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| ==Overview== | | ==Overview== |
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| 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]].
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| ==Pathophysiology== | | ==Pathophysiology== |
| ===Physiology=== | | ===Physiology=== |
| The normal physiology of atopic dermatitis can be understood as follows:
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| '''Epidermal barrier function:'''
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| * '''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.<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 consists of:
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| ** Tightly packed corneocytes layers in the [[stratum corneum]]
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| ** Intercellular lipid bilayers
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| ** Corneocytes layers embedded in the [[extracellular matrix]] derived from lipid lamellae
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| ** Natural moisturising factors (NMF), maintaining the water retention in the [[stratum corneum]]
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| ** [[Antimicrobial peptides]]
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| * '''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>
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| ** 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]].
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| ** 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>
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| ** 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]].
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| ** The degraded products of [[filaggrin]] protein also maintain the acidic pH of the [[stratum corneum]], required to regulate the activity of [[enzymes]].
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| * '''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>
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| * '''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>
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| '''Immune response:'''
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| * '''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>
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| ** ''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>
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| ** ''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>
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| ** [[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>
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| ** ''Immunological'': Immune response includes both [[Innate immune response|non-specific]] and immediate response ([[innate immunity]]) and highly specific and late response ([[adaptive immunity]]).
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| * '''Adaptive Immune response''':<ref name="pmid20109730" />
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| ** The character and magnitude of the [[Adaptive immune response|adaptive immune]] system is determined by the innate immune response by interactions with the epidermal elements and activation of TLRs.<ref name="pmid19078985">{{cite journal |vauthors=De Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA |title=Atopic dermatitis: a disease caused by innate immune defects? |journal=J. Invest. Dermatol. |volume=129 |issue=1 |pages=14–30 |date=January 2009 |pmid=19078985 |doi=10.1038/jid.2008.259 |url=}}</ref>
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| * '''Thymic stromal lymphopoietin:'''
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| **<nowiki/> [[Thymic stromal lymphopoietin]] ([[TSLP]]) is considered as a master switch for [[allergic inflammation]], and is highly expressed by [[epithelial cells]] and epidermal [[keratinocytes]].<ref name="pmid16432252">{{cite journal |vauthors=Liu YJ |title=Thymic stromal lymphopoietin: master switch for allergic inflammation |journal=J. Exp. Med. |volume=203 |issue=2 |pages=269–73 |date=February 2006 |pmid=16432252 |pmc=2118215 |doi=10.1084/jem.20051745 |url=}}</ref><ref name="pmid22270071">{{cite journal |vauthors=Takai T |title=TSLP expression: cellular sources, triggers, and regulatory mechanisms |journal=Allergol Int |volume=61 |issue=1 |pages=3–17 |date=March 2012 |pmid=22270071 |doi=10.2332/allergolint.11-RAI-0395 |url=}}</ref>
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| **<nowiki/>It is an [[Interleukin 7|IL-7]]-like [[cytokine]], which stimulates the differentiation of naïve [[T helper cells]] into [[Th2 response|inflammatory Th2 cells]].<ref name="pmid164322522">{{cite journal |vauthors=Liu YJ |title=Thymic stromal lymphopoietin: master switch for allergic inflammation |journal=J. Exp. Med. |volume=203 |issue=2 |pages=269–73 |date=February 2006 |pmid=16432252 |pmc=2118215 |doi=10.1084/jem.20051745 |url=}}</ref>
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| | '''AAA:''' |
| | * '''AAAA''': |
| | *<nowiki/><nowiki/><nowiki/><nowiki/>'''AAA:''' |
| ===Pathogenesis=== | | ===Pathogenesis=== |
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| * Common cause of ITP is [[autoimmune]] .<ref>{{cite journal |author=Coopamah M, Garvey M, Freedman J, Semple J |title=Cellular immune mechanisms in autoimmune thrombocytopenic purpura: An update |journal=Transfus Med Rev |volume=17 |issue=1 |pages=69–80 |year=2003 |pmid=12522773}}</ref> | | * AA |
| * Auto [[antibodies]] against platelets is detected in approximately 60% of cases.
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| * These antibodies are against platelet membrane [[glycoprotein]]s IIb-IIIa or Ib-IX, and [[IgG]] type.<ref name="pmid18046034">{{cite journal |author=Schwartz RS |title=Immune thrombocytopenic purpura--from agony to agonist |journal=N. Engl. J. Med. |volume=357 |issue=22 |pages=2299–301 |year=2007 |pmid=18046034 |doi=10.1056/NEJMe0707126}}</ref>
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| * Other cause of ITP is due to chronic infections such as HIV, hepatitis C and H. Pylori. It,s due to molecular mimicry, antibody is formed against the infection and this cross-reacts with platelets. Autoantibodies in ITP react with platelet IIb/IIIa glycoprotein, less commonly with GPIb/IX. Lymphocytes in the spleen make the antiplatelet antibody; that,s why splenectomy works so well. There is a correlation between a platelet's short survival and high turnover rate and the subsequent excellent response to [[splenectomy]].
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| * Platelet kinetic studies show that platelet production is normal or reduced rather than increased in about two thirds of ITP patients.
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| * [[autoantibodies]] from patients with ITP inhibit megakaryocyte growth in vitro.
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| * [[IgG]] from ITP-plasma inhibits megakaryocyte production.
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| * Ultrastructural studies of the bone marrow in ITP show increased signs of megakaryocyte [[apoptosis]] and reduced platelet shedding.
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| * Recent studies suggests that the stimulus for autoantibody production in ITP is due to abnormal [[T helper cell]]s reacting with platelet antigens on the surface of antigen presenting cells.<ref>{{cite journal |author=Semple JW, Freedman J |title=Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia |journal=Blood |volume=78 |issue=10 |pages=2619-25 |year=1991 |pmid=1840468 |doi=}}</ref> This important finding suggests that therapies directed towards T cells may be effective in treating ITP.<ref name="pmid28208757">{{cite journal |vauthors=Zufferey A, Kapur R, Semple JW |title=Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP) |journal=J Clin Med |volume=6 |issue=2 |pages= |date=February 2017 |pmid=28208757 |pmc=5332920 |doi=10.3390/jcm6020016 |url=}}</ref>
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| 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>
| | '''AA:'''<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> |
| | | * AA |
| '''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> | | **<nowiki/><nowiki/>jo |
| * The major factors causing abnormal skin barrier include loss-of-function mutations in the [[filaggrin]] gene (FLG) resulting in:<ref name="pmid22521249">{{cite journal |vauthors=Morizane S, Yamasaki K, Kajita A, Ikeda K, Zhan M, Aoyama Y, Gallo RL, Iwatsuki K |title=TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=130 |issue=1 |pages=259–61.e1 |date=July 2012 |pmid=22521249 |pmc=3387356 |doi=10.1016/j.jaci.2012.03.006 |url=}}</ref><ref name="pmid22951058">{{cite journal |vauthors=Margolis DJ, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Campbell LE, Sandilands A, McLean WH, Rebbeck TR, Mitra N |title=The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort |journal=J. Allergy Clin. Immunol. |volume=130 |issue=4 |pages=912–7 |date=October 2012 |pmid=22951058 |pmc=3462287 |doi=10.1016/j.jaci.2012.07.008 |url=}}</ref><ref name="pmid23374260">{{cite journal |vauthors=McAleer MA, Irvine AD |title=The multifunctional role of filaggrin in allergic skin disease |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=280–91 |date=February 2013 |pmid=23374260 |doi=10.1016/j.jaci.2012.12.668 |url=}}</ref> | |
| ** Filaggrin protein deficiency<ref name="pmid19720210">{{cite journal |vauthors=Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY |title=Cytokine modulation of atopic dermatitis filaggrin skin expression |journal=J. Allergy Clin. Immunol. |volume=124 |issue=3 Suppl 2 |pages=R7–R12 |date=September 2009 |pmid=19720210 |doi=10.1016/j.jaci.2009.07.012 |url=}}</ref>
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| ** [[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>
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| ** 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>
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| ** [[Microbial]] colonization
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| ** Altered [[Proteases|protease]] activity in the [[stratum corneum]]<ref name="pmid16815133">{{cite journal |vauthors=Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R |title=New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions |journal=J. Allergy Clin. Immunol. |volume=118 |issue=1 |pages=3–21; quiz 22–3 |date=July 2006 |pmid=16815133 |doi=10.1016/j.jaci.2006.04.042 |url=}}</ref>
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| * Skin barrier abnormalities lead to the increased permeability of the [[epidermis]].
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| ** This leads to entry of [[antigens]] or [[pathogens]] resulting in [[microbial]] colonization, most notably by ''[[staphylococcus aureus]]'' and [[herpes simplex virus (HSV)]].
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| ** 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>
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| * 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>
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| * 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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| '''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>
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| * '''Innate immune response:'''
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| **Pathogens or tissue damage activate pattern recognition receptors including [[toll-like receptors]] (TLRs), which further induces a release of inflammatory mediators<nowiki/>, including [[Antimicrobial peptides|AMP]]<nowiki/>s, [[cytokines]], and [[chemokines]].<ref name="pmid23223142">{{cite journal |vauthors=Kuo IH, Carpenter-Mendini A, Yoshida T, McGirt LY, Ivanov AI, Barnes KC, Gallo RL, Borkowski AW, Yamasaki K, Leung DY, Georas SN, De Benedetto A, Beck LA |title=Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair |journal=J. Invest. Dermatol. |volume=133 |issue=4 |pages=988–98 |date=April 2013 |pmid=23223142 |pmc=3600383 |doi=10.1038/jid.2012.437 |url=}}</ref> | |
| **Defective cutaneous [[Innate immune system|innate immune]]-mediated epidermal barrier repair and maintenance may alter skin-resident normal microbial flora and lead to severe [[inflammation]] as demonstrated with atopic dermatitis patients colonized with [[Staphylococcus aureus|s''taphylococcus aureus'']]''.''<ref name="pmid22310478">{{cite journal |vauthors=Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD, Murray PR, Turner ML, Segre JA |title=Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis |journal=Genome Res. |volume=22 |issue=5 |pages=850–9 |date=May 2012 |pmid=22310478 |pmc=3337431 |doi=10.1101/gr.131029.111 |url=}}</ref>
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| **In intact skin barrier, [[Antimicrobial peptides|antimicrobial peptides (AMPs)]] are regulated by [[cytokines]], [[Interleukin 17|IL-17]], and [[Interleukin 22|IL- 22]], which are secreted by [[T helper 17 cell|Th17]] and [[T helper cell|Th22]] cells. This effect is suppressed in patients with atopic dermatitis.<ref name="pmid21315950">{{cite journal |vauthors=Macias ES, Pereira FA, Rietkerk W, Safai B |title=Superantigens in dermatology |journal=J. Am. Acad. Dermatol. |volume=64 |issue=3 |pages=455–72; quiz 473–4 |date=March 2011 |pmid=21315950 |doi=10.1016/j.jaad.2010.03.044 |url=}}</ref>
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| * '''Adaptive immune response:'''
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| **Increased [[allergen]] penetration through the damaged [[epidermis]] leading to a [[Th2 response|Th2]]-type milieu is thought to explain the critical link between the barrier defect of atopic dermatitis patients with FLG mutations and Th2 polarization.<ref name="pmid216827492">{{cite journal |vauthors=Boguniewicz M, Leung DY |title=Atopic dermatitis: a disease of altered skin barrier and immune dysregulation |journal=Immunol. Rev. |volume=242 |issue=1 |pages=233–46 |date=July 2011 |pmid=21682749 |pmc=3122139 |doi=10.1111/j.1600-065X.2011.01027.x |url=}}</ref>
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| **Enhanced expression of [[Th2 response|Th2]], [[Th17]], and Th22 cytokines, characterize the [[acute]] initiation of atopic dermatitis lesions.<ref name="pmid25282559">{{cite journal |vauthors=Leung DY, Guttman-Yassky E |title=Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=769–79 |date=October 2014 |pmid=25282559 |pmc=4186710 |doi=10.1016/j.jaci.2014.08.008 |url=}}</ref>
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| **Epidermal barrier function is regulated through [[Th2]] and Th22 cytokines ([[Interleukin 4|IL-4]], [[Interleukin 13|IL-13,]] [[Interleukin 31|IL-31]], and [[Interleukin 22|IL-22]]) by:<ref name="pmid252825593">{{cite journal |vauthors=Leung DY, Guttman-Yassky E |title=Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=769–79 |date=October 2014 |pmid=25282559 |pmc=4186710 |doi=10.1016/j.jaci.2014.08.008 |url=}}</ref>
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| ***Stimulating epidermal [[hyperplasia]]
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| ***Inhibiting the expression of terminal keratinocyte differentiation genes (eg, ''FLG'', [[loricrin]], [[involucrin]])
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| ***Suppressing the production of [[Antimicrobial peptides|AMPs]]
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| * '''Thymic stromal lymphopoietin:'''
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| **Defective skin barrier and enhanced [[epidermal]] [[protease]] activity, which is reported in atopic dermatitis, promote [[TSLP]] production and [[Th2 response]], leading to atopic dermatitis-like [[inflammation]].<ref name="pmid222700712">{{cite journal |vauthors=Takai T |title=TSLP expression: cellular sources, triggers, and regulatory mechanisms |journal=Allergol Int |volume=61 |issue=1 |pages=3–17 |date=March 2012 |pmid=22270071 |doi=10.2332/allergolint.11-RAI-0395 |url=}}</ref>
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| **''[[TSLP]]'' polymorphisms have been linked to the severity of atopic dermatitis.
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| **[[TSLP]] genetic variants are associated with atopic dermatitis and [[eczema herpeticum]].<ref name="pmid20466416">{{cite journal |vauthors=Gao PS, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, Gao L, Beaty TH, Beck LA, Leung DY, Barnes KC |title=Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum |journal=J. Allergy Clin. Immunol. |volume=125 |issue=6 |pages=1403–1407.e4 |date=June 2010 |pmid=20466416 |pmc=2925504 |doi=10.1016/j.jaci.2010.03.016 |url=}}</ref>
| |
| **In patients with defective skin barrier due to [[Filaggrin|FLG]] mutations, [[TSLP]] genetic variants are associated with reduced [[probability]] of having persistent atopic dermatitis.<ref name="pmid24401911">{{cite journal |vauthors=Margolis DJ, Kim B, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Mitra N |title=Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis |journal=JAMA Dermatol |volume=150 |issue=3 |pages=254–9 |date=March 2014 |pmid=24401911 |pmc=4414492 |doi=10.1001/jamadermatol.2013.7954 |url=}}</ref>
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| == Genetics == | | == Genetics == |
| Recent studies have established a strong genetic association of atopic dermatitis. Twin studies have indicated high [[heritability]] of atopic dermatitis with a [[Concordance (genetics)|concordance]] rate of 72–86 % for [[monozygotic twins]] compared with 21–23 % for [[dizygotic twins]].<ref name="pmid27004062">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
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|
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| 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>
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| {| class="wikitable"
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| |+
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| ! colspan="3" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Genes involved in the pathogenesis of atopic dermatitis
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| |-
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| | colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Filaggrin Gene mutation'''
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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>
| |
| * 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>
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| * 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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| |-
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| | colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''SPINK5 and LEKTI gene'''
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| * Located on chromosome 5q32, [[SPINK5|Serine Protease Inhibitor Kazal-Type 5 (SPINK5]]) gene encodes a [[protease inhibitor]] lymphoepithelial Kazal-type-Related Inhibitor (LEKTI), which is involved in converting profilaggrin into filaggrin and is responsible for marinating the permeability of the normal skin.<ref name="pmid270040622">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
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| * [[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>
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| | colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''MHC (or HLA) genes'''
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| * Major histocompatibility complex or human leukocyte antigen
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| |-
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| | colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Innate Immune system genes''':
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| * CARD4 (or NOD1) gene: Caspase recruitment domain–containing protein (CARD) 4
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| * CARD15 (or NOD2) gene
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| * Monocyte differentiation antigen (or [[CD14|CD14)]] gene
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| * MBL2 gene: [[Mannose-binding lectin pathway|mannose-binding lectin]] '''('''MBL2) gene
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| * [[Toll-like receptors|Toll-like receptor]]( [[TLR2]], [[TLR4]], [[TLR6]] and [[TLR 9]]) genes
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| * DEFB1 gene: human β-defensin 1
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| |-
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| | rowspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Adaptive immune system genes'''
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| | style="background: #DCDCDC; text-align: center;" |'''Cytokines and related genes''':
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| * [[Interleukin 4|IL-4]] gene
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| * IL-4Rα gene
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| * [[STAT6]] gene (Signal transducer and activator of transcription )
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| * [[Interleukin 10|IL-10]] gene
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| * [[Interleukin 6|IL-6]] gene
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| * [[Tumor necrosis factor-alpha|TNF-α]] gene
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| * TNF-β gene
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| * IL-1α gene
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| * IL-β gene
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| * IFNγ gene
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| * IL-1RL1
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| * [[Interleukin 5|IL-5]] gene
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| * [[Interleukin 12|IL-12]] β gene
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| * IL-12R β
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| * [[Interleukin 13|IL-13]] gene
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| * IL-18 gene
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| * TGF-β1 gene
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| * [[GM-CSF]] gene
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| * [[IL-9]] gene
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| * IL-9R gene
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| |-
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| | style="background: #DCDCDC; text-align: center;" |'''Chemokines and related genes''':
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| * CCL5 gene: Chemokine (C-Cmotif) ligand 5
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| * [[CCL11]] gene
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| * CCL17 gene
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| * CCR3 gene
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| * CCR4 gene
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| * CMA1 gene: Mast cell chymase 1
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| |-
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| | colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Drug-metabolizing genes'''
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| * GST genes: glutathione S-transferase
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| * NAT-2 gene: N-acetyl transferase
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| |-
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| | colspan="2" style="background: #7d7d7d; color: #FFFFFF; text-align: center;" |'''Other genes'''
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| * CTLA-4
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| * KLK
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| * RUNX1 gene
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| * IRF2 gene
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| * FCER1B gene
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| * PHF11 gene
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| |-
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| | colspan="3" |Adapted from ''Molecular Genetic of Atopic dermatitis: An Update''<ref name="pmid270040624">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
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| |}
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| ==Associated Conditions== | | ==Associated Conditions== |
|
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| '''Conditions associated with atopic dermatitis:''' | | '''Conditions associated with''' |
| * Atopic triad | | * |
| ** Atopic dermatitis
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| ** [[Allergic rhinitis]]
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| ** [[Asthma]]
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| * Food-induced urticaria/anaphylaxis
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| * [[Ichthyosis vulgaris]]
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| * Ocular comorbidities
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| ** [[Atopic keratoconjunctivitis]]
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| ** [[Vernal keratoconjunctivitis]]
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| * [[Wiskott-Aldrich syndrome]]
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| ** [[Thrombocytopenia]]
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| ** Eczema (atopic dermatitis)
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| ** Recurrent infections
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| * [[Hyper-IgE syndrome]]:
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| ** Eczema (atopic dermatitis)
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| ** High serum [[IgE]]
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| ** Recurrent cold abscesses
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| * [[Anemia]]
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| * Psychiatric disorders
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| ** [[Depression]]
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| ** [[Anxiety]]
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| ** [[Suicidal|Suicid]]<nowiki/>al ideations
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| ** [[Attention deficit hyperactivity disorder]]
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| * [[Angina pectoris]]
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| ==Gross Pathology== | | ==Gross Pathology== |
| On [[gross pathology]], characteristic findings of atopic dermatitis include:<ref name="MihmSoter19762">{{cite journal|last1=Mihm|first1=Martin C|last2=Soter|first2=Nicholas A|last3=Dvorak|first3=Harold F|last4=Austen|first4=K Frank|title=The Structure Of Normal Skin And The Morphology Of Atopic Eczema|journal=Journal of Investigative Dermatology|volume=67|issue=3|year=1976|pages=305–312|issn=0022202X|doi=10.1111/1523-1747.ep12514346}}</ref> | | On [[gross pathology]], characteristic findings of itp include: |
| * '''Acute atopic dermatitis''': | | * '''Acute atopic dermatitis''': |
| ** [[Erythema]] | | ** |
| ** [[Edema]]
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| ** Vesiculation with oozing
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| * '''Chronic atopic dermatitis:''' | | * '''Chronic atopic dermatitis:''' |
| ** Lichenified plaques | | ** |
| ** Prominent skin markings
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|
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|
| ==Microscopic Pathology== | | ==Microscopic Pathology== |
| On microscopic [[histopathological]] analysis, characteristic findings of atopic dermatitis include:<ref name="MihmSoter19763">{{cite journal|last1=Mihm|first1=Martin C|last2=Soter|first2=Nicholas A|last3=Dvorak|first3=Harold F|last4=Austen|first4=K Frank|title=The Structure Of Normal Skin And The Morphology Of Atopic Eczema|journal=Journal of Investigative Dermatology|volume=67|issue=3|year=1976|pages=305–312|issn=0022202X|doi=10.1111/1523-1747.ep12514346}}</ref> | | On microscopic [[histopathological]] analysis, characteristic findings of itp include: |
| * '''Acute vesicular lesions''': | | * '''Acute vesicular lesions''': |
| ** Epidermal psoriasiform [[hyperplasia]]
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| ** Marked intercellular [[edema]] with spongiotic vesiculation
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| ** Marked perivenular infiltrate
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| ** Epidermal infiltrate, consisting predominately of a lymphohistiocytic infiltrate in the dermis
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| * '''Chronic lichenified plaque''': | | * '''Chronic lichenified plaque''': |
| ** [[Hyperkeratosis]]
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| ** Psoriasiform hyperplasia
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| ** Dyskeratosis
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| ** Marked thickening of the papillary dermis
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| ** Minimal intercellular edema
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| ==References== | | ==References== |
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| {{WS}} | | {{WS}} |
| [[Category: (name of the system)]] | | [[Category: (name of the system)]] |
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