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The normal physiology of Atopic Dermatitis can be understood as follows:
The normal physiology of Atopic Dermatitis can be understood as follows:
* '''Epidermal barrier function:'''
* '''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.<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>
# '''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.<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>
#* Tightly packed corneocytes layers in the stratum corneum.   
#* Tightly packed corneocytes layers in the stratum corneum.   
#* Intercellular lipid bilayers.  
#* Intercellular lipid bilayers.  

Revision as of 21:52, 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 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).[1] 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 brick wall-like’ structure of the stratum corneum is further compromised. Systemically, a dysfunctional innate and adaptive immune response causes further damage to the epidermis[2].

Pathophysiology

Physiology

The normal physiology of Atopic Dermatitis can be understood as follows:

  • Epidermal barrier function:
  1. 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.[3]
    • 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, maintains the water retention in the stratum corneum
    • Antimicrobial peptides production
  2. Filaggrin proteins: 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.[4]
    • 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.[5]
    • 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.
  3. 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.[6]
  4. Other proteins: filaggrin-2, corneodesmosin, desmoglein-1, desmocollin-1, transglutaminase-3 are also part of skin barrier related proteins.[7]
  • Immune response:
  1. Cutaneous immune response: It acts as the 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). The cutaneous immune response includes the following 4 elements:[8]
    • Physical: stratum corneum and the tight junctions in stratum granulosum. The maintenance and repair of epithelial barriers are mediated through the activation of PRRs by the innate immune system.[9]
    • Chemical: 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: 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.[12]
    • Immunological: Immune response includes both non-specific and immediate response (innate immunity) and highly specific and late response (adaptive immunity).
  2. Adaptive Immune response: 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]
  3. Thymic stromal lymphopoietin: Thymic stromal lymphopoietin (TSLP) is considered as a master switch for allergic inflammation[14], and is highly expressed by epithelial cells and epidermal keratinocytes[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]
    1. The major factors to abnormal skin barrier include loss-of-function mutations in the filaggrin gene (FLG) causing Filaggrin deficiency[19], tight junction abnormalities[20], more alkaline surface pH,[21] microbial colonization, altered protease activity in the stratum corneum.[22][23][24][25]
    2. 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.[26]
    3. It leads to increased trans-epidermal water loss, and decreased levels of ceramides and water binding.[27]
    4. Severe atopic dermatitis has been associated with higher levels of trans-epidermal water loss.[28]
  • Immune dysregulation (inside-out’ hypothesis):[29]:
    1. 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[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 T and Th22 cells. This effect is suppressed in patients with atopic dermatitis.[32]
    2. 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
    3. 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 with 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 % percent for dizygotic twins.[39]

Genes involved in the pathogenesis of atopic dermatitis include:[40]

  1. Filaggrin Gene mutation:
    • Located on chromosome 1q21 (epidermal differentiation complex) loss-of-function mutations in the filaggrin gene FLG, is strongly associated with a broad range of skin and allergic diseases including atopic dermatitis[41]. Mutation in this gene is also responsible for ichthyosis vulgaris and pachyonychia congenita.[42] The common genetic variant R510X and 2282del4 are very strongly associated with atopic dermatitis.[43]
    • FLG Gene mutation is associated with developing atopic dermatitis at an early age(≤8 years) but is not associated with late childhood or adulthood atopic dermatitis.[44]
  2. SPINK5 and LEKTI gene:
    • Located on chromosome 5q32, Serine Protease Inhibitor Kazal-Type 5 (SPINK5) gene encodes a protease inhibitor Lymphoepithelial Kazal-Type-Related Inhibitor (LEKTI), which is involved in converting profilaggrin into filaggrin and is responsible for marinating the permeability of the normal skin.[45]
    • LEKTI deficiency leads to enhanced cleavage of intercellular attachments, decreased corneocyte cohesion and impaired skin barrier function.[46]
  3. MHC (or HLA) genes
  4. Innate Immune system genes:
    • CARD4 (or NOD1) gene: Caspase recruitment domain–containing protein (CARD) 4
    • CARD15 (or NOD2) gene
    • Monocyte differentiation antigen (or CD14) gene
    • MBL2 gene: mannose-binding lectin (MBL2) gene
    • Toll-like receptor( TLR2, TLR4, TLR6 and TLR 9) genes
    • DEFB1 gene: human β-defensin 1
  5. Adaptive immune system genes
    • Cytokines and related genes:
      • IL-4 gene
      • IL-4Rα gene
      • STAT6 gene (Signal transducer and activator of transcription )
      • IL-10 gene
      • IL-6 gene
      • TNF-α gene
      • TNF-β gene
      • IL-1α gene
      • IL-β gene
      • IFNγ gene
      • IL1RL1
      • IL-5 gene
      • IL-12 β gene
      • IL-12R β
      • IL-13 gene
      • IL-18 gene
      • TGF-β1 gene
      • GM-CSF gene
      • IL-9 gene
      • IL-9R gene
    • Chemokines and related genes:
      • CCL5 gene: Chemokine (C-Cmotif) ligand 5
      • CCL11 gene
      • CCL17 gene
      • CCR3 gene
      • CCR4 gene
      • CMA1 gene: Mast cell chymase 1
    • Drug-metabolizing genes
      • GST genes: glutathione S-transferase
      • NAT-2 gene: N-acetyl transferase
    • Other genes
      • CTLA-4
      • KLK
      • RUNX1 gene
      • IRF2 gene
      • FCER1B gene
      • PHF11 gene

Associated Conditions

Conditions associated with atopic dermatitis include:

  • Atopic triad[47]
    • Atopic dermatitis
    • Allergic rhinitis
    • Asthma
  • Food-induced urticaria/anaphylaxis [48]
  • Ichthyosis vulgaris[49]
  • Ocular comorbidities:
    • Atopic keratoconjunctivitis[50]
    • Vernal keratoconjunctivitis[51]
  • Wiskott-Aldrich syndrome:[52]
    • Thrombocytopenia
    • Eczema (atopic dermatitis)
    • Recurrent infections
  • Hyper-IgE syndrome:[53]
    • Eczema (atopic dermatitis)
    • High serum IgE
    • Recurrent cold abscesses
  • Anemia[54]
  • Psychiatric disorders:[55]
    • Depression[56]
    • Anxiety[57]
    • Suicidal ideations
    • Attention deficit hyperactivity disorder[58]
  • Angina pectoris[59]

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.[60]

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of atopic dermatitis include:[61]

  • 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

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  2. 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.
  3. 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.
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