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==Pathophysiology==
==Pathogenesis===
===Physiology===
The normal physiology of skin barrier function and immune regulation can be understood as follows:
*Skin Barrier: In the epidermis, stratum corneum consisting of stacks of anucleate corneocytes filled with keratin filaments serves as the first line of defense between the body and the environment.<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> Interactions between terminally differentiated keratinocytes and structural proteins such as lipids, regulatory enzymes, and filaggrin, determine the permeability of epidermis.
**Filaggrin is one of the major determinants of barrier function.<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>. Encoded by the FLG gene, filaggrin monomers constitute keratin-filament-aggregating properties.
**Following its synthesis primarily as profilaggrin, it undergoes extensive phosphorylation, resulting in the formation of filaggrin monomers, which on further breakdown are major components of the natural moisturizer factor (NMF).<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>
**The main function of natural moisturizer factor is to maintains skin hydration and water retention within the stratum corneum.
** Other proteins involved in production of natural moisturizer factor are desmoglein-1, desmocollin-1, filaggrin-2, corneodesmosin,  transglutaminase-3 and enzymes such as caspase-14 and arginase-1.<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 regulation: It constitutes of an innate immune response which is a rapid and first line immune response to the invading pathogen before host initiates the adaptive immune response which is a highly specific and long-lasting response.<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> It consists of 4 types of barrier functions of the epidermis:
It is understood that Atopic dermatitis is the result of 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>
**physical: stratum corneum and tight junctions<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>
*Dysfunction of the skin barrier:
**chemical: antimicrobial peptides, keratinocytes, cytokines, and chemo-kines<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>  
**Skin barrier abnormalities lead to the permeability of epidermis, causing entry of antigens or pathogens and leading to the production of inflammatory cytokines.
**microbiome: skin resident micro-flora promote the preservation of the normal skin flora while inhibiting the skin pathogens.<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>
**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>
**immunologic: T cells, neutrophils, eosinophils, NK cells and antigen presenting cells promote the immunologic recognition of antigens or pathogens.<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>
**It leads to increased trans-epidermal water loss, and decreased levels of ceramides and antimicrobial peptides.<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 transepidermal 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:
*Innate immune response:
**Innate immune system recognizes microbes or pathogens through innate immune receptors known as pattern recognition receptors(PRR) which also includes Toll-like receptors(TLRs).
 
 
*Adaptive immune response:
 
*Thymic stromal lymphopoietin:
 
 
 
 
*[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
*[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
*The progression to [disease name] usually involves the [molecular pathway].
*The pathophysiology of [disease/malignancy] depends on the histological subtype.


==Pathogenesis===
==Pathogenesis===

Revision as of 21:47, 27 September 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

It is thought that Atopic dermatitis is caused by either skin barrier dysfunction or immune dysregulation.


Pathogenesis=

It is understood that Atopic dermatitis is the result of skin barrier dysfunction or by immune dysregulation.[1]

  • Dysfunction of the skin barrier:
    • Skin barrier abnormalities lead to the permeability of epidermis, causing entry of antigens or pathogens and leading to the production of inflammatory cytokines.
    • The major factors to abnormal skin barrier include loss-of-function mutations in the filaggrin gene (FLG) causing Filaggrin deficiency[2], tight junction abnormalities[3], more alkaline surface pH,[4] microbial colonization, altered protease activity in the stratum corneum.[5][6][7][8]
    • It leads to increased trans-epidermal water loss, and decreased levels of ceramides and antimicrobial peptides.[9]
    • Severe Atopic Dermatitis have been associated with higher levels of transepidermal water loss.[10]


Immune dysregulation:

  • Innate immune response:
    • Innate immune system recognizes microbes or pathogens through innate immune receptors known as pattern recognition receptors(PRR) which also includes Toll-like receptors(TLRs).


  • Adaptive immune response:
  • Thymic stromal lymphopoietin:



  • [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
  • Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
  • [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
  • The progression to [disease name] usually involves the [molecular pathway].
  • The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathogenesis=

It is understood that Atopic dermatitis is the result of skin barrier dysfunction or by immune dysregulation.[1]

  • Dysfunction of the skin barrier:
    • Skin barrier abnormalities lead to the permeability of epidermis, causing entry of antigens or pathogens and leading to the production of inflammatory cytokines.
    • The major factors to abnormal skin barrier include loss-of-function mutations in the filaggrin gene (FLG) causing Filaggrin deficiency[2], tight junction abnormalities[3], more alkaline surface pH,[4] microbial colonization, altered protease activity in the stratum corneum.[5][6][7][8]
    • It leads to increased trans-epidermal water loss, and decreased levels of ceramides and antimicrobial peptides.[9]
    • Severe Atopic Dermatitis have been associated with higher levels of transepidermal water loss.[10]


Immune dysregulation:

  • Innate immune response:
  • Adaptive immune response:
  • Thymic stromal lymphopoietin:



  • [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
  • Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
  • [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
  • The progression to [disease name] usually involves the [molecular pathway].
  • The pathophysiology of [disease/malignancy] depends on the histological subtype.

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, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

References

  1. ↑ 1.0 1.1 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.
  2. ↑ 2.0 2.1 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.
  3. ↑ 3.0 3.1 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.
  4. ↑ 4.0 4.1 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.
  5. ↑ 5.0 5.1 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.
  6. ↑ 6.0 6.1 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ 8.0 8.1 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.
  9. ↑ 9.0 9.1 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.
  10. ↑ 10.0 10.1 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.

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