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**In patients with defective skin barrier due to FLG mutations, TSLP genetic variants are associated with reduced probability of having persistent atopic dermatitis<ref name="pmid24401911">{{cite journal |vauthors=Margolis DJ, Kim B, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Mitra N |title=Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis |journal=JAMA Dermatol |volume=150 |issue=3 |pages=254–9 |date=March 2014 |pmid=24401911 |pmc=4414492 |doi=10.1001/jamadermatol.2013.7954 |url=}}</ref>.  
**In patients with defective skin barrier due to FLG mutations, TSLP genetic variants are associated with reduced probability of having persistent atopic dermatitis<ref name="pmid24401911">{{cite journal |vauthors=Margolis DJ, Kim B, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Mitra N |title=Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis |journal=JAMA Dermatol |volume=150 |issue=3 |pages=254–9 |date=March 2014 |pmid=24401911 |pmc=4414492 |doi=10.1001/jamadermatol.2013.7954 |url=}}</ref>.  


== Genetics ==
[Disease name] is transmitted in [mode of genetic transmission] pattern.
[Disease name] is transmitted in [mode of genetic transmission] pattern.


Line 67: Line 68:


Genes involved in the pathogenesis of [disease name] include:
Genes involved in the pathogenesis of [disease name] include:
*[Gene1]
* [Gene1]
*[Gene2]
* [Gene2]
*[Gene3]
* [Gene3]
 
OR
OR


The development of [disease name] is the result of multiple genetic mutations such as:
The development of [disease name] is the result of multiple genetic mutations such as:
* [Mutation 1]
* [Mutation 2]
* [Mutation 3]


*[Mutation 1]
*
*[Mutation 2]
*[Mutation 3]


==Associated Conditions==
==Associated Conditions==

Revision as of 15:24, 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 eczema, an inflammatory chronic pruritic skin disorder with an immunologic background, occurs in patients with a personal or family history of atopy (i.e., asthma or allergic rhinitis).[1] It is thought that atopic dermatitis is caused by either skin barrier dysfunction or immune dysregulation.

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 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..
    • Tightly packed corenocytes 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
  • 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.
    • 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 undergoes extensive phosphorylation and dephosphorylation, to produce Filaggrin monomers, to interact and aggregate with the keratin filaments and provide
    • 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.
  • 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.
  • Other protiens: filaggrin-2, corneodesmosin, desmoglein-1, desmocollin-1, transglutaminase-3 are also part of skin barier related proteins.

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:
    • 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.[2]
    • 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.[3],
    • 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.[4]
    • 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[5]
  • Thymic stromal lymphopoietin: Thymic stromal lymphopoietin (TSLP) is considered as "a master switch for allergic inflammation"[6], and is highly expressed by epithelial cells and epidermal keratinocytes[7] . It is an IL-7-like cytokine, which stimulates the differentiation of naïve T helper cells into inflammatory Th2 cells[8].

Pathogenesis

It is understood that atopic dermatitis is the result of skin barrier dysfunction or by immune dysregulation.[9]

Epidermal barrier dysfunction(outside-in hypothesis):[10]

  • The major factors to abnormal skin barrier include loss-of-function mutations in the filaggrin gene (FLG) causing Filaggrin deficiency[11], tight junction abnormalities[12], more alkaline surface pH,[13] microbial colonization, altered protease activity in the stratum corneum.[14][15][16][17]
  • 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.[18]
  • It leads to increased trans-epidermal water loss, and decreased levels of ceramides and water binding.[19]
  • Severe atopic dermatitis have been associated with higher levels of trans-epidermal water loss.[20]

Immune dysregulation (inside-out’ hypothesis):[21]:

  • 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[22]
    • 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[23]
    • 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.[24]
  • 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[25].
    • Enhanced expression of Th2, Th17 and Th22 cytokines, characterize the acute initiation of atopic dermatitis lesions[26].
    • Epidermal barrier function is regulated through Th2 and Th22 cytokines (IL-4, IL-13, IL-31, and IL-22) by:[27]
      • 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[28].
    • TSLP polymorphisms have been linked to the severity of atopic dermatitis.
    • TSLP genetic variants are associated with atopic dermatitis and eczema herpeticum.[29]
    • In patients with defective skin barrier due to FLG mutations, TSLP genetic variants are associated with reduced probability of having persistent atopic dermatitis[30].

Genetics

[Disease name] is transmitted in [mode of genetic transmission] pattern.

OR

Genes involved in the pathogenesis of [disease name] include:

  • [Gene1]
  • [Gene2]
  • [Gene3]

OR

The development of [disease name] is the result of multiple genetic mutations such as:

  • [Mutation 1]
  • [Mutation 2]
  • [Mutation 3]

Associated Conditions

Conditions associated with [disease name] include:

  • [Condition 1]
  • [Condition 2]
  • [Condition 3]

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.[31]

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of atopic dermatitis includes:[32]

  • 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. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  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. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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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