Allergen sensitization through the skin induces systemic allergic responses.

The skin is a unique immunologic organ that acts as an interface between the external environment and the systemic immune response. As such, it may react directly with allergens that are applied epicutaneously, thereby influencing the systemic allergic response. It is well known that atopic dermatitis (frequently in association with food allergy) predates the development of asthma and allergic rhinitis by several years. The possibility that atopic dermatitis may influence the course of asthma is suggested by several interesting observations. First, children with atopic dermatitis and positive skin tests to allergens frequently have more severe asthma than asthmatic children without atopic dermatitis. Second, because total serum IgE is strongly associated with the prevalence of asthma, it raises the interesting question of whether allergen sensitization through the skin predisposes to more severe and persistent respiratory disease because of its effects on the systemic allergic response. Indeed, epicutaneous sensitization of mice to a protein antigen induces both a localized allergic dermatitis and hyperresponsiveness to methacholine, which suggests that epicutaneous exposure to antigen in atopic dermatitis may enhance the development of asthma. Finally, systemic immune activation in atopic dermatitis is supported by the observation that these patients have increased numbers of circulating activated T(H)2 cells, eosinophils, macrophages, and IgE. Many of the markers of leukocyte activation have been shown to correlate with the severity of atopic dermatitis disease. This systemic activation might facilitate local infiltration of primed T cells, eosinophils, and macrophages into the respiratory mucosa after inhalation of allergen in genetically predisposed hosts. The systemic aspects of atopic dermatitis, with an emphasis on respiratory effects, are summarized.

[1]  James J. Campbell,et al.  The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells , 1999, Nature.

[2]  L. Picker,et al.  Differential expression of lymphocyte homing receptors by human memory/effector T cells in pulmonary versus cutaneous immune effector sites , 1994, European journal of immunology.

[3]  L. Picker,et al.  Milk-induced eczema is associated with the expansion of T cells expressing cutaneous lymphocyte antigen. , 1995, The Journal of clinical investigation.

[4]  E. Knol,et al.  Adhesion molecule expression on skin endothelia in atopic dermatitis: Effects of TNF-α and IL-4 , 1998 .

[5]  J. Pober,et al.  Mechanism of sustained E-selectin expression in cultured human dermal microvascular endothelial cells. , 1997, Journal of immunology.

[6]  D. Leung,et al.  Atopic dermatitis: new insights and opportunities for therapeutic intervention. , 2000, The Journal of allergy and clinical immunology.

[7]  M. Furue,et al.  Serum soluble IL-2 receptor (sIL-2R) and eosinophil cationic protein (ECP) levels in atopic dermatitis. , 1994, Journal of dermatological science.

[8]  L. Picker,et al.  Evidence for superantigen involvement in skin homing of T cells in atopic dermatitis. , 1999, The Journal of investigative dermatology.

[9]  A. Wardlaw Molecular basis for selective eosinophil trafficking in asthma: A multistep paradigm. , 1999, The Journal of allergy and clinical immunology.

[10]  G. Imokawa,et al.  Percutaneous sensitization with allergens through barrier‐disrupted skin elicits a Th2‐dominant cytokine response , 1998, European journal of immunology.

[11]  C. Bruijnzeel-Koomen,et al.  IL-4 induces chemotaxis of blood eosinophils from atopic dermatitis patients, but not from normal individuals. , 1994, The Journal of investigative dermatology.

[12]  T. Bieber,et al.  IL-4 induces the intracellular expression of the alpha chain of the high-affinity receptor for IgE in in vitro-generated dendritic cells. , 2000, The Journal of allergy and clinical immunology.

[13]  N. Copeland,et al.  CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  H. Sampson,et al.  Food hypersensitivity and atopic dermatitis: pathophysiology, epidemiology, diagnosis, and management. , 1999, The Journal of allergy and clinical immunology.

[15]  K. Asadullah,et al.  Enhanced expression of T-cell activation and natural killer cell antigens indicates systemic anti-tumor response in early primary cutaneous T-cell lymphoma. , 1997, The Journal of investigative dermatology.

[16]  C. Akdis,et al.  Skin-homing, CLA+ memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-dominated cytokine pattern: IgG4 counter-regulation by CLA- memory T cells. , 1997, Journal of immunology.

[17]  H. Nakagawa,et al.  Linkage and association of an interleukin 4 gene polymorphism with atopic dermatitis in Japanese families. , 1998, Journal of medical genetics.

[18]  R. Tupker,et al.  Induction of atopic dermatitis by inhalation of house dust mite. , 1996, The Journal of allergy and clinical immunology.

[19]  E. Knol,et al.  Clinical and immunologic variables in skin of patients with atopic eczema and either positive or negative atopy patch test reactions. , 2000, The Journal of allergy and clinical immunology.

[20]  C. Naspitz,et al.  Prevention of asthma by ketotifen in infants with atopic dermatitis. , 1992, Annals of allergy.

[21]  J. Fehr,et al.  IL-4 controls the selective endothelium-driven transmigration of eosinophils from allergic individuals. , 1992, Journal of immunology.

[22]  L. Koenderman,et al.  Eosinophil migration in atopic dermatitis. I: Increased migratory responses to N-formyl-methionyl-leucyl-phenylalanine, neutrophil-activating factor, platelet-activating factor, and platelet factor 4. , 1993, The Journal of investigative dermatology.

[23]  E. Knol,et al.  Adhesion molecule expression on skin endothelia in atopic dermatitis: effects of TNF-alpha and IL-4. , 1998, The Journal of allergy and clinical immunology.

[24]  Li-Fang Wang,et al.  Epicutaneous exposure of protein antigen induces a predominant Th2-like response with high IgE production in mice. , 1996, Journal of immunology.

[25]  B. Wedi,et al.  Significant Delay of Apoptosis and Fas Resistance in Eosinophils of Subjects with Intrinsic and Extrinsic Type of Atopic Dermatitis , 1999, International Archives of Allergy and Immunology.

[26]  M. McCarthy,et al.  Identifying genes predisposing to atopic eczema. , 1999, The Journal of allergy and clinical immunology.

[27]  U. Gieler,et al.  Blood eosinophils, eosinophil‐derived proteins, and leukotriene C4 generation in relation to bronchial hyperreactivity in children with atopic dermatitis , 1995, Allergy.

[28]  R. Geha,et al.  Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. , 1998, The Journal of clinical investigation.

[29]  R. Cotran,et al.  Expression of endothelial-leukocyte adhesion molecule-1 in elicited late phase allergic reactions. , 1991, The Journal of clinical investigation.

[30]  T. Chatila,et al.  The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. , 1997, The New England journal of medicine.

[31]  I. Bellinghausen,et al.  Signals involved in the early TH1/TH2 polarization of an immune response depending on the type of antigen. , 1999, The Journal of allergy and clinical immunology.

[32]  W. Paul,et al.  T helper cells grown with hapten‐modified cultured Langerhans' cells produce interleukin 4 and stimulate IgE production by B cells , 1989, European journal of immunology.

[33]  L. Picker,et al.  Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen , 1995, The Journal of experimental medicine.

[34]  L. Picker,et al.  Skin disease‐related T cells bind to endothelial selectins: expression of cutaneous lymphocyte antigen (CLA) predicts E‐selectin but not P‐selectin binding , 1994, European journal of immunology.

[35]  E. Novembre,et al.  Urinary eosinophil protein X and serum eosinophil cationic protein in infants and young children with atopic dermatitis: correlation with disease activity. , 2000, The Journal of allergy and clinical immunology.

[36]  G. Settipane,et al.  Prognosis of asthma in childhood. , 1966, American journal of diseases of children.

[37]  R. Schleimer,et al.  Cutaneous injection of RANTES causes eosinophil recruitment: comparison of nonallergic and allergic human subjects. , 1997, Journal of immunology.

[38]  J. Kieffer,et al.  Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells , 1997, Nature.

[39]  D. Printz,et al.  Skin-associated lymphocytes in the peripheral blood of patients with atopic dermatitis: signs of subset expansion and stimulation. , 1999, The Journal of allergy and clinical immunology.

[40]  L. Koenderman,et al.  Bronchial and skin reactivity in asthmatic patients with and without atopic dermatitis. , 1997, The European respiratory journal.