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 [[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 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]].   
[[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==
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'''Epidermal barrier function:'''
'''Epidermal barrier function:'''


*'''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. 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>
*'''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>
**Tightly packed corneocytes layers in the [[stratum corneum]]
**Tightly packed corneocytes layers in the [[stratum corneum]]
**Intercellular lipid bilayers
**Intercellular lipid bilayers
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**[[Antimicrobial peptides]]
**[[Antimicrobial peptides]]
*'''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>
*'''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]] 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]].
**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]].
**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>
**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 are one of the major components of natural moisturising factors (NMF), which prevents excess water loss from the [[stratum corneum]].
**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]].
**The degraded products of [[filaggrin]] protein also maintain the [[Acid|acidic]] [[pH]] of the [[stratum corneum]], required to regulate the activity of [[enzymes]].
**The degraded products of [[filaggrin]] protein also maintain the [[Acid|acidic]] [[pH]] of the [[stratum corneum]], required to regulate the activity of [[enzymes]].
*'''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>
*'''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>
*'''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>
*'''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>
**''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>
**''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>
**''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>
**''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>
**''[[Microbiome|Microbiome]]'': 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>
**''[[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>
**''Immunological'': Immune response includes both [[Innate immune response|non-specific]] and immediate response ([[innate immunity]]) and highly specific and late response ([[adaptive immunity]]).
**''Immunological'': Immune response includes both [[Innate immune response|non-specific]] and immediate response ([[innate immunity]]) and highly specific and late response ([[adaptive immunity]]).
*'''Adaptive Immune response''':<ref name="pmid20109730" />
*'''Adaptive Immune response''':<ref name="pmid20109730" />
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===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>
'''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>
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*Skin barrier abnormalities lead to the increased permeability of the [[epidermis]].
*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 leads to entry of [[antigens]] or [[pathogens]] resulting in [[microbial]] colonization, most notably by ''[[staphylococcus aureus]]'' and [[herpes simplex virus (HSV)]].
**These 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>
**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>


*Skin barrier abnormalities also leads 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>
*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>


*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>
*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>
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*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>
*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>
*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>
*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>
*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>
*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>
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*[[IL-β]] gene
*[[IL-β]] gene
*[[IFNγ]] gene
*[[IFNγ]] gene
*IL-1RL1
*[[IL-1RL1]]
*[[Interleukin 5|IL-5]] gene
*[[Interleukin 5|IL-5]] gene
*[[Interleukin 12|IL-12]] β gene
*[[Interleukin 12|IL-12]] β gene
*IL-12R β
*[[IL-12R β]]
*[[Interleukin 13|IL-13]] gene
*[[Interleukin 13|IL-13]] gene
*IL-18 gene
*IL-18 gene
Line 211: Line 211:
**Marked intercellular [[edema]] with spongiotic vesiculation
**Marked intercellular [[edema]] with spongiotic vesiculation
**Marked perivenular infiltrate
**Marked perivenular infiltrate
**Epidermal infiltrate, consisting predominately of a lymphohistiocytic infiltrate in the dermis
**Epidermal infiltrate, consisting predominately of a [[lymphohistiocytic]] infiltrate in the dermis
*'''Chronic lichenified plaque''':
*'''Chronic lichenified plaque''':
**[[Hyperkeratosis]]
**[[Hyperkeratosis]]
**Psoriasiform hyperplasia
**[[Psoriasiform hyperplasia]]
**Dyskeratosis
**[[Dyskeratosis]]
**Marked thickening of the [[papillary]] dermis
**Marked thickening of the [[papillary]] dermis
**Minimal intercellular [[edema]]
**Minimal intercellular [[edema]]
Line 222: Line 222:
{{Reflist|2}}
{{Reflist|2}}
[[Category:Dermatology]]
[[Category:Dermatology]]
[[Category:Needs English Review]]
[[Category:Up-To-Date]]

Latest revision as of 06:01, 16 October 2021

Atopic dermatitis Microchapters

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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

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  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.
  4. 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.
  5. 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 (March 2011). "Tight junction defects in patients with atopic dermatitis". J. Allergy Clin. Immunol. 127 (3): 773–86.e1–7. doi:10.1016/j.jaci.2010.10.018. PMC 3049863. PMID 21163515.
  6. Broccardo CJ, Mahaffey S, Schwarz J, Wruck L, David G, Schlievert PM, Reisdorph NA, Leung DY (January 2011). "Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization". J. Allergy Clin. Immunol. 127 (1): 186–93, 193.e1–11. doi:10.1016/j.jaci.2010.10.033. PMC 3059191. PMID 21211653.
  7. 7.0 7.1 Barnes KC (January 2010). "An update on the genetics of atopic dermatitis: scratching the surface in 2009". J. Allergy Clin. Immunol. 125 (1): 16–29.e1–11, quiz 30–1. doi:10.1016/j.jaci.2009.11.008. PMC 2874322. PMID 20109730.
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  10. Kuo IH, Yoshida T, De Benedetto A, Beck LA (February 2013). "The cutaneous innate immune response in patients with atopic dermatitis". J. Allergy Clin. Immunol. 131 (2): 266–78. doi:10.1016/j.jaci.2012.12.1563. PMID 23374259.
  11. 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 (April 2013). "Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair". J. Invest. Dermatol. 133 (4): 988–98. doi:10.1038/jid.2012.437. PMC 3600383. PMID 23223142.
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  13. De Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA (January 2009). "Atopic dermatitis: a disease caused by innate immune defects?". J. Invest. Dermatol. 129 (1): 14–30. doi:10.1038/jid.2008.259. PMID 19078985.
  14. Liu YJ (February 2006). "Thymic stromal lymphopoietin: master switch for allergic inflammation". J. Exp. Med. 203 (2): 269–73. doi:10.1084/jem.20051745. PMC 2118215. PMID 16432252.
  15. Takai T (March 2012). "TSLP expression: cellular sources, triggers, and regulatory mechanisms". Allergol Int. 61 (1): 3–17. doi:10.2332/allergolint.11-RAI-0395. PMID 22270071.
  16. Liu YJ (February 2006). "Thymic stromal lymphopoietin: master switch for allergic inflammation". J. Exp. Med. 203 (2): 269–73. doi:10.1084/jem.20051745. PMC 2118215. PMID 16432252.
  17. Boguniewicz M, Leung DY (July 2011). "Atopic dermatitis: a disease of altered skin barrier and immune dysregulation". Immunol. Rev. 242 (1): 233–46. doi:10.1111/j.1600-065X.2011.01027.x. PMC 3122139. PMID 21682749.
  18. Elias PM, Hatano Y, Williams ML (June 2008). "Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms". J. Allergy Clin. Immunol. 121 (6): 1337–43. doi:10.1016/j.jaci.2008.01.022. PMC 2706021. PMID 18329087.
  19. Morizane S, Yamasaki K, Kajita A, Ikeda K, Zhan M, Aoyama Y, Gallo RL, Iwatsuki K (July 2012). "TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis". J. Allergy Clin. Immunol. 130 (1): 259–61.e1. doi:10.1016/j.jaci.2012.03.006. PMC 3387356. PMID 22521249.
  20. Margolis DJ, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Campbell LE, Sandilands A, McLean WH, Rebbeck TR, Mitra N (October 2012). "The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort". J. Allergy Clin. Immunol. 130 (4): 912–7. doi:10.1016/j.jaci.2012.07.008. PMC 3462287. PMID 22951058.
  21. McAleer MA, Irvine AD (February 2013). "The multifunctional role of filaggrin in allergic skin disease". J. Allergy Clin. Immunol. 131 (2): 280–91. doi:10.1016/j.jaci.2012.12.668. PMID 23374260.
  22. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY (September 2009). "Cytokine modulation of atopic dermatitis filaggrin skin expression". J. Allergy Clin. Immunol. 124 (3 Suppl 2): R7–R12. doi:10.1016/j.jaci.2009.07.012. PMID 19720210.
  23. 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 (March 2011). "Tight junction defects in patients with atopic dermatitis". J. Allergy Clin. Immunol. 127 (3): 773–86.e1–7. doi:10.1016/j.jaci.2010.10.018. PMC 3049863. PMID 21163515.
  24. Elias PM, Hatano Y, Williams ML (June 2008). "Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms". J. Allergy Clin. Immunol. 121 (6): 1337–43. doi:10.1016/j.jaci.2008.01.022. PMC 2706021. PMID 18329087.
  25. Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R (July 2006). "New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions". J. Allergy Clin. Immunol. 118 (1): 3–21, quiz 22–3. doi:10.1016/j.jaci.2006.04.042. PMID 16815133.
  26. Leung DY (June 2013). "New insights into atopic dermatitis: role of skin barrier and immune dysregulation". Allergol Int. 62 (2): 151–61. doi:10.2332/allergolint.13-RAI-0564. PMID 23712284.
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  28. Flohr C, England K, Radulovic S, McLean WH, Campbel LE, Barker J, Perkin M, Lack G (December 2010). "Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age". Br. J. Dermatol. 163 (6): 1333–6. PMID 21137118.
  29. Elias PM, Hatano Y, Williams ML (June 2008). "Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms". J. Allergy Clin. Immunol. 121 (6): 1337–43. doi:10.1016/j.jaci.2008.01.022. PMC 2706021. PMID 18329087.
  30. 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 (April 2013). "Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair". J. Invest. Dermatol. 133 (4): 988–98. doi:10.1038/jid.2012.437. PMC 3600383. PMID 23223142.
  31. Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD, Murray PR, Turner ML, Segre JA (May 2012). "Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis". Genome Res. 22 (5): 850–9. doi:10.1101/gr.131029.111. PMC 3337431. PMID 22310478.
  32. Macias ES, Pereira FA, Rietkerk W, Safai B (March 2011). "Superantigens in dermatology". J. Am. Acad. Dermatol. 64 (3): 455–72, quiz 473–4. doi:10.1016/j.jaad.2010.03.044. PMID 21315950.
  33. Boguniewicz M, Leung DY (July 2011). "Atopic dermatitis: a disease of altered skin barrier and immune dysregulation". Immunol. Rev. 242 (1): 233–46. doi:10.1111/j.1600-065X.2011.01027.x. PMC 3122139. PMID 21682749.
  34. Leung DY, Guttman-Yassky E (October 2014). "Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches". J. Allergy Clin. Immunol. 134 (4): 769–79. doi:10.1016/j.jaci.2014.08.008. PMC 4186710. PMID 25282559.
  35. Leung DY, Guttman-Yassky E (October 2014). "Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches". J. Allergy Clin. Immunol. 134 (4): 769–79. doi:10.1016/j.jaci.2014.08.008. PMC 4186710. PMID 25282559.
  36. Takai T (March 2012). "TSLP expression: cellular sources, triggers, and regulatory mechanisms". Allergol Int. 61 (1): 3–17. doi:10.2332/allergolint.11-RAI-0395. PMID 22270071.
  37. 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 (June 2010). "Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum". J. Allergy Clin. Immunol. 125 (6): 1403–1407.e4. doi:10.1016/j.jaci.2010.03.016. PMC 2925504. PMID 20466416.
  38. Margolis DJ, Kim B, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Mitra N (March 2014). "Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis". JAMA Dermatol. 150 (3): 254–9. doi:10.1001/jamadermatol.2013.7954. PMC 4414492. PMID 24401911.
  39. Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z (January 2016). "Molecular Genetic of Atopic dermatitis: An Update". Int J Health Sci (Qassim). 10 (1): 96–120. PMC 4791162. PMID 27004062.
  40. Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z (January 2016). "Molecular Genetic of Atopic dermatitis: An Update". Int J Health Sci (Qassim). 10 (1): 96–120. PMC 4791162. PMID 27004062.
  41. Irvine AD, McLean WH, Leung DY (October 2011). "Filaggrin mutations associated with skin and allergic diseases". N. Engl. J. Med. 365 (14): 1315–27. doi:10.1056/NEJMra1011040. PMID 21991953.
  42. Liao H, Waters AJ, Goudie DR, Aitken DA, Graham G, Smith FJ, Lewis-Jones S, McLean WH (December 2007). "Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis". J. Invest. Dermatol. 127 (12): 2795–8. doi:10.1038/sj.jid.5700971. PMID 17657246.
  43. 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 (April 2006). "Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis". Nat. Genet. 38 (4): 441–6. doi:10.1038/ng1767. PMID 16550169.
  44. Rupnik H, Rijavec M, Korošec P (February 2015). "Filaggrin loss-of-function mutations are not associated with atopic dermatitis that develops in late childhood or adulthood". Br. J. Dermatol. 172 (2): 455–61. doi:10.1111/bjd.13477. PMID 25314673.
  45. Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z (January 2016). "Molecular Genetic of Atopic dermatitis: An Update". Int J Health Sci (Qassim). 10 (1): 96–120. PMC 4791162. PMID 27004062.
  46. Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R (July 2006). "New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions". J. Allergy Clin. Immunol. 118 (1): 3–21, quiz 22–3. doi:10.1016/j.jaci.2006.04.042. PMID 16815133.
  47. Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z (January 2016). "Molecular Genetic of Atopic dermatitis: An Update". Int J Health Sci (Qassim). 10 (1): 96–120. PMC 4791162. PMID 27004062.
  48. Mihm, Martin C; Soter, Nicholas A; Dvorak, Harold F; Austen, K Frank (1976). "The Structure Of Normal Skin And The Morphology Of Atopic Eczema". Journal of Investigative Dermatology. 67 (3): 305–312. doi:10.1111/1523-1747.ep12514346. ISSN 0022-202X.
  49. Mihm, Martin C; Soter, Nicholas A; Dvorak, Harold F; Austen, K Frank (1976). "The Structure Of Normal Skin And The Morphology Of Atopic Eczema". Journal of Investigative Dermatology. 67 (3): 305–312. doi:10.1111/1523-1747.ep12514346. ISSN 0022-202X.