Sandbox:Shalinder

Jump to navigation Jump to search


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 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 degradated products of Filaggrin protien are one of the major components of Natural Moisturising Factors(NMF), which prevents excess water loss from the stratum corneum
    • The degradated products of Filaggrin protien 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.[1]
    • 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 neutro, phils.[2],
    • 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.[3]
    • 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 of adaptive immune system is determined by innate immune response by interactions with the epidermal elements.[4]

Pathogenesis=

It is understood that atopic dermatitis is the result of skin barrier dysfunction or by immune dysregulation.[5]

Epidermal barrier dysfunction:

  • The major factors to abnormal skin barrier include loss-of-function mutations in the filaggrin gene (FLG) causing Filaggrin deficiency[6], tight junction abnormalities[7], more alkaline surface pH,[8] microbial colonization, altered protease activity in the stratum corneum.[9][10][11][12]
  • Skin barrier abnormalities lead to the permeability of epidermis, causing entry of antigens or pathogens, microbial colonization and leading to the production of inflammatory cytokines and Impaired production of antimicrobial peptides.
  • It leads to increased trans-epidermal water loss, and decreased levels of ceramides and water binding.[13]
  • Severe atopic dermatitis have been associated with higher levels of transepidermal water loss.[14]

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.

[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. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.

Template:WH Template:WS

Retrieved from "https://www.wikidoc.org/index.php?title=Sandbox:Shalinder&oldid=1495866"