(AD) is a highly pruritic, recurring inflammatory skin disease. It usually develops in early childhood and is frequently seen in children with a personal history of respiratory allergy and/or a family history of atopic disease.
Genetically defined PDE isoforms lead to inadequate cellular cAMP levels.
cAMP normally causes negative modulation of immune and inflammatory responses.
Inflammatory cells in AD fail to shut off normally leading to increased production of IL-4 and IgE , secretion of IL-10 and prostaglandin E2 by monocyte , and excessive release of histamine by mast cells and basophils .
Early (perhaps even in utero) antigenic exposures cause the genetically susceptible person to proliferate antigenically stimulated Th2-dominant T-cell clones , elaborating IL-4 , IL-5 , IL-6 , IL-10 , and IL-13 on re-exposure to the antigen , thus stimulating excessive IgE production by the B cell and a tendency to eosinophil -rich inflammation.
The epidermis : hyperplastic with elongation of the rete ridges, prominent hyperkeratosis, and minimal spongiosis. An increased number of Langerhans cells in the epidermis, and macrophages dominate the dermal mononuclear cell infiltrate. Mast cells are increased in number & fully granulated.
Increased numbers of eosinophils showing various stages of degeneration.
In both acute and chronic lesions :
The endothelial cells exhibit E-selectin , intercellular adhesion molecule-1 , and vascular cell adhesion molecule-1
linkage of AD to chromosome 1q21 , the region containing the epidermal differentiation complex ( EDC ), was reported
ِ Atopic skin lesions revealed altered expression of genes located within the EDC , in particular up regulation of S100A8 and S100A7 and down regulation of loricrin and filaggrin ( FLG )( loss-of-function mutations in the filaggrin FLG gene ) , compared with healthy control samples
The epidermal differentiation complex ( EDC ) is a cluster of genes on chromosome 1q21 encoding proteins that fulfil important functions in terminal differentiation in the human epidermis, including filaggrin , loricrin , S100 proteins and others.
Variation within EDC genes plays an important role in the pathogenesis
of three common skin disorders, ichthyosis vulgaris, atopic dermatitis ( AD ) and psoriasis .
FLG expression and functions in the skin barrier:1
The precursor proprotein profilaggrin is strongly expressed within keratohyalin granules, tightly limited to and accounting for the typical appearance of the granular layer.
The SC stains strongly positive for filaggrin.
Filaggrin has several proposed site-specific functions under the influence of the epidermal terminal differentiation program through the outer granular layer
Cleavage of profilaggrin to filaggrin and the lipid bilayer of the inner SC (filament compaction, contribution to barrier integrity)
During desquamation of the outer SC (production of amino acid degradation products that contribute to the hydration of these outer layers and likely contribute to the ‘‘acid mantle’’).
FLG expression and functions in the skin barrier:2
Profilaggrin is dephosphorylated in conditions of increasing calcium concentration and is then proteolytically cleaved by the proteases matriptase (inhibited by the protease inhibitor LETKI).
After proteolysis, the filaggrin B domain locates to the nucleus as part of the terminal differentiation process.
Free filaggrin protein is crosslinked to keratin filaments by transglutaminases and subsequently deiminated by peptidylarginine deiminases (PADs) 1 and 3.
Further posttranslational modification is undertaken by caspase 14 to produce the free amino acid hygroscopic degradation products urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA; ) which contribute to SC hydration.
Leukocytes from patients with AD have increased cyclic adenosine monophosphate (cAMP)-phospho-diesterase (PDE) enzyme contributing to the increased IgE synthesis by B cells and IL-4 production by T cells
Elevated cAMP-PDE in atopic monocytes contributes to the secretion of increased levels of IL-10 and PGE2 & inhibits IFN-gamma production by T cells .
Generation of TH 2 cells is dependent on the interaction of cluster differentiation (CD) 28 with B7.2 expressed on B cells of patients with AD. Langerhans' cells in the lesional skin of AD express B7.2 .
The chemokines stimulating migration of inflammatory cells to the skin are expressed by keratinocytes , endothelial cells and, dendritic cells .
The chemokines, monocyte chemotactic protein-4, and eotaxin in AD skin lesions induce chemotaxis of eosinophils and Th2 lymphocytes into the skin.
Leukotriene B4 is also released on exposure of AD skin to allergens acting as a chemoattractant for the initial influx of inflammatory cells
Factors contributing to Skin Localization of Allergic Disease
1-Route of allergen sensitization.
2-Tissue chemokine expression.
3-Expression of homing receptors on memory effector T cells: regulated by interaction of expressed T-cell homing receptors with vascular endothelial-cell surface antigens. The cell adhesion molecule that results in T-cell homing to the skin is termed cutaneous lymphocyte-associated antigen (CLA).
1-Epidermal keratinocytes produce increased levels of chemokines enhancing the chemotaxis of eosinophils.
2-Mechanical trauma : induces the release of TNF-α and many other proinflammatory cytokines from epidermal kera-tinocytes .
3-Enhanced production of GM-CSF by epidermal keratinocytes and infiltrating macrophages plays an important role in maintaining the survival and function of monocyte-macrophages, Langerhans' cells, and eosinophils.
4-The prolonged survival of eosinophils:due to Increased IL-5 expression during the transition from acute to chronic AD and secretion of autocrine factors inhibiting cell apoptosis
5-Colonization by superantigen-producing Staphylococcus aureus :
Superantigens stimulate epidermal macrophages & Langerhan s cells to produce IL-1 , TNF , and IL-12 inducing the expression of E-selectin on vascular endothelium, allowing an initial influx of CLA+ memory/effector cells.
The xerotic epidermis due to ceramides reduction & loss-of-function mutations in the filaggrin ( FLG ) gene ( impaired barrier function ), provokes and sustains inflammation by activation of an epidermis-initiated cytokine cascade. The impaired barrier function of atopic skin allows greater absorption of irritant agents and contact allergens.
FLG insufficiency and bacterial infections in atopic dermatitis
Exposure of immune system to Staph. aureus superantigens can trigger and establish a permanent TH2 immune response through activation and amplification of innate immune responses.
The neutralizing acid SC pH has also been shown to independently facilitate excessive protease activity and reduce the activity of key lipid processing enzymes, resulting in the formation of defective lamellar membranes and a disrupted permeability barrier.
DIFFERENTIAL DIGNOSIS of AD History of recurrent infection Immunodeficiency disorder Serpiginous plaques with central clearing, positive potassium hydroxide preparation Dermatophyte infection Vesicles over extensor areas and associated enteropathy Dermatitis herpetiformis Findings on complete history and physical examination vary by disease Systemic diseases Papules, finger web involvement, positive skin scraping Scabies Positive exposure history, rash in area of exposure, absence of family history Contact dermatitis Usually, a single patch in an area accessible to itching; absence of family history Neurodermatitis Localized patches on extensor surfaces, scalp, buttocks; pitted nails Psoriasis
In patients with severe treatment-resistant A D. Oral corticosteroids improve the lesions of atopic dermatitis. Flare occurs when these medications are stopped. . The potential for a rebound effect can be decreased by tapering the drug while increasing topical corticosteroid treatment and aggressively hydrating the skin.
Interferon gamma is a Th1 cytokine suppressing IL-4–mediated IgE production and is beneficial , effective and safe in the treatment of moderate-to-severe AD. Clinical improvement in their patients correlated with reductions in white blood cell counts, eosinophil and lymphocyte counts, and with normalization of the CD4-to-CD8 ratio among lymphocytes.
Used in severe AD due to anti-inflammatory and immunomodulatory properties.
IVIg reduces IL-4 protein expression in AD and decreases in ICAM-1, ELAM-1, and ECP levels.
IVIG's role in apoptosis, and Fc receptor function and its influence on cytokine cascades
Omalizumab ( Xolair --Genentech) is currently indicated for adults and adolescents (12 years of age and older) with moderate to severe persistent asthma, a positive skin test or in vitro reactivity to a perennial aeroallergen, and symptoms that are inadequately controlled with inhaled corticosteroids.
The use of omalizumab in the treatment of atopic dermatitis has yet to be clearly defined.
Corticosteroids, UV therapy including NB UVB(311 nm) and the immunosuppressant macrolides are all therapeutic agents that are likely to be effective in controlling the complex inflammatory cascades of chronic AD.
Given the central role of TH 2 cytokines and chemokines in the development of AD, strategies directed at reducing TH 2 responses and blocking the action of chemokines by antagonists of relevant receptors will be important.
The potential role of IFN-γ, IL-12, and IL-18 in restoring the shift toward a more balanced TH 0 response with equal production of TH 1 and TH 2 cytokines warrants studies .Further studies upon the cytokines blocking agents may present a safe and effective modality for AD therapy