Atopic dermatitis pathophysiology
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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). 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 the tightly packed structure of the stratum corneum is further compromised. Systemically, a dysfunctional innate and adaptive immune response causes further damage to the epidermis.
Pathophysiology
Physiology
The normal physiology of atopic dermatitis can be understood as follows:
Epidermal barrier function:
- 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.[1] Epidermis consists of:
- 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 (NMF), maintaining the water retention in the stratum corneum
- Antimicrobial peptides
- Filaggrin proteins: It is encoded by 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.[2][3]
- 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.[4]
- 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 stratum corneum, required to regulate the activity of enzymes.
- Proteins related to tight junctions: These transmembrane proteins are present in the stratum granulosum of the epidermis and compose together to form tight junctions which includes claudin-1, occludin, junctional adhesion molecule.[5]
- Other proteins: Filaggrin-2, corneodesmosin, desmoglein-1, desmocollin-1, transglutaminase-3 are also part of skin barrier related proteins.[6]
Immune response:
- Cutaneous immune response: It acts as the first-line barrier and constitutes the rapid response mechanism to the invading allergen or pathogen.[7] 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 forms the physical barrier. The maintenance and repair of epithelial barriers are mediated through the activation of PRRs by the innate immune system.[9]
- 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.[10][11]
- 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.[12]
- Immunological: Immune response includes both non-specific and immediate response (innate immunity) and highly specific and late response (adaptive immunity).
- Adaptive Immune response:[7]
- 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]
- Thymic stromal lymphopoietin:
- Thymic stromal lymphopoietin (TSLP) is considered as a master switch for allergic inflammation, and is highly expressed by epithelial cells and epidermal keratinocytes.[14][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]
- The major factors causing abnormal skin barrier include loss-of-function mutations in the filaggrin gene (FLG) resulting in:[19][20][21]
- Filaggrin protein deficiency[22]
- Tight junction abnormalities[23]
- More alkaline surface pH[24]
- Microbial colonization
- Altered protease activity in the stratum corneum[25]
- Skin barrier abnormalities lead to the increased permeability of the epidermis.
- This leads to entry of antigens or pathogens resulting in microbial colonization, most notably by staphylococcus aureus and herpes simplex virus (HSV).
- These sequence of events results in the production of inflammatory cytokines and impaired production of antimicrobial peptides.[26]
- Skin barrier abnormalities also leads to increased trans-epidermal water loss, and decreased levels of ceramides and water binding.[27]
- Severe atopic dermatitis has been associated with higher levels of trans-epidermal water loss.[28]
Immune dysregulation (inside-out’ hypothesis):[29]
- Innate immune response:
- Pathogens or tissue damage activate pattern recognition receptors including toll-like receptors (TLRs), which further induces 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 and Th22 cells. This effect is suppressed in patients with atopic dermatitis.[32]
- 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
- Thymic stromal lymphopoietin:
- Defective skin barrier and enhanced epidermal protease activity, which is reported in atopic dermatitis, promote TSLP production and Th2 response, leading to atopic dermatitis-like inflammation.[36]
- TSLP polymorphisms have been linked to the severity of atopic dermatitis.
- TSLP genetic variants are associated with atopic dermatitis and eczema herpeticum.[37]
- In patients with defective skin barrier due to FLG mutations, TSLP genetic variants are associated with reduced probability of having persistent atopic dermatitis.[38]
Genetics
Recent studies have established a strong genetic association of atopic dermatitis. Twin studies have indicated high heritability of atopic dermatitis with a concordance rate of 72–86 % for monozygotic twins compared with 21–23 % for dizygotic twins.[39]
Genes involved in the pathogenesis of atopic dermatitis include:[40]
| Genes involved in the pathogenesis of atopic dermatitis | ||
|---|---|---|
| Filaggrin Gene mutation |
| |
| SPINK5 and LEKTI gene |
| |
| MHC (or HLA) genes |
| |
| Innate Immune system genes: |
| |
| Adaptive immune system genes | Cytokines and related genes: | |
| Chemokines and related genes: |
| |
| Drug-metabolizing genes |
| |
| Other genes |
| |
| Adapted from Molecular Genetic of Atopic dermatitis: An Update[47] | ||
Associated Conditions
Conditions associated with atopic dermatitis:
- Atopic triad
- Atopic dermatitis
- Allergic rhinitis
- Asthma
- Food-induced urticaria/anaphylaxis
- Ichthyosis vulgaris
- Ocular comorbidities
- Wiskott-Aldrich syndrome
- Thrombocytopenia
- Eczema (atopic dermatitis)
- Recurrent infections
- Hyper-IgE syndrome:
- Eczema (atopic dermatitis)
- High serum IgE
- Recurrent cold abscesses
- Anemia
- Psychiatric disorders
- Angina pectoris
Gross Pathology
On gross pathology, characteristic findings of atopic dermatitis include:[48]
- Acute atopic dermatitis:
- Chronic atopic dermatitis:
- Lichenified plaques
- Prominent skin markings
Microscopic Pathology
On microscopic histopathological analysis, characteristic findings of atopic dermatitis include:[49]
- 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
- ↑ 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.
- ↑ 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.
- ↑ Ständer, Sonja; Ropper, Allan H. (2021). "Atopic Dermatitis". New England Journal of Medicine. 384 (12): 1136–1143. doi:10.1056/NEJMra2023911. ISSN 0028-4793.
- ↑ 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.
- ↑ 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.
- ↑ Broccardo CJ, Mahaffey S, Schwarz J, Wruck L, David G, Schlievert PM, Reisdorph NA, Leung DY (January 2011). "Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization". J. Allergy Clin. Immunol. 127 (1): 186–93, 193.e1–11. doi:10.1016/j.jaci.2010.10.033. PMC 3059191. PMID 21211653.
- ↑ 7.0 7.1 Barnes KC (January 2010). "An update on the genetics of atopic dermatitis: scratching the surface in 2009". J. Allergy Clin. Immunol. 125 (1): 16–29.e1–11, quiz 30–1. doi:10.1016/j.jaci.2009.11.008. PMC 2874322. PMID 20109730.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.