ ŝŶŇĂŵŵĂƚŽƌLJ ĐLJƚŽŬŝŶĞƐ ĂŶĚ ĚŝīĞƌĞŶƟĂƟŽŶ ŽĨ dŚϭ ĐĞůůƐ

͕ ƚŚĞƌĞďLJ

ĞŶŚĂŶĐŝŶŐƚŚĞƌĞƐƉŽŶƐĞƚŽŐůƵƚĞŶ;&ŝŐƵƌĞϰͿ͘^ƵďƐĞƋƵĞŶƚůLJ͕ƚŚĞĐŽŵďŝŶĞĚĞīĞĐƚŽĨůŽǁͲ ůĞǀĞůŐůƵƚĞŶƌĞĂĐƟǀŝƚLJĂŶĚƉĂƚŚŽŐĞŶŝŶĚƵĐĞĚŝŶŇĂŵŵĂƟŽŶĐŽƵůĚůĞĂĚƚŽƟƐƐƵĞĚĂŵĂŐĞ

ĂŶĚƚŚĞƌĞůĞĂƐĞŽĨd'Ϯ͘/ŶƚƵƌŶ͕ƚŚĞĂĐƟǀŝƚLJŽĨd'ϮǁŽƵůĚŐĞŶĞƌĂƚĞĂůĂƌŐĞƌĞƉĞƌƚŽŝƌĞŽĨ

ĚĞĂŵŝĚĂƚĞĚŐůƵƚĞŶƉĞƉƟĚĞƐǁŝƚŚŚŝŐŚĂĸŶŝƚLJĨŽƌ,>ͲY͕ƚŚĞƌĞďLJƐƟŶŐƚŚĞŐůƵƚĞŶͲ ƐƉĞĐŝĮĐdĐĞůůƌĞƐƉŽŶƐĞ;&ŝŐƵƌĞϰͿ͘ƚƚŚŝƐƉŽŝŶƚŝŶĚĞǀĞůŽƉŵĞŶƚ͕ƐĞůĨͲĂŵƉůŝĨLJŝŶŐůŽŽƉƐ

ĂƌĞŝŶĂĐƟŽŶ͗ϰ

dĐĞůůƌĞƐƉŽŶƐĞƐĂŐĂŝŶƐƚŶĂƟǀĞŐůƵƚĞŶƉĞƉƟĚĞƐůĞĂĚƚŚƌŽƵŐŚ/&EͲɶ

ƉƌŽĚƵĐƟŽŶƚŽƵƉƌĞŐƵůĂƟŽŶŽĨ,>ĂŶĚĨƵƌƚŚĞƌĂŵƉůŝĮĐĂƟŽŶŽĨƚŚĞŐůƵƚĞŶͲƐƉĞĐŝĮĐdĐĞůů

ƌĞƐƉŽŶƐĞ͘ d'Ϯ ƌĞůĞĂƐĞĚ ƵƉŽŶ ƟƐƐƵĞ ĚĂŵĂŐĞ ĞdžƉĂŶĚƐ ƚŚĞ ƉƌĞƐĞŶƚĂďůĞ ŐůƵƚĞŶ ƉĞƉƟĚĞ

ƌĞƉĞƌƚŽŝƌĞ ǁŚŝĐŚ ǁŝůů ƵůƟŵĂƚĞůLJ ůĞĂĚ ƚŽ ŵŽƌĞ ƟƐƐƵĞ ĚĂŵĂŐĞ ;&ŝŐƵƌĞ ϮͿ͘ ƵĞ ƚŽ ƚŚĞ

ŵĂƐƐŝǀĞĞdžƉĂŶƐŝŽŶŽĨƚŚĞŐůƵƚĞŶͲƐƉĞĐŝĮĐdĐĞůůƉŽŽů͕ƌĞŐƵůĂƚŽƌLJƉƌŽĐĞƐƐĞƐĂƌĞŶŽůŽŶŐĞƌ

ĂďůĞ ƚŽ ĐŽŶƚĂŝŶ ƚŚĞ d ĐĞůů ƌĞƐƉŽŶƐĞƐ͕ ĂŶĚ ĞdžƉŽƐƵƌĞ ƚŽ ŐůƵƚĞŶ ƐƵĸĐĞƐ ƚŽ ƉĞƌƉĞƚƵĂƚĞ

ŝŶŇĂŵŵĂƟŽŶ͘ůŝŵŝŶĂƟŶŐŐůƵƚĞŶĨƌŽŵƚŚĞĚŝĞƚŝƐƚŚĞŽŶůLJǁĂLJƚŽƐƚŽƉƚŚŝƐƉƌŽĐĞƐƐ͘ƚ

ĂůůƐƚĂŐĞƐŝŶƚŚŝƐƐĐĞŶĂƌŝŽƚŚĞƌŝƐŬƚŽĚĞǀĞůŽƉŝƐŝŶŇƵĞŶĐĞĚďLJƚŚĞ,>ͲYŐĞŶŽƚLJƉĞ

ĂƐ ,>ͲYϮ͘ϱ ŚŽŵŽnjLJŐŽƵƐ ŝŶĚŝǀŝĚƵĂůƐ ǁŝůů ƉƌĞƐĞŶƚ ŵŽƌĞ ,>ͲŐůƵƚĞŶ ĐŽŵƉůĞdžĞƐ ƚŚĂŶ

,>ͲYϮ͘ϱŚĞƚĞƌŽnjLJŐŽƵƐŝŶĚŝǀŝĚƵĂůƐ;&ŝŐƵƌĞϰͿ͘^ŝŵƵůƚĂŶĞŽƵƐůLJ͕ĂŶŝŶĮůƚƌĂƚĞŽĨ/>ƐŝƐ

ĨŽƌŵĞĚŝŶƚŚĞĞƉŝƚŚĞůŝƵŵ͕ǁŚŝĐŚŝƐƉŽƚĞŶƟĂůůLJĚƌŝǀĞŶďLJƚŚĞŝŶŇĂŵŵĂƚŽƌLJŵŝůŝĞƵĐƌĞĂƚĞĚ

Ϯϯ

«ƒÖã›Ù

=

General Introduction

&®¦çٛ ϰ͘ d«Ù›Ý«Ê½— Ãʗ›½ ¥ÊÙ  —›ò›½ÊÖÛÄã͘ Ɛ ,>ͲYϮ͘ϱ ŚŽŵŽnjLJŐŽƵƐ ŝŶĚŝǀŝĚƵĂůƐ ĐĂŶ ƉƌĞƐĞŶƚ

ŵŽƌĞŐůƵƚĞŶƉĞƉƟĚĞƐŽŶƚŚĞŝƌWƚŚĂŶ,>ͲYϮ͘ϱŚĞƚĞƌŽnjLJŐŽƵƐŝŶĚŝǀŝĚƵĂůƐ͕,>ͲYϮ͘ϱŚŽŵŽnjLJŐŽƚĞƐŚĂǀĞ

ĂŚŝŐŚĞƌƌŝƐŬŽĨĚĞǀĞůŽƉŵĞŶƚĂƉƌŝŽƌŝ͘/ŶƐƚĞĂĚLJƐƚĂƚĞĐŽŶĚŝƟŽŶƐ͕ƉƌĞƐĞŶƚĂƟŽŶŽĨŶĂƟǀĞŐůƵƚĞŶƉĞƉƟĚĞƐ

ŝƐƵŶůŝŬĞůLJƚŽŝŶĚƵĐĞĚŝƐĞĂƐĞ͘dŚŝƐƐƚĞĂĚLJƐƚĂƚĞĐĂŶďĞďƌĞĂĐŚĞĚďLJĨƌĞƋƵĞŶƚǀŝƌĂůŝŶĨĞĐƟŽŶƐĂŶĚůŽǁͲŐƌĂĚĞ

d ĐĞůů ƌĞƐƉŽŶƐĞƐ ƚŽ ŶĂƟǀĞ ŐůƵƚĞŶ ƉĞƉƟĚĞƐ ƚŚĂƚ ůĞĂĚ ƚŽ ƌĞůĞĂƐĞ ŽĨ d'Ϯ ƵƉŽŶ ƟƐƐƵĞ ĚĂŵĂŐĞ͘ d'Ϯ ĂĐƟǀŝƚLJ

ǁŝůů ĞdžƉĂŶĚ ƚŚĞ ƉƌĞƐĞŶƚĂďůĞ ŐůƵƚĞŶ ƉĞƉƟĚĞ ƌĞƉĞƌƚŽŝƌĞ ĞdžƚĞŶƐŝǀĞůLJ͕ ƚŚĞƌĞďLJ ŝŶĐƌĞĂƐŝŶŐ ƚŚĞ ƌŝƐŬ ƚŽ ĚĞǀĞůŽƉ

͘ dŚĞ ƌĞĐĞŶƚůLJ ƵŶĐŽǀĞƌĞĚ ŶŽŶͲ,> ŐĞŶĞƐ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ  ůŝŬĞůLJ ůŽǁĞƌ ƚŚĞ ƚŚƌĞƐŚŽůĚ ƚŽ ĚĞǀĞůŽƉ ͘

ďLJϰ

dĐĞůůƐŝŶƚŚĞůĂŵŝŶĂƉƌŽƉƌŝĂ͘dŚĞƐĞ/>ƐƵƉƌĞŐƵůĂƚĞĂĐƟǀĂƟŶŐE<ĐĞůůƌĞĐĞƉƚŽƌƐ

ĂŶĚĂĐƋƵŝƌĞƚŚĞĂďŝůŝƚLJƚŽůLJƐĞĞŶƚĞƌŽĐLJƚĞƐŝŶĚĞƉĞŶĚĞŶƚŽĨƚŚĞdZ͘

dŚĞĚĞǀĞůŽƉŵĞŶƚŽĨĨƵůůͲďůŽǁŶŝƐŵŽƐƚůŝŬĞůLJƚŚĞƌĞƐƵůƚŽĨĂŶƵŶĨŽƌƚƵŶĂƚĞƐĞƌŝĞƐŽĨ

ĞǀĞŶƚƐǁŚŝĐŚ͕ŝŶŝƐŽůĂƟŽŶ͕ǁŽƵůĚŶŽƚůĞĂĚƚŽĚŝƐĞĂƐĞ͕ďƵƚ͕ĐŽŵďŝŶĞĚŚĂǀĞĂĚĞƚƌŝŵĞŶƚĂů

ŽƵƚĐŽŵĞ͘/ƚŝƐŝŵƉŽƌƚĂŶƚƚŽŶŽƚĞƚŚĂƚĞdžƉŽƐƵƌĞƚŽŐůƵƚĞŶ͕ĨƌĞƋƵĞŶƚĞŶƚĞƌŽǀŝƌĂůŝŶĨĞĐƟŽŶƐ

ĂŶĚŽĐĐĂƐŝŽŶĂůd'ϮĂĐƟǀĂƟŽŶůŝŬĞůLJŽĐĐƵƌŝŶĞǀĞƌLJŝŶĚŝǀŝĚƵĂůďƵƚƵƐƵĂůůLJĚŽŶŽƚƌĞƐƵůƚŝŶ

ĚĞǀĞůŽƉŵĞŶƚ͕ĞǀĞŶŝŶ,>ͲYϮ

ĂŶĚͬŽƌ,>ͲYϴ

ŝŶĚŝǀŝĚƵĂůƐ;&ŝŐƵƌĞϭͿ͘/ƚŚĂƐŶŽǁ

ďĞĐŽŵĞĐůĞĂƌƚŚĂƚƚŚĞƉƌĞƐĞŶĐĞŽĨĂŚŝŐŚĞƌŶƵŵďĞƌŽĨĂĚĚŝƟŽŶĂůŶŽŶͲ,>ƌŝƐŬĂůůĞůĞƐ

;dĂďůĞϭͿŝƐĚŝƌĞĐƚůLJĐŽƌƌĞůĂƚĞĚǁŝƚŚĂŶŝŶĐƌĞĂƐĞŝŶƚŚĞƌŝƐŬƚŽĚĞǀĞůŽƉ

͘dŚŝƐƐƵŐŐĞƐƚƐ

ƚŚĂƚƚŚĞŝŶŇƵĞŶĐĞŽĨŶŽŶͲ,>ŐĞŶĞƐůŽǁĞƌƐƚŚĞƚŚƌĞƐŚŽůĚƚŽĚĞǀĞůŽƉĂŶĚĐŽƵůĚƐŬĞǁ

ƚŚĞďĂůĂŶĐĞƚŽǁĂƌĚƐĚŝƐĞĂƐĞĚĞǀĞůŽƉŵĞŶƚ;&ŝŐƵƌĞϰͿ͘/ƚŝƐƉůĂƵƐŝďůĞƚŚĂƚŶŽŶͲ,>ŐĞŶĞƐ

ĂůƐŽŝŶĐƌĞĂƐĞƚŚĞƌŝƐŬƚŽĚĞǀĞůŽƉĐŽŵƉůŝĐĂƚĞĚ͕ĂůƚŚŽƵŐŚƚŚŝƐŚLJƉŽƚŚĞƐŝƐǁŝůůďĞĚŝĸĐƵůƚ

ƚŽƚĞƐƚĂƐƚŚŝƐƉĂƟĞŶƚƉŽƉƵůĂƟŽŶŝƐǀĞƌLJƐŵĂůů͘dŚƵƐ͕ĞǀĞŶƚŚŽƵŐŚŬĞLJƉŝĞĐĞƐŽĨƚŚĞĐĞůŝĂĐ

ƉƵnjnjůĞŚĂǀĞďĞĞŶĐŽůůĞĐƚĞĚĂŶĚĂƐƐĞŵďůĞĚ͕ƚŚĞƉŝĐƚƵƌĞŝƐŶŽƚLJĞƚĐŽŵƉůĞƚĞ͘