Atopic dermatitis pathophysiology: Difference between revisions

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{{Atopic dermatitis}}
{{Atopic dermatitis}}


{{CMG}}; {{AE}} {{S.S}}
{{CMG}}; {{AE}} [[Ogechukwu Hannah Nnabude, MD]]; {{S.S}}


==Overview==
==Overview==
   
   
Atopic dermatitis is a chronic inflammatory skin disorder with an immunologic background and occurs in patients with a personal or family history of atopy (i.e., asthma or allergic rhinitis). It is caused by either skin barrier dysfunction or immune dysregulation of the adaptive and innate immune response leading to an enhanced IgE-mediated, systemic Th2 response. The skin barrier is invaded by exogenous substances, including allergens, irritants and microbes; and brick wall-like’ structure of the stratum corneum is further compromised. Systemically, a dysfunctional innate and adaptive immune response causes further damage to the epidermis.   
[[Atopic dermatitis]] is a [[chronic]] [[inflammatory]] [[skin disorder]] with an [[Immunology|immunologic]] background and occurs in patients with a personal or [[family history]] of [[atopy]] (i.e. [[asthma]] or [[allergic rhinitis]]). It is caused by either a skin barrier dysfunction or [[immune]] dysregulation of the [[Adaptive immunity|adaptive]] and [[innate immune response]] leading to an enhanced [[IgE]]-mediated, systemic [[Th2 response]]. The skin barrier is invaded by [[exogenous]] substances, including [[allergens]], [[irritants]] and [[microbes]]; and the tightly packed structure of the [[stratum corneum]] is further compromised. Systemically, a dysfunctional [[Innate immune system|innate]] and [[adaptive immune response]] causes further damage to the [[epidermis]].   


==Pathophysiology==
==Pathophysiology==
===Physiology===
===Physiology===
The normal physiology of atopic dermatitis can be understood as follows:
The normal physiology of [[atopic dermatitis]] can be understood as follows:


'''Epidermal barrier function:'''
'''Epidermal barrier function:'''
* '''Epidermis''': It directly interfaces with the environment and acts as the 1st line of defense. It is primarily dependent on the structure and composition of the most outermost layer of the skin, i.e. [[Stratum corneum]]. It protects the body from irritants, allergens, microbes, and pathogens from invading the skin as well as preventing the excess water loss.<ref name="pmid25131691">{{cite journal |vauthors=Elias PM, Wakefield JS |title=Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=781–791.e1 |date=October 2014 |pmid=25131691 |pmc=4186911 |doi=10.1016/j.jaci.2014.05.048 |url=}}</ref>
 
** Tightly packed corneocytes layers in the [[stratum corneum]]
*'''Epidermis''': It directly interfaces with the [[Environment (biophysical)|environment]] and acts as the 1st line of defense. It is primarily dependent on the structure and composition of the most outermost layer of the skin, i.e. [[stratum corneum]]. It protects the body from [[irritants]], [[allergens]], [[microbes]], and [[pathogens]] from invading the skin as well as preventing the excess water loss. The epidermis consists of:<ref name="pmid25131691">{{cite journal |vauthors=Elias PM, Wakefield JS |title=Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=781–791.e1 |date=October 2014 |pmid=25131691 |pmc=4186911 |doi=10.1016/j.jaci.2014.05.048 |url=}}</ref>
** Intercellular lipid bilayers  
**Tightly packed corneocytes layers in the [[stratum corneum]]
** Corneocytes layers embedded in the [[extracellular matrix]] derived from lipid lamellae  
**Intercellular lipid bilayers
** Natural moisturising factors (NMF), maintains the water retention in the [[stratum corneum]]  
**Corneocytes layers embedded in the [[extracellular matrix]] derived from [[lipid]] [[Lamellae (zoology)|lamellae]]
** [[Antimicrobial peptides]] production
**Natural moisturizing factors (NMF), maintaining the water retention in the [[stratum corneum]]
* '''Filaggrin proteins:''' Encoded by [[Filaggrin|filaggrin gene ''FLG'']] on chromosome 1q21 (contains the genes of the [[epidermal differentiation complex]] (EDC)) and is the main component required to form corneocytes in the [[stratum corneum]].<ref name="pmid19386895">{{cite journal |vauthors=Sandilands A, Sutherland C, Irvine AD, McLean WH |title=Filaggrin in the frontline: role in skin barrier function and disease |journal=J. Cell. Sci. |volume=122 |issue=Pt 9 |pages=1285–94 |date=May 2009 |pmid=19386895 |pmc=2721001 |doi=10.1242/jcs.033969 |url=}}</ref>
**[[Antimicrobial peptides]]
** Pro-filaggrin is required for the formation of dense cytoplasmic granules, which along with other proteins forms the corneocytes, that acts as a primary unit for the barrier function of the skin.
*'''Filaggrin proteins:''' It is encoded by [[Filaggrin|filaggrin gene ''FLG'']] on [[chromosome]] 1q21 (contains the genes of the [[epidermal differentiation complex]] (EDC)) and is the main component required to form corneocytes in the [[stratum corneum]].<ref name="pmid19386895">{{cite journal |vauthors=Sandilands A, Sutherland C, Irvine AD, McLean WH |title=Filaggrin in the frontline: role in skin barrier function and disease |journal=J. Cell. Sci. |volume=122 |issue=Pt 9 |pages=1285–94 |date=May 2009 |pmid=19386895 |pmc=2721001 |doi=10.1242/jcs.033969 |url=}}</ref><ref name="StänderRopper2021">{{cite journal|last1=Ständer|first1=Sonja|last2=Ropper|first2=Allan H.|title=Atopic Dermatitis|journal=New England Journal of Medicine|volume=384|issue=12|year=2021|pages=1136–1143|issn=0028-4793|doi=10.1056/NEJMra2023911}}</ref>
** Pro-filaggrin undergoes extensive [[phosphorylation]] and [[dephosphorylation]], to produce [[filaggrin]] monomers, to interact and aggregate with the [[keratin]] filaments and permits extensive crosslinking, to form a highly insoluble keratin matrix.<ref name="pmid193868952">{{cite journal |vauthors=Sandilands A, Sutherland C, Irvine AD, McLean WH |title=Filaggrin in the frontline: role in skin barrier function and disease |journal=J. Cell. Sci. |volume=122 |issue=Pt 9 |pages=1285–94 |date=May 2009 |pmid=19386895 |pmc=2721001 |doi=10.1242/jcs.033969 |url=}}</ref>  
**Pro-[[filaggrin]] is required for the formation of [[dense]] [[cytoplasmic]] [[granules]], which along with other [[Protein|proteins]], forms the corneocytes that acts as a primary unit for the barrier function of the [[skin]].
** The degraded products of filaggrin protein are one of the major components of natural moisturising factors (NMF), which prevents excess water loss from the stratum corneum.
**Pro-[[filaggrin]] undergoes extensive [[phosphorylation]] and [[dephosphorylation]], to produce [[filaggrin]] [[Monomer|monomers]] to interact and aggregate with the [[keratin]] filaments and permits extensive crosslinking, to form a highly insoluble [[keratin]] matrix.<ref name="pmid193868952">{{cite journal |vauthors=Sandilands A, Sutherland C, Irvine AD, McLean WH |title=Filaggrin in the frontline: role in skin barrier function and disease |journal=J. Cell. Sci. |volume=122 |issue=Pt 9 |pages=1285–94 |date=May 2009 |pmid=19386895 |pmc=2721001 |doi=10.1242/jcs.033969 |url=}}</ref>
** The degraded products of filaggrin protein also maintain the acidic pH of the [[stratum corneum]], required to regulate the activity of [[enzymes]].
**The degraded products of [[filaggrin]] protein are one of the major components of natural moisturizing factors (NMF), which prevents excess water loss from the [[stratum corneum]].
* '''Proteins related to tight junctions''': These [[transmembrane proteins]] are present in the [[stratum granulosum]] of the [[epidermis]] and compose together to form [[tight junctions]] which includes [[Claudins|claudin-1]], [[occludin]], junctional adhesion molecule.<ref name="pmid211635152">{{cite journal |vauthors=De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Novak N, Weidinger S, Beaty TH, Leung DY, Barnes KC, Beck LA |title=Tight junction defects in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=127 |issue=3 |pages=773–86.e1–7 |date=March 2011 |pmid=21163515 |pmc=3049863 |doi=10.1016/j.jaci.2010.10.018 |url=}}</ref>
**The degraded products of [[filaggrin]] protein also maintain the [[Acid|acidic]] [[pH]] of the [[stratum corneum]], required to regulate the activity of [[enzymes]].
* '''Other proteins''': Filaggrin-2, [[corneodesmosin]], [[desmoglein-1]], desmocollin-1, [[Transglutaminase|transglutaminase-3]] are also part of skin barrier related proteins.<ref name="pmid21211653">{{cite journal |vauthors=Broccardo CJ, Mahaffey S, Schwarz J, Wruck L, David G, Schlievert PM, Reisdorph NA, Leung DY |title=Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization |journal=J. Allergy Clin. Immunol. |volume=127 |issue=1 |pages=186–93, 193.e1–11 |date=January 2011 |pmid=21211653 |pmc=3059191 |doi=10.1016/j.jaci.2010.10.033 |url=}}</ref>
*'''Proteins related to tight junctions''': These [[transmembrane proteins]] are present in the [[stratum granulosum]] of the [[epidermis]] and come together to form [[tight junctions]] which includes the [[Claudins|claudin-1]], [[occludin]], junctional [[adhesion]] molecule.<ref name="pmid211635152">{{cite journal |vauthors=De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Novak N, Weidinger S, Beaty TH, Leung DY, Barnes KC, Beck LA |title=Tight junction defects in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=127 |issue=3 |pages=773–86.e1–7 |date=March 2011 |pmid=21163515 |pmc=3049863 |doi=10.1016/j.jaci.2010.10.018 |url=}}</ref>
*'''Other proteins''': [[Filaggrin]]-2, [[corneodesmosin]], [[desmoglein-1]], desmocollin-1, [[Transglutaminase|transglutaminase-3]] are also part of skin barrier related proteins.<ref name="pmid21211653">{{cite journal |vauthors=Broccardo CJ, Mahaffey S, Schwarz J, Wruck L, David G, Schlievert PM, Reisdorph NA, Leung DY |title=Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization |journal=J. Allergy Clin. Immunol. |volume=127 |issue=1 |pages=186–93, 193.e1–11 |date=January 2011 |pmid=21211653 |pmc=3059191 |doi=10.1016/j.jaci.2010.10.033 |url=}}</ref>
 
'''Immune response:'''
'''Immune response:'''
* '''Cutaneous immune response''': It acts as the first-line barrier and constitutes the rapid response mechanism to the invading [[Allergens|allergen]] or pathogen.<ref name="pmid20109730">{{cite journal |vauthors=Barnes KC |title=An update on the genetics of atopic dermatitis: scratching the surface in 2009 |journal=J. Allergy Clin. Immunol. |volume=125 |issue=1 |pages=16–29.e1–11; quiz 30–1 |date=January 2010 |pmid=20109730 |pmc=2874322 |doi=10.1016/j.jaci.2009.11.008 |url=}}</ref> It recognizes the microbes through receptors known as [[pattern recognition receptors]] (PRRs). The cutaneous immune response includes the following 4 elements:<ref name="pmid233742592">{{cite journal |vauthors=Kuo IH, Yoshida T, De Benedetto A, Beck LA |title=The cutaneous innate immune response in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=266–78 |date=February 2013 |pmid=23374259 |doi=10.1016/j.jaci.2012.12.1563 |url=}}</ref>
 
** Physical: [[Stratum corneum]] and the [[tight junctions]] in [[stratum granulosum]] forms the physical barrier. The maintenance and repair of epithelial barriers are mediated th<nowiki/>rough the activation of [[Pattern recognition receptors|PRR]]<nowiki/>s by the [[innate immune system]].<ref name="pmid15236188">{{cite journal |vauthors=Cario E, Gerken G, Podolsky DK |title=Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C |journal=Gastroenterology |volume=127 |issue=1 |pages=224–38 |date=July 2004 |pmid=15236188 |doi= |url=}}</ref>
*'''Cutaneous immune response''': Acts as the first-line barrier and constitutes the rapid response mechanism to the invading [[Allergens|allergen]] or [[pathogen]].<ref name="pmid20109730">{{cite journal |vauthors=Barnes KC |title=An update on the genetics of atopic dermatitis: scratching the surface in 2009 |journal=J. Allergy Clin. Immunol. |volume=125 |issue=1 |pages=16–29.e1–11; quiz 30–1 |date=January 2010 |pmid=20109730 |pmc=2874322 |doi=10.1016/j.jaci.2009.11.008 |url=}}</ref> It recognizes the [[microbes]] through receptors known as [[pattern recognition receptors]] (PRRs). The cutaneous immune response includes the following 4 elements:<ref name="pmid233742592">{{cite journal |vauthors=Kuo IH, Yoshida T, De Benedetto A, Beck LA |title=The cutaneous innate immune response in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=266–78 |date=February 2013 |pmid=23374259 |doi=10.1016/j.jaci.2012.12.1563 |url=}}</ref>
** Chemical: Antimicrobial proteins including [[antimicrobial peptides]] (AMPs), S100 proteins, [[cytokines]] as well as [[chemokines]], innate lymphoid cells group 2 (ILC-2), [[toll-like receptors]] (TLRs), [[keratinocytes]], filaggrin degraded products, and [[neutrophils]].<ref name="pmid23374259">{{cite journal |vauthors=Kuo IH, Yoshida T, De Benedetto A, Beck LA |title=The cutaneous innate immune response in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=266–78 |date=February 2013 |pmid=23374259 |doi=10.1016/j.jaci.2012.12.1563 |url=}}</ref><ref name="pmid232231422">{{cite journal |vauthors=Kuo IH, Carpenter-Mendini A, Yoshida T, McGirt LY, Ivanov AI, Barnes KC, Gallo RL, Borkowski AW, Yamasaki K, Leung DY, Georas SN, De Benedetto A, Beck LA |title=Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair |journal=J. Invest. Dermatol. |volume=133 |issue=4 |pages=988–98 |date=April 2013 |pmid=23223142 |pmc=3600383 |doi=10.1038/jid.2012.437 |url=}}</ref>
**''Physical:'' [[Stratum corneum]] and the [[tight junctions]] in [[stratum granulosum]] forms the physical barrier. The maintenance and repair of [[epithelial]] barriers are mediated th<nowiki/>rough the activation of [[Pattern recognition receptors|PRR]]<nowiki/>s by the [[innate immune system]].<ref name="pmid15236188">{{cite journal |vauthors=Cario E, Gerken G, Podolsky DK |title=Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C |journal=Gastroenterology |volume=127 |issue=1 |pages=224–38 |date=July 2004 |pmid=15236188 |doi= |url=}}</ref>
** [[Microbiome]]: Skin-resident normal microbial flora including bacteria, fungi, and viruses. Protects from invading [[microbes]] and [[pathogens]] and modulates the balance between [[inflammation]] and [[immune responses]].<ref name="pmid279740402">{{cite journal |vauthors=Lynch SV, Pedersen O |title=The Human Intestinal Microbiome in Health and Disease |journal=N. Engl. J. Med. |volume=375 |issue=24 |pages=2369–2379 |date=December 2016 |pmid=27974040 |doi=10.1056/NEJMra1600266 |url=}}</ref>
**''Chemical:'' Chemical constitutes antimicrobial proteins including [[antimicrobial peptides]] (AMPs), S100 proteins, [[cytokines]] as well as [[chemokines]], innate lymphoid cells group 2 (ILC-2), [[toll-like receptors]] (TLRs), [[keratinocytes]], filaggrin degraded products, and [[neutrophils]].<ref name="pmid23374259">{{cite journal |vauthors=Kuo IH, Yoshida T, De Benedetto A, Beck LA |title=The cutaneous innate immune response in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=266–78 |date=February 2013 |pmid=23374259 |doi=10.1016/j.jaci.2012.12.1563 |url=}}</ref><ref name="pmid232231422">{{cite journal |vauthors=Kuo IH, Carpenter-Mendini A, Yoshida T, McGirt LY, Ivanov AI, Barnes KC, Gallo RL, Borkowski AW, Yamasaki K, Leung DY, Georas SN, De Benedetto A, Beck LA |title=Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair |journal=J. Invest. Dermatol. |volume=133 |issue=4 |pages=988–98 |date=April 2013 |pmid=23223142 |pmc=3600383 |doi=10.1038/jid.2012.437 |url=}}</ref>
** Immunological: Immune response includes both non-specific and immediate response ([[innate immunity]]) and highly specific and late response ([[adaptive immunity]])
**''[[Microbiome|Microbiome]]'': The microbiome consists of skin-resident normal microbial flora including [[bacteria]], [[fungi]], and [[viruses]]. It provides protection against invading [[microbes]] and [[pathogens]], and modulates the balance between [[inflammation]] and [[immune responses]].<ref name="pmid279740402">{{cite journal |vauthors=Lynch SV, Pedersen O |title=The Human Intestinal Microbiome in Health and Disease |journal=N. Engl. J. Med. |volume=375 |issue=24 |pages=2369–2379 |date=December 2016 |pmid=27974040 |doi=10.1056/NEJMra1600266 |url=}}</ref>
* '''Adaptive Immune response''':<ref name="pmid20109730" />
**''Immunological'': Immune response includes both [[Innate immune response|non-specific]] and immediate response ([[innate immunity]]) and highly specific and late response ([[adaptive immunity]]).
** The character and magnitude of the [[Adaptive immune response|adaptive immune]] system is determined by the innate immune response by interactions with the epidermal elements and activation of TLRs.<ref name="pmid19078985">{{cite journal |vauthors=De Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA |title=Atopic dermatitis: a disease caused by innate immune defects? |journal=J. Invest. Dermatol. |volume=129 |issue=1 |pages=14–30 |date=January 2009 |pmid=19078985 |doi=10.1038/jid.2008.259 |url=}}</ref>
*'''Adaptive Immune response''':<ref name="pmid20109730" />
* '''Thymic stromal lymphopoietin:'''
**The character and magnitude of the [[Adaptive immune response|adaptive immune]] system is determined by the innate immune response by interactions with the epidermal elements and activation of TLRs.<ref name="pmid19078985">{{cite journal |vauthors=De Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA |title=Atopic dermatitis: a disease caused by innate immune defects? |journal=J. Invest. Dermatol. |volume=129 |issue=1 |pages=14–30 |date=January 2009 |pmid=19078985 |doi=10.1038/jid.2008.259 |url=}}</ref>
**<nowiki/> [[Thymic stromal lymphopoietin]] ([[TSLP]]) is considered as a master switch for [[allergic inflammation]], and is highly expressed by [[epithelial cells]] and epidermal [[keratinocytes]].<ref name="pmid16432252">{{cite journal |vauthors=Liu YJ |title=Thymic stromal lymphopoietin: master switch for allergic inflammation |journal=J. Exp. Med. |volume=203 |issue=2 |pages=269–73 |date=February 2006 |pmid=16432252 |pmc=2118215 |doi=10.1084/jem.20051745 |url=}}</ref><ref name="pmid22270071">{{cite journal |vauthors=Takai T |title=TSLP expression: cellular sources, triggers, and regulatory mechanisms |journal=Allergol Int |volume=61 |issue=1 |pages=3–17 |date=March 2012 |pmid=22270071 |doi=10.2332/allergolint.11-RAI-0395 |url=}}</ref> It is an [[Interleukin 7|IL-7]]-like [[cytokine]], which stimulates the differentiation of naïve [[T helper cells]] into [[Th2 response|inflammatory Th2 cells]].<ref name="pmid164322522">{{cite journal |vauthors=Liu YJ |title=Thymic stromal lymphopoietin: master switch for allergic inflammation |journal=J. Exp. Med. |volume=203 |issue=2 |pages=269–73 |date=February 2006 |pmid=16432252 |pmc=2118215 |doi=10.1084/jem.20051745 |url=}}</ref>
*'''Thymic stromal lymphopoietin:'''
**<nowiki/> [[Thymic stromal lymphopoietin]] ([[TSLP]]) is considered as a master switch for [[allergic inflammation]], and is highly expressed by [[epithelial cells]] and epidermal [[keratinocytes]].<ref name="pmid16432252">{{cite journal |vauthors=Liu YJ |title=Thymic stromal lymphopoietin: master switch for allergic inflammation |journal=J. Exp. Med. |volume=203 |issue=2 |pages=269–73 |date=February 2006 |pmid=16432252 |pmc=2118215 |doi=10.1084/jem.20051745 |url=}}</ref><ref name="pmid22270071">{{cite journal |vauthors=Takai T |title=TSLP expression: cellular sources, triggers, and regulatory mechanisms |journal=Allergol Int |volume=61 |issue=1 |pages=3–17 |date=March 2012 |pmid=22270071 |doi=10.2332/allergolint.11-RAI-0395 |url=}}</ref>
**<nowiki/>It is an [[Interleukin 7|IL-7]]-like [[cytokine]], which stimulates the differentiation of naïve [[T helper cells]] into [[Th2 response|inflammatory Th2 cells]].<ref name="pmid164322522">{{cite journal |vauthors=Liu YJ |title=Thymic stromal lymphopoietin: master switch for allergic inflammation |journal=J. Exp. Med. |volume=203 |issue=2 |pages=269–73 |date=February 2006 |pmid=16432252 |pmc=2118215 |doi=10.1084/jem.20051745 |url=}}</ref>


===Pathogenesis===
===Pathogenesis===


It is understood that atopic dermatitis is the result of either skin barrier dysfunction or by immune dysregulation.<ref name="pmid21682749">{{cite journal |vauthors=Boguniewicz M, Leung DY |title=Atopic dermatitis: a disease of altered skin barrier and immune dysregulation |journal=Immunol. Rev. |volume=242 |issue=1 |pages=233–46 |date=July 2011 |pmid=21682749 |pmc=3122139 |doi=10.1111/j.1600-065X.2011.01027.x |url=}}</ref>
It is understood that atopic dermatitis is the result of either skin barrier dysfunction or immune dysregulation.<ref name="pmid21682749">{{cite journal |vauthors=Boguniewicz M, Leung DY |title=Atopic dermatitis: a disease of altered skin barrier and immune dysregulation |journal=Immunol. Rev. |volume=242 |issue=1 |pages=233–46 |date=July 2011 |pmid=21682749 |pmc=3122139 |doi=10.1111/j.1600-065X.2011.01027.x |url=}}</ref>
 
'''Epidermal barrier dysfunction (outside-in hypothesis):'''<ref name="pmid183290874">{{cite journal |vauthors=Elias PM, Hatano Y, Williams ML |title=Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms |journal=J. Allergy Clin. Immunol. |volume=121 |issue=6 |pages=1337–43 |date=June 2008 |pmid=18329087 |pmc=2706021 |doi=10.1016/j.jaci.2008.01.022 |url=}}</ref>
 
*The major factors causing abnormal skin barrier include loss-of-function mutations in the [[filaggrin]] gene (FLG) resulting in:<ref name="pmid22521249">{{cite journal |vauthors=Morizane S, Yamasaki K, Kajita A, Ikeda K, Zhan M, Aoyama Y, Gallo RL, Iwatsuki K |title=TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=130 |issue=1 |pages=259–61.e1 |date=July 2012 |pmid=22521249 |pmc=3387356 |doi=10.1016/j.jaci.2012.03.006 |url=}}</ref><ref name="pmid22951058">{{cite journal |vauthors=Margolis DJ, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Campbell LE, Sandilands A, McLean WH, Rebbeck TR, Mitra N |title=The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort |journal=J. Allergy Clin. Immunol. |volume=130 |issue=4 |pages=912–7 |date=October 2012 |pmid=22951058 |pmc=3462287 |doi=10.1016/j.jaci.2012.07.008 |url=}}</ref><ref name="pmid23374260">{{cite journal |vauthors=McAleer MA, Irvine AD |title=The multifunctional role of filaggrin in allergic skin disease |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=280–91 |date=February 2013 |pmid=23374260 |doi=10.1016/j.jaci.2012.12.668 |url=}}</ref>
**Filaggrin protein deficiency<ref name="pmid19720210">{{cite journal |vauthors=Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY |title=Cytokine modulation of atopic dermatitis filaggrin skin expression |journal=J. Allergy Clin. Immunol. |volume=124 |issue=3 Suppl 2 |pages=R7–R12 |date=September 2009 |pmid=19720210 |doi=10.1016/j.jaci.2009.07.012 |url=}}</ref>
**[[Tight junction]] abnormalities<ref name="pmid21163515">{{cite journal |vauthors=De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Novak N, Weidinger S, Beaty TH, Leung DY, Barnes KC, Beck LA |title=Tight junction defects in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=127 |issue=3 |pages=773–86.e1–7 |date=March 2011 |pmid=21163515 |pmc=3049863 |doi=10.1016/j.jaci.2010.10.018 |url=}}</ref>
**More [[alkaline]] surface pH<ref name="pmid18329087">{{cite journal |vauthors=Elias PM, Hatano Y, Williams ML |title=Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms |journal=J. Allergy Clin. Immunol. |volume=121 |issue=6 |pages=1337–43 |date=June 2008 |pmid=18329087 |pmc=2706021 |doi=10.1016/j.jaci.2008.01.022 |url=}}</ref>
**[[Microbial]] colonization
**Altered [[Proteases|protease]] activity in the [[stratum corneum]]<ref name="pmid16815133">{{cite journal |vauthors=Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R |title=New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions |journal=J. Allergy Clin. Immunol. |volume=118 |issue=1 |pages=3–21; quiz 22–3 |date=July 2006 |pmid=16815133 |doi=10.1016/j.jaci.2006.04.042 |url=}}</ref>
 
*Skin barrier abnormalities lead to the increased permeability of the [[epidermis]].
**This leads to entry of [[antigens]] or [[pathogens]] resulting in [[microbial]] colonization, most notably by ''[[staphylococcus aureus]]'' and [[herpes simplex virus (HSV)]].
**This sequence of events results in the production of inflammatory [[cytokines]] and impaired production of [[antimicrobial peptides]].<ref name="pmid23712284">{{cite journal |vauthors=Leung DY |title=New insights into atopic dermatitis: role of skin barrier and immune dysregulation |journal=Allergol Int |volume=62 |issue=2 |pages=151–61 |date=June 2013 |pmid=23712284 |doi=10.2332/allergolint.13-RAI-0564 |url=}}</ref>


'''Epidermal barrier dysfunction(outside-in hypothesis):'''<ref name="pmid183290874">{{cite journal |vauthors=Elias PM, Hatano Y, Williams ML |title=Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms |journal=J. Allergy Clin. Immunol. |volume=121 |issue=6 |pages=1337–43 |date=June 2008 |pmid=18329087 |pmc=2706021 |doi=10.1016/j.jaci.2008.01.022 |url=}}</ref>
*Skin barrier abnormalities also lead to increased [[Transepidermal water loss|trans-epidermal water loss]], and decreased levels of [[Ceramide|ceramides]] and water binding.<ref name="pmid19494826">{{cite journal| author=Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M et al.| title=Epidermal barrier dysfunction in atopic dermatitis. | journal=J Invest Dermatol | year= 2009 | volume= 129 | issue= 8 | pages= 1892-908 | pmid=19494826 | doi=10.1038/jid.2009.133 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19494826  }} </ref><ref name="StänderRopper2021">{{cite journal|last1=Ständer|first1=Sonja|last2=Ropper|first2=Allan H.|title=Atopic Dermatitis|journal=New England Journal of Medicine|volume=384|issue=12|year=2021|pages=1136–1143|issn=0028-4793|doi=10.1056/NEJMra2023911}}</ref>
* The major factors to abnormal skin barrier include loss-of-function mutations in the [[filaggrin]] gene (FLG) causing:
** filaggrin deficiency<ref name="pmid19720210">{{cite journal |vauthors=Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY |title=Cytokine modulation of atopic dermatitis filaggrin skin expression |journal=J. Allergy Clin. Immunol. |volume=124 |issue=3 Suppl 2 |pages=R7–R12 |date=September 2009 |pmid=19720210 |doi=10.1016/j.jaci.2009.07.012 |url=}}</ref>
** [[Tight junctions|tight junction]] abnormalities<ref name="pmid21163515">{{cite journal |vauthors=De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Novak N, Weidinger S, Beaty TH, Leung DY, Barnes KC, Beck LA |title=Tight junction defects in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=127 |issue=3 |pages=773–86.e1–7 |date=March 2011 |pmid=21163515 |pmc=3049863 |doi=10.1016/j.jaci.2010.10.018 |url=}}</ref>
** more alkaline surface pH<ref name="pmid18329087">{{cite journal |vauthors=Elias PM, Hatano Y, Williams ML |title=Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms |journal=J. Allergy Clin. Immunol. |volume=121 |issue=6 |pages=1337–43 |date=June 2008 |pmid=18329087 |pmc=2706021 |doi=10.1016/j.jaci.2008.01.022 |url=}}</ref>
** microbial colonization
** altered [[Proteases|protease]] activity in the [[stratum corneum]]<ref name="pmid16815133">{{cite journal |vauthors=Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R |title=New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions |journal=J. Allergy Clin. Immunol. |volume=118 |issue=1 |pages=3–21; quiz 22–3 |date=July 2006 |pmid=16815133 |doi=10.1016/j.jaci.2006.04.042 |url=}}</ref><ref name="pmid23374260">{{cite journal |vauthors=McAleer MA, Irvine AD |title=The multifunctional role of filaggrin in allergic skin disease |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=280–91 |date=February 2013 |pmid=23374260 |doi=10.1016/j.jaci.2012.12.668 |url=}}</ref><ref name="pmid22951058">{{cite journal |vauthors=Margolis DJ, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Campbell LE, Sandilands A, McLean WH, Rebbeck TR, Mitra N |title=The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort |journal=J. Allergy Clin. Immunol. |volume=130 |issue=4 |pages=912–7 |date=October 2012 |pmid=22951058 |pmc=3462287 |doi=10.1016/j.jaci.2012.07.008 |url=}}</ref><ref name="pmid22521249">{{cite journal |vauthors=Morizane S, Yamasaki K, Kajita A, Ikeda K, Zhan M, Aoyama Y, Gallo RL, Iwatsuki K |title=TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=130 |issue=1 |pages=259–61.e1 |date=July 2012 |pmid=22521249 |pmc=3387356 |doi=10.1016/j.jaci.2012.03.006 |url=}}</ref>


* Skin barrier abnormalities lead to the permeability of epidermis, causing entry of antigens or pathogens, microbial colonization most notably by ''[[Staphylococcus aureus]]'' and [[Herpes simplex|Herpes simplex virus (HSV]]); leading to the production of inflammatory [[cytokines]] and Impaired production of [[antimicrobial peptides]].<ref name="pmid23712284">{{cite journal |vauthors=Leung DY |title=New insights into atopic dermatitis: role of skin barrier and immune dysregulation |journal=Allergol Int |volume=62 |issue=2 |pages=151–61 |date=June 2013 |pmid=23712284 |doi=10.2332/allergolint.13-RAI-0564 |url=}}</ref>
*Severe atopic dermatitis has been associated with higher levels of [[Transepidermal water loss|trans-epidermal water loss]].<ref name="pmid21137118">{{cite journal |vauthors=Flohr C, England K, Radulovic S, McLean WH, Campbel LE, Barker J, Perkin M, Lack G |title=Filaggrin loss-of-function mutations are associated with  early-onset eczema, eczema severity and transepidermal  water loss at 3 months of age |journal=Br. J. Dermatol. |volume=163 |issue=6 |pages=1333–6 |date=December 2010 |pmid=21137118 |doi= |url=}}</ref>


* Skin barrier abnormalities also leads to increased [[Transepidermal water loss|trans-epidermal water loss]], and decreased levels of ceramides and water binding.<ref name="pmid19494826">{{cite journal| author=Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M et al.| title=Epidermal barrier dysfunction in atopic dermatitis. | journal=J Invest Dermatol | year= 2009 | volume= 129 | issue= 8 | pages= 1892-908 | pmid=19494826 | doi=10.1038/jid.2009.133 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19494826  }} </ref>
'''Immune dysregulation (inside-out’ hypothesis):'''<ref name="pmid183290872">{{cite journal |vauthors=Elias PM, Hatano Y, Williams ML |title=Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms |journal=J. Allergy Clin. Immunol. |volume=121 |issue=6 |pages=1337–43 |date=June 2008 |pmid=18329087 |pmc=2706021 |doi=10.1016/j.jaci.2008.01.022 |url=}}</ref>


* Severe atopic dermatitis has been associated with higher levels of [[Transepidermal water loss|trans-epidermal water loss]].<ref name="pmid21137118">{{cite journal |vauthors=Flohr C, England K, Radulovic S, McLean WH, Campbel LE, Barker J, Perkin M, Lack G |title=Filaggrin loss-of-function mutations are associated with  early-onset eczema, eczema severity and transepidermal  water loss at 3 months of age |journal=Br. J. Dermatol. |volume=163 |issue=6 |pages=1333–6 |date=December 2010 |pmid=21137118 |doi= |url=}}</ref>
*'''Innate immune response:'''
'''Immune dysregulation (inside-out’ hypothesis):'''<ref name="pmid183290872">{{cite journal |vauthors=Elias PM, Hatano Y, Williams ML |title=Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms |journal=J. Allergy Clin. Immunol. |volume=121 |issue=6 |pages=1337–43 |date=June 2008 |pmid=18329087 |pmc=2706021 |doi=10.1016/j.jaci.2008.01.022 |url=}}</ref>:
**Pathogens or tissue damage activate pattern recognition receptors including [[toll-like receptors]] (TLRs), which further induces a release of inflammatory mediators<nowiki/>, including [[Antimicrobial peptides|AMP]]<nowiki/>s, [[cytokines]], and [[chemokines]].<ref name="pmid23223142">{{cite journal |vauthors=Kuo IH, Carpenter-Mendini A, Yoshida T, McGirt LY, Ivanov AI, Barnes KC, Gallo RL, Borkowski AW, Yamasaki K, Leung DY, Georas SN, De Benedetto A, Beck LA |title=Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair |journal=J. Invest. Dermatol. |volume=133 |issue=4 |pages=988–98 |date=April 2013 |pmid=23223142 |pmc=3600383 |doi=10.1038/jid.2012.437 |url=}}</ref>
* '''Innate immune response:'''
**Defective cutaneous [[Innate immune system|innate immune]]-mediated epidermal barrier repair and maintenance may alter skin-resident normal microbial flora and lead to severe [[inflammation]] as demonstrated with atopic dermatitis patients colonized with [[Staphylococcus aureus|s''taphylococcus aureus'']]''.''<ref name="pmid22310478">{{cite journal |vauthors=Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD, Murray PR, Turner ML, Segre JA |title=Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis |journal=Genome Res. |volume=22 |issue=5 |pages=850–9 |date=May 2012 |pmid=22310478 |pmc=3337431 |doi=10.1101/gr.131029.111 |url=}}</ref>
**Pathogens or tissue damage activate pattern recognition receptors including [[Toll-like receptors]] (TLRs), induce a release of inflammatory mediators, including [[Antimicrobial peptides|AMP]]<nowiki/>s, [[cytokines]], and [[chemokines]].<ref name="pmid23223142">{{cite journal |vauthors=Kuo IH, Carpenter-Mendini A, Yoshida T, McGirt LY, Ivanov AI, Barnes KC, Gallo RL, Borkowski AW, Yamasaki K, Leung DY, Georas SN, De Benedetto A, Beck LA |title=Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair |journal=J. Invest. Dermatol. |volume=133 |issue=4 |pages=988–98 |date=April 2013 |pmid=23223142 |pmc=3600383 |doi=10.1038/jid.2012.437 |url=}}</ref>  
**In intact skin barrier, [[Antimicrobial peptides|antimicrobial peptides (AMPs)]] are regulated by [[cytokines]], [[Interleukin 17|IL-17]], and [[Interleukin 22|IL- 22]], which are secreted by [[T helper 17 cell|Th17]] and [[T helper cell|Th22]] cells. This effect is suppressed in patients with atopic dermatitis.<ref name="pmid21315950">{{cite journal |vauthors=Macias ES, Pereira FA, Rietkerk W, Safai B |title=Superantigens in dermatology |journal=J. Am. Acad. Dermatol. |volume=64 |issue=3 |pages=455–72; quiz 473–4 |date=March 2011 |pmid=21315950 |doi=10.1016/j.jaad.2010.03.044 |url=}}</ref>
**Defective cutaneous innate immune-mediated epidermal barrier repair and maintenance may alter skin-resident normal microbial flora and lead to severe inflammation as demonstrated with atopic dermatitis patients colonized with ''[[Staphylococcus aureus]].''<ref name="pmid22310478">{{cite journal |vauthors=Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD, Murray PR, Turner ML, Segre JA |title=Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis |journal=Genome Res. |volume=22 |issue=5 |pages=850–9 |date=May 2012 |pmid=22310478 |pmc=3337431 |doi=10.1101/gr.131029.111 |url=}}</ref>  
*'''Adaptive immune response:'''
**In intact skin barrier, [[Antimicrobial peptides|antimicrobial peptides(AMPs)]] are regulated by [[cytokines]], [[Interleukin 17|IL-17]], and [[Interleukin 22|IL- 22]], which are secreted by [[T helper 17 cell|Th17]] and [[T helper cell|Th22]] cells. This effect is suppressed in patients with atopic dermatitis.<ref name="pmid21315950">{{cite journal |vauthors=Macias ES, Pereira FA, Rietkerk W, Safai B |title=Superantigens in dermatology |journal=J. Am. Acad. Dermatol. |volume=64 |issue=3 |pages=455–72; quiz 473–4 |date=March 2011 |pmid=21315950 |doi=10.1016/j.jaad.2010.03.044 |url=}}</ref>  
**Increased [[allergen]] penetration through the damaged [[epidermis]] leading to a [[Th2 response|Th2]]-type milieu is thought to explain the critical link between the barrier defect of atopic dermatitis patients with FLG mutations and Th2 polarization.<ref name="pmid216827492">{{cite journal |vauthors=Boguniewicz M, Leung DY |title=Atopic dermatitis: a disease of altered skin barrier and immune dysregulation |journal=Immunol. Rev. |volume=242 |issue=1 |pages=233–46 |date=July 2011 |pmid=21682749 |pmc=3122139 |doi=10.1111/j.1600-065X.2011.01027.x |url=}}</ref>
* '''Adaptive immune response:'''
**Enhanced expression of [[Th2 response|Th2]], [[Th17]], and Th22 cytokines, characterize the [[acute]] initiation of atopic dermatitis lesions.<ref name="pmid25282559">{{cite journal |vauthors=Leung DY, Guttman-Yassky E |title=Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=769–79 |date=October 2014 |pmid=25282559 |pmc=4186710 |doi=10.1016/j.jaci.2014.08.008 |url=}}</ref><ref name="StänderRopper2021">{{cite journal|last1=Ständer|first1=Sonja|last2=Ropper|first2=Allan H.|title=Atopic Dermatitis|journal=New England Journal of Medicine|volume=384|issue=12|year=2021|pages=1136–1143|issn=0028-4793|doi=10.1056/NEJMra2023911}}</ref>
**Increased allergen penetration through the damaged epidermis leading to a [[Th2 response|Th2]]-type milieu is thought to explain the critical link between the barrier defect of atopic dermatitis patients with FLG mutations and Th2 polarization.<ref name="pmid216827492">{{cite journal |vauthors=Boguniewicz M, Leung DY |title=Atopic dermatitis: a disease of altered skin barrier and immune dysregulation |journal=Immunol. Rev. |volume=242 |issue=1 |pages=233–46 |date=July 2011 |pmid=21682749 |pmc=3122139 |doi=10.1111/j.1600-065X.2011.01027.x |url=}}</ref>  
**Epidermal barrier function is regulated through [[Th2]] and Th22 cytokines ([[Interleukin 4|IL-4]], [[Interleukin 13|IL-13,]] [[Interleukin 31|IL-31]], and [[Interleukin 22|IL-22]]) by:<ref name="pmid252825593">{{cite journal |vauthors=Leung DY, Guttman-Yassky E |title=Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=769–79 |date=October 2014 |pmid=25282559 |pmc=4186710 |doi=10.1016/j.jaci.2014.08.008 |url=}}</ref><ref name="StänderRopper2021">{{cite journal|last1=Ständer|first1=Sonja|last2=Ropper|first2=Allan H.|title=Atopic Dermatitis|journal=New England Journal of Medicine|volume=384|issue=12|year=2021|pages=1136–1143|issn=0028-4793|doi=10.1056/NEJMra2023911}}</ref>
**Enhanced expression of [[Th2 response|Th2]], [[Th17]], and Th22 cytokines, characterize the acute initiation of atopic dermatitis lesions.<ref name="pmid25282559">{{cite journal |vauthors=Leung DY, Guttman-Yassky E |title=Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=769–79 |date=October 2014 |pmid=25282559 |pmc=4186710 |doi=10.1016/j.jaci.2014.08.008 |url=}}</ref>  
***Stimulating epidermal [[hyperplasia]]
**Epidermal barrier function is regulated through Th2 and Th22 cytokines ([[Interleukin 4|IL-4]], [[Interleukin 13|IL-13,]] [[Interleukin 31|IL-31]], and [[Interleukin 22|IL-22]]) by:<ref name="pmid252825593">{{cite journal |vauthors=Leung DY, Guttman-Yassky E |title=Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=769–79 |date=October 2014 |pmid=25282559 |pmc=4186710 |doi=10.1016/j.jaci.2014.08.008 |url=}}</ref>
***Inhibiting the expression of terminal keratinocyte differentiation genes (eg, ''FLG'', [[loricrin]], [[involucrin]])
***stimulating epidermal [[hyperplasia]]
***Suppressing the production of [[Antimicrobial peptides|AMPs]]
***inhibiting the expression of terminal keratinocyte differentiation genes (eg, ''FLG'', [[loricrin]], [[involucrin]])
*'''Thymic stromal lymphopoietin:'''
***suppressing the production of AMPs
**Defective skin barrier and enhanced [[epidermal]] [[protease]] activity, which is reported in atopic dermatitis, promote [[TSLP]] production and [[Th2 response]], leading to atopic dermatitis-like [[inflammation]].<ref name="pmid222700712">{{cite journal |vauthors=Takai T |title=TSLP expression: cellular sources, triggers, and regulatory mechanisms |journal=Allergol Int |volume=61 |issue=1 |pages=3–17 |date=March 2012 |pmid=22270071 |doi=10.2332/allergolint.11-RAI-0395 |url=}}</ref>
* '''Thymic stromal lymphopoietin:'''
**''[[TSLP]]'' polymorphisms have been linked to the severity of atopic dermatitis.
**Defective skin  barrier and enhanced epidermal [[protease]] activity, which is reported in atopic dermatitis, promote [[TSLP]] production and Th2 response, leading to atopic dermatitis-like inflammation.<ref name="pmid222700712">{{cite journal |vauthors=Takai T |title=TSLP expression: cellular sources, triggers, and regulatory mechanisms |journal=Allergol Int |volume=61 |issue=1 |pages=3–17 |date=March 2012 |pmid=22270071 |doi=10.2332/allergolint.11-RAI-0395 |url=}}</ref>  
**[[TSLP]] genetic variants are associated with atopic dermatitis and [[eczema herpeticum]].<ref name="pmid20466416">{{cite journal |vauthors=Gao PS, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, Gao L, Beaty TH, Beck LA, Leung DY, Barnes KC |title=Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum |journal=J. Allergy Clin. Immunol. |volume=125 |issue=6 |pages=1403–1407.e4 |date=June 2010 |pmid=20466416 |pmc=2925504 |doi=10.1016/j.jaci.2010.03.016 |url=}}</ref>
**''[[TSLP]]'' polymorphisms have been linked to the severity of atopic dermatitis.
**In patients with defective skin barrier due to [[Filaggrin|FLG]] mutations, [[TSLP]] genetic variants are associated with reduced [[probability]] of having persistent atopic dermatitis.<ref name="pmid24401911">{{cite journal |vauthors=Margolis DJ, Kim B, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Mitra N |title=Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis |journal=JAMA Dermatol |volume=150 |issue=3 |pages=254–9 |date=March 2014 |pmid=24401911 |pmc=4414492 |doi=10.1001/jamadermatol.2013.7954 |url=}}</ref>
**TSLP genetic variants are associated with atopic dermatitis and [[eczema herpeticum]].<ref name="pmid20466416">{{cite journal |vauthors=Gao PS, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, Gao L, Beaty TH, Beck LA, Leung DY, Barnes KC |title=Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum |journal=J. Allergy Clin. Immunol. |volume=125 |issue=6 |pages=1403–1407.e4 |date=June 2010 |pmid=20466416 |pmc=2925504 |doi=10.1016/j.jaci.2010.03.016 |url=}}</ref>
**In patients with defective skin barrier due to FLG mutations, [[TSLP]] genetic variants are associated with reduced probability of having persistent atopic dermatitis.<ref name="pmid24401911">{{cite journal |vauthors=Margolis DJ, Kim B, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Mitra N |title=Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis |journal=JAMA Dermatol |volume=150 |issue=3 |pages=254–9 |date=March 2014 |pmid=24401911 |pmc=4414492 |doi=10.1001/jamadermatol.2013.7954 |url=}}</ref>


== Genetics ==
==Genetics==
Recent studies have established a strong genetic association with atopic dermatitis. Twin studies have indicated high [[heritability]] of atopic dermatitis with a [[Concordance (genetics)|concordance]] rate of 72–86 % for [[monozygotic twins]] compared with 21–23 % for [[dizygotic twins]].<ref name="pmid27004062">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
Recent studies have established a strong genetic association of atopic dermatitis. Twin studies have indicated high [[heritability]] of atopic dermatitis with a [[Concordance (genetics)|concordance]] rate of 72–86 % for [[monozygotic twins]] compared with 21–23 % for [[dizygotic twins]].<ref name="pmid27004062">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>


Genes involved in the pathogenesis of atopic dermatitis include:<ref name="pmid270040623">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
Genes involved in the pathogenesis of atopic dermatitis include:<ref name="pmid270040623">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
# '''Filaggrin Gene mutation''':  
{| class="wikitable"
#* Located on chromosome 1q21 [[Epidermal differentiation complex|(epidermal differentiation complex]]) loss-of-function mutations in the filaggrin gene FLG, is strongly associated with a broad range of skin and allergic diseases including atopic dermatitis.<ref name="pmid21991953">{{cite journal |vauthors=Irvine AD, McLean WH, Leung DY |title=Filaggrin mutations associated with skin and allergic diseases |journal=N. Engl. J. Med. |volume=365 |issue=14 |pages=1315–27 |date=October 2011 |pmid=21991953 |doi=10.1056/NEJMra1011040 |url=}}</ref>  
|+
#* Mutation in this gene is also responsible for [[ichthyosis vulgaris]] and [[pachyonychia congenita]].<ref name="pmid17657246">{{cite journal |vauthors=Liao H, Waters AJ, Goudie DR, Aitken DA, Graham G, Smith FJ, Lewis-Jones S, McLean WH |title=Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis |journal=J. Invest. Dermatol. |volume=127 |issue=12 |pages=2795–8 |date=December 2007 |pmid=17657246 |doi=10.1038/sj.jid.5700971 |url=}}</ref>  
! colspan="3" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Genes involved in the pathogenesis of atopic dermatitis
#* The common genetic variant R510X and 2282del4 are very strongly associated with atopic dermatitis.<ref name="pmid16550169">{{cite journal |vauthors=Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH |title=Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis |journal=Nat. Genet. |volume=38 |issue=4 |pages=441–6 |date=April 2006 |pmid=16550169 |doi=10.1038/ng1767 |url=}}</ref>  
|-
#* FLG Gene mutation is associated with developing atopic dermatitis at an early age(≤8 years) but is not associated with late childhood or adulthood atopic dermatitis.<ref name="pmid25314673">{{cite journal |vauthors=Rupnik H, Rijavec M, Korošec P |title=Filaggrin loss-of-function mutations are not associated with atopic dermatitis that develops in late childhood or adulthood |journal=Br. J. Dermatol. |volume=172 |issue=2 |pages=455–61 |date=February 2015 |pmid=25314673 |doi=10.1111/bjd.13477 |url=}}</ref>
| colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Filaggrin Gene mutation'''
# '''SPINK5 and LEKTI gene''':
|
#* Located on chromosome 5q32, [[SPINK5|Serine Protease Inhibitor Kazal-Type 5 (SPINK5]]) gene encodes a [[protease inhibitor]] lymphoepithelial Kazal-type-Related Inhibitor (LEKTI), which is involved in converting profilaggrin into filaggrin and is responsible for marinating the permeability of the normal skin.<ref name="pmid270040622">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
*Located on [[chromosome]] 1q21 [[Epidermal differentiation complex|(epidermal differentiation complex]]) loss-of-function mutations in the filaggrin gene FLG, is strongly associated with a broad range of skin and [[allergic]] diseases including atopic dermatitis.<ref name="pmid21991953">{{cite journal |vauthors=Irvine AD, McLean WH, Leung DY |title=Filaggrin mutations associated with skin and allergic diseases |journal=N. Engl. J. Med. |volume=365 |issue=14 |pages=1315–27 |date=October 2011 |pmid=21991953 |doi=10.1056/NEJMra1011040 |url=}}</ref>
#* [[LEKTI]] deficiency leads to enhanced cleavage of intercellular attachments, decreased corneocyte cohesion and impaired skin barrier function.<ref name="pmid168151332">{{cite journal |vauthors=Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R |title=New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions |journal=J. Allergy Clin. Immunol. |volume=118 |issue=1 |pages=3–21; quiz 22–3 |date=July 2006 |pmid=16815133 |doi=10.1016/j.jaci.2006.04.042 |url=}}</ref>
*Mutation in this gene is also responsible for [[ichthyosis vulgaris]] and [[pachyonychia congenita]].<ref name="pmid17657246">{{cite journal |vauthors=Liao H, Waters AJ, Goudie DR, Aitken DA, Graham G, Smith FJ, Lewis-Jones S, McLean WH |title=Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis |journal=J. Invest. Dermatol. |volume=127 |issue=12 |pages=2795–8 |date=December 2007 |pmid=17657246 |doi=10.1038/sj.jid.5700971 |url=}}</ref>
# '''MHC (or HLA) genes'''
*The common genetic variant R510X and 2282del4 are very strongly associated with [[atopic dermatitis]].<ref name="pmid16550169">{{cite journal |vauthors=Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH |title=Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis |journal=Nat. Genet. |volume=38 |issue=4 |pages=441–6 |date=April 2006 |pmid=16550169 |doi=10.1038/ng1767 |url=}}</ref>
# '''Innate Immune system genes''':
*FLG [[gene mutation]] is associated with developing [[atopic dermatitis]] at an early age(≤8 years) but is not associated with late childhood or adulthood atopic dermatitis.<ref name="pmid25314673">{{cite journal |vauthors=Rupnik H, Rijavec M, Korošec P |title=Filaggrin loss-of-function mutations are not associated with atopic dermatitis that develops in late childhood or adulthood |journal=Br. J. Dermatol. |volume=172 |issue=2 |pages=455–61 |date=February 2015 |pmid=25314673 |doi=10.1111/bjd.13477 |url=}}</ref>
#* CARD4 (or NOD1) gene: Caspase recruitment domain–containing protein (CARD) 4
|-
#* CARD15 (or NOD2) gene
| colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''SPINK5 and LEKTI gene'''
#* Monocyte differentiation antigen (or [[CD14|CD14)]] gene
|
#* MBL2 gene:  [[Mannose-binding lectin pathway|mannose-binding lectin]] '''('''MBL2) gene
*Located on [[chromosome]] 5q32, [[SPINK5|Serine Protease Inhibitor Kazal-Type 5 (SPINK5]]) gene encodes a [[protease inhibitor]] lymphoepithelial Kazal-type-Related Inhibitor ([[LEKTI]]), which is involved in converting profilaggrin into [[filaggrin]] and is responsible for marinating the permeability of the normal skin.<ref name="pmid270040622">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
#* [[Toll-like receptors|Toll-like receptor]]( [[TLR2]], [[TLR4]], [[TLR6]] and [[TLR 9]]) genes
*[[LEKTI]] deficiency leads to enhanced cleavage of intercellular attachments, decreased corneocyte [[cohesion]] and impaired skin barrier function.<ref name="pmid168151332">{{cite journal |vauthors=Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R |title=New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions |journal=J. Allergy Clin. Immunol. |volume=118 |issue=1 |pages=3–21; quiz 22–3 |date=July 2006 |pmid=16815133 |doi=10.1016/j.jaci.2006.04.042 |url=}}</ref>
#* DEFB1 gene: human β-defensin 1
|-
# '''Adaptive immune system genes'''
| colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''MHC (or HLA) genes'''
#* '''Cytokines and related genes''':  
|
#** [[Interleukin 4|IL-4]] gene
*Major [[histocompatibility]] complex or [[human leukocyte antigen]]
#** IL-4Rα gene
|-
#** [[STAT6]] gene (Signal transducer and activator of transcription )
| colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Innate Immune system genes''':
#** [[Interleukin 10|IL-10]] gene
|
#** [[Interleukin 6|IL-6]] gene
*CARD4 (or [[NOD1]]) gene: [[Caspase]] recruitment domain–containing protein (CARD) 4
#** [[Tumor necrosis factor-alpha|TNF-α]] gene
*[[CARD15]] (or [[NOD2]]) gene
#** TNF-β gene
*[[Monocyte]] differentiation antigen (or [[CD14|CD14)]] gene
#** IL-1α gene
*MBL2 gene:  [[Mannose-binding lectin pathway|mannose-binding lectin]] '''('''MBL2) gene
#** IL-β gene
*[[Toll-like receptors|Toll-like receptor]]( [[TLR2]], [[TLR4]], [[TLR6]] and [[TLR 9]]) genes
#** IFNγ gene
*DEFB1 gene: human β-defensin 1
#** IL-1RL1
|-
#** [[Interleukin 5|IL-5]] gene
| rowspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Adaptive immune system genes'''
#** [[Interleukin 12|IL-12]] β gene
| style="background: #DCDCDC; text-align: center;" |'''Cytokines and related genes''':
#** IL-12R β
|
#** [[Interleukin 13|IL-13]] gene
*[[Interleukin 4|IL-4]] gene
#** IL-18 gene
*IL-4Rα gene
#** TGF-β1 gene
*[[STAT6]] gene (Signal transducer and activator of transcription )
#** [[GM-CSF]] gene
*[[Interleukin 10|IL-10]] gene
#** [[IL-9]] gene
*[[Interleukin 6|IL-6]] gene
#** IL-9R gene
*[[Tumor necrosis factor-alpha|TNF-α]] gene
#* '''Chemokines and related genes''':
*[[TNF]]-β gene
#** CCL5 gene: Chemokine (C-Cmotif) ligand 5
*[[IL-1]]α gene
#** [[CCL11]] gene
*[[IL-β]] gene
#** CCL17 gene
*[[IFNγ]] gene
#** CCR3 gene
*[[IL-1RL1]]
#** CCR4 gene
*[[Interleukin 5|IL-5]] gene
#** CMA1 gene: Mast cell chymase 1
*[[Interleukin 12|IL-12]] β gene
# '''Drug-metabolizing genes'''
*[[IL-12R β]]
#* GST genes: glutathione S-transferase
*[[Interleukin 13|IL-13]] gene
#* NAT-2 gene: N-acetyl transferase
*IL-18 gene
# '''Other genes'''
*TGF-β1 gene
#* CTLA-4
*[[GM-CSF]] gene
#* KLK
*[[IL-9]] gene
#* RUNX1 gene
*[[IL-9R]] gene
#* IRF2 gene
|-
#* FCER1B gene
| style="background: #DCDCDC; text-align: center;" |'''Chemokines and related genes''':
#* PHF11 gene
|
*
*[[CCL5]] gene: [[Chemokine]] (C-Cmotif) ligand 5
*[[CCL11]] gene
*[[CCL17]] gene
*[[CCR3 (gene)|CCR3]] gene
*[[CCR4]] gene
*[[CMA1]] gene: [[Mast cell]] [[chymase]] 1
|-
| colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Drug-metabolizing genes'''
|
*[[GST]] genes: [[glutathione]] S-transferase
*[[NAT-2]] gene: N-acetyl transferase
|-
| colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Other genes'''
|
*[[CTLA-4]]
*KLK
*[[RUNX1]] gene
*[[IRF2]] gene
*[[FCER1B]] gene
*[[PHF11]] gene
|-
| colspan="3" |Adapted from ''Molecular Genetic of Atopic dermatitis: An Update''<ref name="pmid270040624">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
|}


==Associated Conditions==
==Associated Conditions==
Conditions associated with atopic dermatitis include:


*Atopic triad<ref name="pmid17692428">{{cite journal |vauthors=Kapoor R, Menon C, Hoffstad O, Bilker W, Leclerc P, Margolis DJ |title=The prevalence of atopic triad in children with physician-confirmed atopic dermatitis |journal=J. Am. Acad. Dermatol. |volume=58 |issue=1 |pages=68–73 |date=January 2008 |pmid=17692428 |doi=10.1016/j.jaad.2007.06.041 |url=}}</ref>
'''Conditions associated with atopic dermatitis:'''
**Atopic dermatitis
 
**Allergic rhinitis
*[[Atopic]] triad <ref name="StänderRopper2021">{{cite journal|last1=Ständer|first1=Sonja|last2=Ropper|first2=Allan H.|title=Atopic Dermatitis|journal=New England Journal of Medicine|volume=384|issue=12|year=2021|pages=1136–1143|issn=0028-4793|doi=10.1056/NEJMra2023911}}</ref>
**[[Atopic dermatitis]]
**[[Allergic rhinitis]]
**[[Asthma]]
**[[Asthma]]
*Food-induced urticaria/anaphylaxis <ref name="pmid10893011">{{cite journal |vauthors=Eigenmann PA, Calza AM |title=Diagnosis of IgE-mediated food allergy among Swiss children with atopic dermatitis |journal=Pediatr Allergy Immunol |volume=11 |issue=2 |pages=95–100 |date=May 2000 |pmid=10893011 |doi= |url=}}</ref>
*Food-induced [[urticaria]]/[[anaphylaxis]]
*[[Ichthyosis vulgaris]]<ref name="pmid18455261">{{cite journal |vauthors=Bremmer SF, Hanifin JM, Simpson EL |title=Clinical detection of ichthyosis vulgaris in an atopic dermatitis clinic: implications for allergic respiratory disease and prognosis |journal=J. Am. Acad. Dermatol. |volume=59 |issue=1 |pages=72–8 |date=July 2008 |pmid=18455261 |doi=10.1016/j.jaad.2008.03.029 |url=}}</ref>
*[[Ichthyosis vulgaris]]
*Ocular comorbidities
*[[Ocular]] comorbidities
**[[Atopic keratoconjunctivitis]]<ref name="pmid24342754">{{cite journal |vauthors=Chen JJ, Applebaum DS, Sun GS, Pflugfelder SC |title=Atopic keratoconjunctivitis: A review |journal=J. Am. Acad. Dermatol. |volume=70 |issue=3 |pages=569–75 |date=March 2014 |pmid=24342754 |doi=10.1016/j.jaad.2013.10.036 |url=}}</ref>
**[[Atopic keratoconjunctivitis]]
**[[Vernal keratoconjunctivitis]]<ref name="pmid25744396">{{cite journal |vauthors=Pattnaik L, Acharya L |title=A comprehensive review on vernal keratoconjunctivitis with emphasis on proteomics |journal=Life Sci. |volume=128 |issue= |pages=47–54 |date=May 2015 |pmid=25744396 |doi=10.1016/j.lfs.2015.01.040 |url=}}</ref>
**[[Vernal keratoconjunctivitis]]
* [[Wiskott-Aldrich syndrome]]<ref name="pmid11800140">{{cite journal |vauthors=Bradley M, Söderhäll C, Wahlgren CF, Luthman H, Nordenskjöld M, Kockum I |title=The Wiskott-Aldrich syndrome gene as a candidate gene for atopic dermatitis |journal=Acta Derm. Venereol. |volume=81 |issue=5 |pages=340–2 |date=2001 |pmid=11800140 |doi= |url=}}</ref>
*[[Wiskott-Aldrich syndrome]]
** Thrombocytopenia
**[[Thrombocytopenia]]
** Eczema (atopic dermatitis)
**[[Eczema]] (atopic dermatitis)
** Recurrent infections
**Recurrent [[Infection|infections]]
*[[Hyper-IgE syndrome]]:<ref name="pmid16913276">{{cite journal |vauthors=Ohameje NU, Loveless JW, Saini SS |title=Atopic dermatitis or hyper-IgE syndrome? |journal=Allergy Asthma Proc |volume=27 |issue=3 |pages=289–91 |date=2006 |pmid=16913276 |doi= |url=}}</ref>
*[[Hyper-IgE syndrome]]:
**Eczema (atopic dermatitis)
**[[Eczema]] (atopic dermatitis)
**High serum [[IgE]]
**High serum [[IgE]]
**Recurrent cold abscesses
**Recurrent cold abscesses
* [[Anemia]]<ref name="pmid26619045">{{cite journal |vauthors=Drury KE, Schaeffer M, Silverberg JI |title=Association Between Atopic Disease and Anemia in US Children |journal=JAMA Pediatr |volume=170 |issue=1 |pages=29–34 |date=January 2016 |pmid=26619045 |doi=10.1001/jamapediatrics.2015.3065 |url=}}</ref>
*[[Anemia]]
* Psychiatric disorders<ref name="pmid30119868">{{cite journal |vauthors=Rønnstad ATM, Halling-Overgaard AS, Hamann CR, Skov L, Egeberg A, Thyssen JP |title=Association of atopic dermatitis with depression, anxiety, and suicidal ideation in children and adults: A systematic review and meta-analysis |journal=J. Am. Acad. Dermatol. |volume=79 |issue=3 |pages=448–456.e30 |date=September 2018 |pmid=30119868 |doi=10.1016/j.jaad.2018.03.017 |url=}}</ref>
*[[Psychiatric]] [[disorders]]
** [[Depression]]<ref name="pmid29929155">{{cite journal |vauthors=Bao Q, Chen L, Lu Z, Ma Y, Guo L, Zhang S, Huang X, Xu S, Ruan L |title=Association between eczema and risk of depression: A systematic review and meta-analysis of 188,495 participants |journal=J Affect Disord |volume=238 |issue= |pages=458–464 |date=October 2018 |pmid=29929155 |doi=10.1016/j.jad.2018.05.007 |url=}}</ref>
**[[Depression]]
** [[Anxiety]]<ref name="pmid25795537">{{cite journal |vauthors=Cheng CM, Hsu JW, Huang KL, Bai YM, Su TP, Li CT, Yang AC, Chang WH, Chen TJ, Tsai SJ, Chen MH |title=Risk of developing major depressive disorder and anxiety disorders among adolescents and adults with atopic dermatitis: a nationwide longitudinal study |journal=J Affect Disord |volume=178 |issue= |pages=60–5 |date=June 2015 |pmid=25795537 |doi=10.1016/j.jad.2015.02.025 |url=}}</ref>
**[[Anxiety]]
** [[Suicidal|Suicid]]<nowiki/>al ideations
**[[Suicidal|Suicid]]<nowiki/>[[Suicidal|al]] ideations
** [[Attention deficit hyperactivity disorder]]<ref name="pmid27105659">{{cite journal |vauthors=Strom MA, Fishbein AB, Paller AS, Silverberg JI |title=Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults |journal=Br. J. Dermatol. |volume=175 |issue=5 |pages=920–929 |date=November 2016 |pmid=27105659 |pmc=5216180 |doi=10.1111/bjd.14697 |url=}}</ref>
**[[Attention deficit hyperactivity disorder]]
* [[Angina pectoris]]<ref name="pmid29210061">{{cite journal |vauthors=Thyssen JP, Halling-Overgaard AS, Andersen YMF, Gislason G, Skov L, Egeberg A |title=The association with cardiovascular disease and type 2 diabetes in adults with atopic dermatitis: a systematic review and meta-analysis |journal=Br. J. Dermatol. |volume=178 |issue=6 |pages=1272–1279 |date=June 2018 |pmid=29210061 |doi=10.1111/bjd.16215 |url=}}</ref>
*[[Angina pectoris]]


==Gross Pathology==
==Gross Pathology==
On gross pathology, erythema, edema, and vesiculation with oozing are characteristic findings of atopic dermatitis while chronic atopic dermatitis is characterized by lichenified plaques with prominent skin markings.<ref name="MihmSoter19762">{{cite journal|last1=Mihm|first1=Martin C|last2=Soter|first2=Nicholas A|last3=Dvorak|first3=Harold F|last4=Austen|first4=K Frank|title=The Structure Of Normal Skin And The Morphology Of Atopic Eczema|journal=Journal of Investigative Dermatology|volume=67|issue=3|year=1976|pages=305–312|issn=0022202X|doi=10.1111/1523-1747.ep12514346}}</ref>
On [[gross pathology]], characteristic findings of atopic dermatitis include:<ref name="MihmSoter19762">{{cite journal|last1=Mihm|first1=Martin C|last2=Soter|first2=Nicholas A|last3=Dvorak|first3=Harold F|last4=Austen|first4=K Frank|title=The Structure Of Normal Skin And The Morphology Of Atopic Eczema|journal=Journal of Investigative Dermatology|volume=67|issue=3|year=1976|pages=305–312|issn=0022202X|doi=10.1111/1523-1747.ep12514346}}</ref>
 
*'''Acute atopic dermatitis''':
**[[Erythema]]
**[[Edema]]
**Vesiculation with oozing
*'''Chronic atopic dermatitis:'''
**Lichenified plaques
**Prominent skin markings


==Microscopic Pathology==
==Microscopic Pathology==
On microscopic histopathological analysis, characteristic findings of atopic dermatitis include:<ref name="MihmSoter19763">{{cite journal|last1=Mihm|first1=Martin C|last2=Soter|first2=Nicholas A|last3=Dvorak|first3=Harold F|last4=Austen|first4=K Frank|title=The Structure Of Normal Skin And The Morphology Of Atopic Eczema|journal=Journal of Investigative Dermatology|volume=67|issue=3|year=1976|pages=305–312|issn=0022202X|doi=10.1111/1523-1747.ep12514346}}</ref>
On microscopic [[histopathological]] analysis, characteristic findings of [[atopic dermatitis]] include:<ref name="MihmSoter19763">{{cite journal|last1=Mihm|first1=Martin C|last2=Soter|first2=Nicholas A|last3=Dvorak|first3=Harold F|last4=Austen|first4=K Frank|title=The Structure Of Normal Skin And The Morphology Of Atopic Eczema|journal=Journal of Investigative Dermatology|volume=67|issue=3|year=1976|pages=305–312|issn=0022202X|doi=10.1111/1523-1747.ep12514346}}</ref>
* '''Acute vesicular lesions''':  
 
** Epidermal psoriasiform hyperplasia
*'''Acute vesicular lesions''':  
** Marked intercellular edema with spongiotic vesiculation
**[[Epidermal]] psoriasiform [[hyperplasia]]
** Marked perivenular infiltrate
**Marked intercellular [[edema]] with spongiotic vesiculation
** Epidermal infiltrate, consisting predominately of a lymphohistiocytic infiltrate in the dermis
**Marked perivenular infiltrate
* '''Chronic lichenified plaque''':
**Epidermal infiltrate, consisting predominately of a [[lymphohistiocytic]] infiltrate in the dermis
** [[Hyperkeratosis]]
*'''Chronic lichenified plaque''':
** psoriasiform hyperplasia
**[[Hyperkeratosis]]
** dyskeratosis
**[[Psoriasiform hyperplasia]]
** Marked thickening of the papillary dermis
**[[Dyskeratosis]]
** Minimal intercellular edema
**Marked thickening of the [[papillary]] dermis
**Minimal intercellular [[edema]]


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
 
[[Category:Dermatology]]
{{WH}}
[[Category:Up-To-Date]]
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogechukwu Hannah Nnabude, MD; Shalinder Singh, M.B.B.S.[2]

Overview

Atopic dermatitis is a chronic inflammatory skin disorder with an immunologic background and occurs in patients with a personal or family history of atopy (i.e. asthma or allergic rhinitis). It is caused by either a skin barrier dysfunction or immune dysregulation of the adaptive and innate immune response leading to an enhanced IgE-mediated, systemic Th2 response. The skin barrier is invaded by exogenous substances, including allergens, irritants and microbes; and the tightly packed structure of the stratum corneum is further compromised. Systemically, a dysfunctional innate and adaptive immune response causes further damage to the epidermis.

Pathophysiology

Physiology

The normal physiology of atopic dermatitis can be understood as follows:

Epidermal barrier function:

Immune response:

Pathogenesis

It is understood that atopic dermatitis is the result of either skin barrier dysfunction or immune dysregulation.[17]

Epidermal barrier dysfunction (outside-in hypothesis):[18]

Immune dysregulation (inside-out’ hypothesis):[29]

  • Innate immune response:
  • Adaptive immune response:
    • Increased allergen penetration through the damaged epidermis leading to a Th2-type milieu is thought to explain the critical link between the barrier defect of atopic dermatitis patients with FLG mutations and Th2 polarization.[33]
    • Enhanced expression of Th2, Th17, and Th22 cytokines, characterize the acute initiation of atopic dermatitis lesions.[34][3]
    • Epidermal barrier function is regulated through Th2 and Th22 cytokines (IL-4, IL-13, IL-31, and IL-22) by:[35][3]
      • Stimulating epidermal hyperplasia
      • Inhibiting the expression of terminal keratinocyte differentiation genes (eg, FLG, loricrin, involucrin)
      • Suppressing the production of AMPs
  • Thymic stromal lymphopoietin:
    • Defective skin barrier and enhanced epidermal protease activity, which is reported in atopic dermatitis, promote TSLP production and Th2 response, leading to atopic dermatitis-like inflammation.[36]
    • TSLP polymorphisms have been linked to the severity of atopic dermatitis.
    • TSLP genetic variants are associated with atopic dermatitis and eczema herpeticum.[37]
    • In patients with defective skin barrier due to FLG mutations, TSLP genetic variants are associated with reduced probability of having persistent atopic dermatitis.[38]

Genetics

Recent studies have established a strong genetic association of atopic dermatitis. Twin studies have indicated high heritability of atopic dermatitis with a concordance rate of 72–86 % for monozygotic twins compared with 21–23 % for dizygotic twins.[39]

Genes involved in the pathogenesis of atopic dermatitis include:[40]

Genes involved in the pathogenesis of atopic dermatitis
Filaggrin Gene mutation
SPINK5 and LEKTI gene
MHC (or HLA) genes
Innate Immune system genes:
Adaptive immune system genes Cytokines and related genes:
Chemokines and related genes:
Drug-metabolizing genes
Other genes
Adapted from Molecular Genetic of Atopic dermatitis: An Update[47]

Associated Conditions

Conditions associated with atopic dermatitis:

Gross Pathology

On gross pathology, characteristic findings of atopic dermatitis include:[48]

  • Acute atopic dermatitis:
  • Chronic atopic dermatitis:
    • Lichenified plaques
    • Prominent skin markings

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of atopic dermatitis include:[49]

References

  1. Elias PM, Wakefield JS (October 2014). "Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis". J. Allergy Clin. Immunol. 134 (4): 781–791.e1. doi:10.1016/j.jaci.2014.05.048. PMC 4186911. PMID 25131691.
  2. Sandilands A, Sutherland C, Irvine AD, McLean WH (May 2009). "Filaggrin in the frontline: role in skin barrier function and disease". J. Cell. Sci. 122 (Pt 9): 1285–94. doi:10.1242/jcs.033969. PMC 2721001. PMID 19386895.
  3. 3.0 3.1 3.2 3.3 3.4 Ständer, Sonja; Ropper, Allan H. (2021). "Atopic Dermatitis". New England Journal of Medicine. 384 (12): 1136–1143. doi:10.1056/NEJMra2023911. ISSN 0028-4793.
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