Sandbox:Shalinder

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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

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


Pathophysiology

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.[1] 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.[2]. 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).[3]
    • 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.[4]
  • 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.[5] It consists of 4 types of barrier functions of the epidermis:
    • physical: stratum corneum and tight junctions[5]
    • chemical: antimicrobial peptides, keratinocytes, cytokines, and chemo-kines[5]
    • microbiome: skin resident micro-flora promote the preservation of the normal skin flora while inhibiting the skin pathogens.[5]
    • immunologic: T cells, neutrophils, eosinophils, NK cells and antigen presenting cells promote the immunologic recognition of antigens or pathogens.[5]

Pathogenesis=

It is understood that Atopic dermatitis is the result of skin barrier dysfunction or by immune dysregulation.[6]

    • Epidermal 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, tight junction abnormalities, microbial colonization, and release of pro inflammatory cytokines and imbalance between protease and antiprotease (LEKTI) activity in the stratum corneum.[7][8][9]
      • It leads to increased trans-epidermal water loss, and decreased levels of ceramides and antimicrobial peptides.[10]
      • Severe Atopic Dermatitis have been associated with higher levels of transepidermal water loss.[11]



  • [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. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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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