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==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 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>
# '''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 corenocytes layers in the stratum corneum.   
#* Tightly packed corneocytes layers in the stratum corneum.   
#* Intercellular lipid bilayers.  
#* Intercellular lipid bilayers.  
#* Corneocytes layers embedded in the extracellular matrix  derived from lipid lamellae.  
#* Corneocytes layers embedded in the extracellular matrix  derived from lipid lamellae.  
#* Natural Moisturising Factors, maintains the water retention in the stratum corneum  
#* Natural Moisturising Factors, maintains the water retention in the stratum corneum  
#* Antimicrobial peptides production
#* Antimicrobial peptides production
# '''Filaggrin protien:''' Encoded by FLG gene 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>
# '''Filaggrin proteins:''' Encoded by FLG gene 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>
#* Pro-filaggrin is required for the formation of dense cytoplasmic granules, which along with other proteins forms the corneocytes, that acts as primary unit for barrier function of the skin.
#* 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.
#* 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 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>  
#* 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 Moisturising Factors(NMF), which prevents excess water loss from the stratum corneum
#* The degraded products of Filaggrin protein also maintain the acidic pH of the SC, required to regulate the activity of enzymes in stratum corneum.
#* The degraded products of Filaggrin protein also maintain the acidic pH of the SC, required to regulate the activity of enzymes in 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. e.g. claudin-1, occludin, junctional adhesion molecule, etc.<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 compose together to form tight junctions. e.g. claudin-1, occludin, junctional adhesion molecule, etc.<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 protiens''': filaggrin-2, corneodesmosin, desmoglein-1, desmocollin-1, 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-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 first line barrier and constitutes the rapid response mechanism to the invading allergen or pathogen. It recognizes the microbes through receptors known as pattern recognition receptors (PRRs). Cutaneous immune response includes 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''': It acts as the first-line barrier and constitutes the rapid response mechanism to the invading allergen or pathogen. 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 . The maintenance and repair of epithelial barriers, is mediated through the activation of PRRs 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. The maintenance and repair of epithelial barriers are mediated through the activation of PRRs 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: antimicrobial proteins including  antimicrobial peptides (AMPs), S100 protiens, 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: 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: 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>
#* 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>
#* Immunological: Immune response includes both non specific and immediate response (innate immunity) and highly specific and late response (adaptive immunity).  
#* Immunological: Immune response includes both non-specific and immediate response (innate immunity) and highly specific and late response (adaptive immunity).  
# '''Adaptive Immune response''':The character and magnitude of adaptive immune system is determined by 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''': The character and magnitude of the 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>
# '''Thymic stromal lymphopoietin:''' Thymic stromal lymphopoietin (TSLP) is considered as a master switch for allergic inflammation<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>, and is highly expressed by epithelial cells and epidermal keratinocytes<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 IL-7-like cytokine, which stimulates the differentiation of naïve T helper cells into 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:''' Thymic stromal lymphopoietin (TSLP) is considered as a master switch for allergic inflammation<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>, and is highly expressed by epithelial cells and epidermal keratinocytes<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 IL-7-like cytokine, which stimulates the differentiation of naïve T helper cells into 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==
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* '''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>
*# 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 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 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>
*# 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 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 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 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>
*# 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 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>
*# It leads to increased 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>
*# It leads to increased 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>
*# Severe atopic dermatitis have been associated with higher levels of 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 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>
* '''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>:
* '''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>:
*# '''Innate immune response:'''
*# '''Innate immune response:'''
*#*Pathogens or tissue damage activate pattern recognition receptors including toll-like receptors (TLRs), induce a release of inflammatory mediators, including AMPs, 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>  
*#*Pathogens or tissue damage activate pattern recognition receptors including Toll-like receptors (TLRs), induce a release of inflammatory mediators, including AMPs, 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>  
*#*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>  
*#*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>  
*#*In intact skin barrier, antimicrobial peptides(AMPs) are regulated by cytokines, IL-17 and IL- 22, which are secreted by Th17 T and 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>  
*#*In intact skin barrier, antimicrobial peptides(AMPs) are regulated by cytokines, IL-17, and IL- 22, which are secreted by Th17 T and 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>  
*# '''Adaptive 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 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>.  
*#*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<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>.  
*#*Enhanced expression of 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>.  
*#*Enhanced expression of 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>.  
*#*Epidermal barrier function is regulated through Th2 and Th22 cytokines (IL-4, IL-13, IL-31, and 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>
*#*Epidermal barrier function is regulated through Th2 and Th22 cytokines (IL-4, IL-13, IL-31, and 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>
*#**stimulating epidermal hyperplasia  
*#**stimulating epidermal hyperplasia  
Line 59: Line 59:


== Genetics ==
== Genetics ==
Recent studies has established strong strong genetic association with 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 % percent 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 with 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 % percent 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''':  
# '''Filaggrin Gene mutation''':  
#* Located on chromosome 1q21 (epidermal differentiation complex) loss-of-function mutations in the filaggrin gene FLG, is strongly associated with 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> 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>
#* Located on chromosome 1q21 (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> 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 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>
# '''SPINK5 and LEKTI gene''':  
# '''SPINK5 and LEKTI gene''':  
#* Located on chromosome 5q32, 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 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 5q32, 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>
#* 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>
#* 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>
# '''MHC (or HLA) genes'''
# '''MHC (or HLA) genes'''
# '''Innate Immune system genes''':
# '''Innate Immune system genes''':
#* CARD4 (or NOD1) gene: Caspase recruitment domain – containing protein (CARD) 4
#* CARD4 (or NOD1) gene: Caspase recruitment domain–containing protein (CARD) 4
#* CARD15 (or NOD2) gene
#* CARD15 (or NOD2) gene
#* Monocyte differentiation antigen (or CD14) gene
#* Monocyte differentiation antigen (or CD14) gene
Line 139: Line 139:
**High serum IgE
**High serum IgE
**Recurrent cold abscesses
**Recurrent cold abscesses
* '''Anaemia'''<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'''<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>
* '''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''':<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>
** 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<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>
Line 148: Line 148:


==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, 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>   


==Microscopic Pathology==
==Microscopic Pathology==
On microscopic histopathological analysis, characteristic findings of atopic dermatitis includes:<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''':  
* '''Acute vesicular lesions''':  
** Epidermal psoriasiform hyperplasia
** Epidermal psoriasiform hyperplasia

Revision as of 21:50, 1 October 2018


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: 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).[1] 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[2].

Pathophysiology

Physiology

The normal physiology of Atopic Dermatitis can be understood as follows:

  • Epidermal barrier function:
  1. 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.[3]
    • Tightly packed corneocytes layers in the stratum corneum.
    • Intercellular lipid bilayers.
    • Corneocytes layers embedded in the extracellular matrix derived from lipid lamellae.
    • Natural Moisturising Factors, maintains the water retention in the stratum corneum
    • Antimicrobial peptides production
  2. Filaggrin proteins: Encoded by FLG gene 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.[4]
    • 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.
    • 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.[5]
    • 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 also maintain the acidic pH of the SC, required to regulate the activity of enzymes in stratum corneum.
  3. Proteins related to tight junctions: These transmembrane proteins are present in the stratum granulosum of the epidermis and compose together to form tight junctions. e.g. claudin-1, occludin, junctional adhesion molecule, etc.[6]
  4. Other proteins: filaggrin-2, corneodesmosin, desmoglein-1, desmocollin-1, transglutaminase-3 are also part of skin barrier related proteins.[7]
  • Immune response:
  1. Cutaneous immune response: It acts as the first-line barrier and constitutes the rapid response mechanism to the invading allergen or pathogen. It recognizes the microbes through receptors known as pattern recognition receptors (PRRs). The cutaneous immune response includes the following 4 elements:[8]
    • Physical: stratum corneum and the tight junctions in stratum granulosum. The maintenance and repair of epithelial barriers are mediated through the activation of PRRs by the innate immune system.[9]
    • 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.[10],[11]
    • 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.[12]
    • Immunological: Immune response includes both non-specific and immediate response (innate immunity) and highly specific and late response (adaptive immunity).
  2. Adaptive Immune response: The character and magnitude of the adaptive immune system is determined by the innate immune response by interactions with the epidermal elements and activation of TLRs[13]
  3. Thymic stromal lymphopoietin: Thymic stromal lymphopoietin (TSLP) is considered as a master switch for allergic inflammation[14], and is highly expressed by epithelial cells and epidermal keratinocytes[15]. It is an IL-7-like cytokine, which stimulates the differentiation of naïve T helper cells into inflammatory Th2 cells[16].

Pathogenesis

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

  • Epidermal barrier dysfunction(outside-in hypothesis):[18]
    1. The major factors to abnormal skin barrier include loss-of-function mutations in the filaggrin gene (FLG) causing Filaggrin deficiency[19], tight junction abnormalities[20], more alkaline surface pH,[21] microbial colonization, altered protease activity in the stratum corneum.[22][23][24][25]
    2. 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 virus (HSV); leading to the production of inflammatory cytokines and Impaired production of antimicrobial peptides.[26]
    3. It leads to increased trans-epidermal water loss, and decreased levels of ceramides and water binding.[27]
    4. Severe atopic dermatitis has been associated with higher levels of trans-epidermal water loss.[28]
  • Immune dysregulation (inside-out’ hypothesis):[29]:
    1. Innate immune response:
      • Pathogens or tissue damage activate pattern recognition receptors including Toll-like receptors (TLRs), induce a release of inflammatory mediators, including AMPs, cytokines, and chemokines[30]
      • 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[31]
      • In intact skin barrier, antimicrobial peptides(AMPs) are regulated by cytokines, IL-17, and IL- 22, which are secreted by Th17 T and Th22 cells. This effect is suppressed in patients with atopic dermatitis.[32]
    2. 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].
      • Epidermal barrier function is regulated through Th2 and Th22 cytokines (IL-4, IL-13, IL-31, and IL-22) by:[35]
        • stimulating epidermal hyperplasia
        • inhibiting the expression of terminal keratinocyte differentiation genes (eg, FLG, loricrin, involucrin)
        • suppressing the production of AMPs
    3. 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 with 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 % percent for dizygotic twins.[39]

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

  1. Filaggrin Gene mutation:
    • Located on chromosome 1q21 (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[41]. Mutation in this gene is also responsible for ichthyosis vulgaris and pachyonychia congenita.[42] The common genetic variant R510X and 2282del4 are very strongly associated with atopic dermatitis.[43]
    • 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.[44]
  2. SPINK5 and LEKTI gene:
    • Located on chromosome 5q32, 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.[45]
    • LEKTI deficiency leads to enhanced cleavage of intercellular attachments, decreased corneocyte cohesion and impaired skin barrier function.[46]
  3. MHC (or HLA) genes
  4. Innate Immune system genes:
    • CARD4 (or NOD1) gene: Caspase recruitment domain–containing protein (CARD) 4
    • CARD15 (or NOD2) gene
    • Monocyte differentiation antigen (or CD14) gene
    • MBL2 gene: mannose-binding lectin (MBL2) gene
    • Toll-like receptor( TLR2, TLR4, TLR6 and TLR 9) genes
    • DEFB1 gene: human β-defensin 1
  5. Adaptive immune system genes
    • Cytokines and related genes:
      • IL-4 gene
      • IL-4Rα gene
      • STAT6 gene (Signal transducer and activator of transcription )
      • IL-10 gene
      • IL-6 gene
      • TNF-α gene
      • TNF-β gene
      • IL-1α gene
      • IL-β gene
      • IFNγ gene
      • IL1RL1
      • IL-5 gene
      • IL-12 β gene
      • IL-12R β
      • IL-13 gene
      • IL-18 gene
      • TGF-β1 gene
      • GM-CSF gene
      • IL-9 gene
      • IL-9R gene
    • Chemokines and related genes:
      • CCL5 gene: Chemokine (C-Cmotif) ligand 5
      • CCL11 gene
      • CCL17 gene
      • CCR3 gene
      • CCR4 gene
      • CMA1 gene: Mast cell chymase 1
    • Drug-metabolizing genes
      • GST genes: glutathione S-transferase
      • NAT-2 gene: N-acetyl transferase
    • Other genes
      • CTLA-4
      • KLK
      • RUNX1 gene
      • IRF2 gene
      • FCER1B gene
      • PHF11 gene

Associated Conditions

Conditions associated with atopic dermatitis include:

  • Atopic triad[47]
    • Atopic dermatitis
    • Allergic rhinitis
    • Asthma
  • Food-induced urticaria/anaphylaxis [48]
  • Ichthyosis vulgaris[49]
  • Ocular comorbidities:
    • Atopic keratoconjunctivitis[50]
    • Vernal keratoconjunctivitis[51]
  • Wiskott-Aldrich syndrome:[52]
    • Thrombocytopenia
    • Eczema (atopic dermatitis)
    • Recurrent infections
  • Hyper-IgE syndrome:[53]
    • Eczema (atopic dermatitis)
    • High serum IgE
    • Recurrent cold abscesses
  • Anemia[54]
  • Psychiatric disorders:[55]
    • Depression[56]
    • Anxiety[57]
    • Suicidal ideations
    • Attention deficit hyperactivity disorder[58]
  • Angina pectoris[59]

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.[60]

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of atopic dermatitis include:[61]

  • Acute vesicular lesions:
    • Epidermal psoriasiform hyperplasia
    • Marked intercellular edema with spongiotic vesiculation
    • Marked perivenular infiltrate
    • Epidermal infiltrate, consisting predominately of a lymphohistiocytic infiltrate in the dermis
  • Chronic lichenified plaque:
    • Hyperkeratosis
    • psoriasiform hyperplasia
    • dyskeratosis
    • Marked thickening of the papillary dermis
    • Minimal intercellular edema

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  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. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Cario E, Gerken G, Podolsky DK (July 2004). "Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C". Gastroenterology. 127 (1): 224–38. PMID 15236188.
  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.
  12. ↑ Lynch SV, Pedersen O (December 2016). "The Human Intestinal Microbiome in Health and Disease". N. Engl. J. Med. 375 (24): 2369–2379. doi:10.1056/NEJMra1600266. PMID 27974040.
  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. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  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.
  27. ↑ Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M; et al. (2009). "Epidermal barrier dysfunction in atopic dermatitis". J Invest Dermatol. 129 (8): 1892–908. doi:10.1038/jid.2009.133. PMID 19494826.
  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. ↑ Kapoor R, Menon C, Hoffstad O, Bilker W, Leclerc P, Margolis DJ (January 2008). "The prevalence of atopic triad in children with physician-confirmed atopic dermatitis". J. Am. Acad. Dermatol. 58 (1): 68–73. doi:10.1016/j.jaad.2007.06.041. PMID 17692428.
  48. ↑ Eigenmann PA, Calza AM (May 2000). "Diagnosis of IgE-mediated food allergy among Swiss children with atopic dermatitis". Pediatr Allergy Immunol. 11 (2): 95–100. PMID 10893011.
  49. ↑ Bremmer SF, Hanifin JM, Simpson EL (July 2008). "Clinical detection of ichthyosis vulgaris in an atopic dermatitis clinic: implications for allergic respiratory disease and prognosis". J. Am. Acad. Dermatol. 59 (1): 72–8. doi:10.1016/j.jaad.2008.03.029. PMID 18455261.
  50. ↑ Chen JJ, Applebaum DS, Sun GS, Pflugfelder SC (March 2014). "Atopic keratoconjunctivitis: A review". J. Am. Acad. Dermatol. 70 (3): 569–75. doi:10.1016/j.jaad.2013.10.036. PMID 24342754.
  51. ↑ Pattnaik L, Acharya L (May 2015). "A comprehensive review on vernal keratoconjunctivitis with emphasis on proteomics". Life Sci. 128: 47–54. doi:10.1016/j.lfs.2015.01.040. PMID 25744396.
  52. ↑ Bradley M, Söderhäll C, Wahlgren CF, Luthman H, Nordenskjöld M, Kockum I (2001). "The Wiskott-Aldrich syndrome gene as a candidate gene for atopic dermatitis". Acta Derm. Venereol. 81 (5): 340–2. PMID 11800140.
  53. ↑ Ohameje NU, Loveless JW, Saini SS (2006). "Atopic dermatitis or hyper-IgE syndrome?". Allergy Asthma Proc. 27 (3): 289–91. PMID 16913276.
  54. ↑ Drury KE, Schaeffer M, Silverberg JI (January 2016). "Association Between Atopic Disease and Anemia in US Children". JAMA Pediatr. 170 (1): 29–34. doi:10.1001/jamapediatrics.2015.3065. PMID 26619045.
  55. ↑ Rønnstad A, Halling-Overgaard AS, Hamann CR, Skov L, Egeberg A, Thyssen JP (September 2018). "Association of atopic dermatitis with depression, anxiety, and suicidal ideation in children and adults: A systematic review and meta-analysis". J. Am. Acad. Dermatol. 79 (3): 448–456.e30. doi:10.1016/j.jaad.2018.03.017. PMID 30119868. Vancouver style error: initials (help)
  56. ↑ Bao Q, Chen L, Lu Z, Ma Y, Guo L, Zhang S, Huang X, Xu S, Ruan L (October 2018). "Association between eczema and risk of depression: A systematic review and meta-analysis of 188,495 participants". J Affect Disord. 238: 458–464. doi:10.1016/j.jad.2018.05.007. PMID 29929155.
  57. ↑ Cheng CM, Hsu JW, Huang KL, Bai YM, Su TP, Li CT, Yang AC, Chang WH, Chen TJ, Tsai SJ, Chen MH (June 2015). "Risk of developing major depressive disorder and anxiety disorders among adolescents and adults with atopic dermatitis: a nationwide longitudinal study". J Affect Disord. 178: 60–5. doi:10.1016/j.jad.2015.02.025. PMID 25795537.
  58. ↑ Strom MA, Fishbein AB, Paller AS, Silverberg JI (November 2016). "Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults". Br. J. Dermatol. 175 (5): 920–929. doi:10.1111/bjd.14697. PMC 5216180. PMID 27105659.
  59. ↑ Thyssen JP, Halling-Overgaard AS, Andersen Y, Gislason G, Skov L, Egeberg A (June 2018). "The association with cardiovascular disease and type 2 diabetes in adults with atopic dermatitis: a systematic review and meta-analysis". Br. J. Dermatol. 178 (6): 1272–1279. doi:10.1111/bjd.16215. PMID 29210061. Vancouver style error: initials (help)
  60. ↑ 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.
  61. ↑ 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.

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