Tacrolimus: A new topical immunomodulatory therapy for atopic dermatitis

Abstract

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease in which both inherited and environmental factors play a role in maintaining and exacerbating the condition.1Leung DYM Atopic dermatitis: new insights and opportunities for therapeutic intervention.J Allergy Clin Immunol. 2000; 105: 860-876Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar Treatment options are few, with topical corticosteroids being the principal treatment for acute episodes. Secondary treatments with UV light irradiation or immune suppressive drugs generally do not replace topical corticosteroids but rather act as steroid-sparing therapies. The development of new corticosteroid preparations, with an aim to reduce side effects, has not significantly changed the benefit-risk ratio. The side effects of topical cortico-steroids relate to the wide distribution of steroid-responsive elements in various cells and tissues. In general, the most clinically relevant are atrophogenicity, growth retardation in children, poor long-term control of AD, and, in some patients, therapeutic resistance.Tacrolimus ointment, which recently received marketing approval in the United States under the trade name Protopic, offers the first new therapy for AD. Clinical studies performed in Europe, Japan, and the United States have shown short- and long-term therapy with tacrolimus ointment to be effective and safe for adults and children with moderate-to-severe AD.2Nakagawa H Etoh T Ishibashi Y et al.Tacrolimus ointment for atopic dermatitis.Lancet. 1994; 344: 883Abstract PubMed Scopus (222) Google Scholar, 3Boguniewicz M Fiedler VC Raimer S Lawrence ID Leung DY Hanifin JM A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children.J Allergy Clin Immunol. 1998; 102: 637-644Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 4Ruzicka T Bieber T Schöpf E et al.A short-term trial of tacrolimus ointment for atopic dermatitis.N Engl J Med. 1997; 337: 816-821Crossref PubMed Scopus (508) Google Scholar, 5Reitamo S Wollenberg A Schöpf E et al.Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis.Arch Dermatol. 2000; 136: 999-1006Crossref PubMed Scopus (365) Google Scholar A major advantage over topical corticosteroid therapy is that skin atrophy does not occur.6Reitamo S Rissanen J Remitz A et al.Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial.J Invest Dermatol. 1998; 111: 396-398Crossref PubMed Scopus (251) Google Scholar Tacrolimus ointment targets the local immune pathology of AD. The absence of a systemic effect is supported by minimal systemic exposure and by clinical findings that show no apparent increased risk of cutaneous or systemic infections.4Ruzicka T Bieber T Schöpf E et al.A short-term trial of tacrolimus ointment for atopic dermatitis.N Engl J Med. 1997; 337: 816-821Crossref PubMed Scopus (508) Google Scholar, 5Reitamo S Wollenberg A Schöpf E et al.Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis.Arch Dermatol. 2000; 136: 999-1006Crossref PubMed Scopus (365) Google Scholar, 7Alaiti S Kang S Fiedler C et al.Tacrolimus (FK506) 0.3% ointment for atopic dermatitis: a phase I study in adults and children.J Am Acad Dermatol. 1998; 38: 9-76Abstract Full Text Full Text PDF Scopus (189) Google Scholar It is also of interest to note that long-term use of tacrolimus ointment in adult patients with AD did not reduce cell-mediated immunity, as assessed in the Recall Antigen Test,5Reitamo S Wollenberg A Schöpf E et al.Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis.Arch Dermatol. 2000; 136: 999-1006Crossref PubMed Scopus (365) Google Scholar and was associated with a decrease in staphylococcal colonization.8Remitz A Kyllönen H Granlund H Reitamo S. Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions.J Allergy Clin Immunol. 2001; 107 ([letter]): 196Abstract Full Text PDF PubMed Scopus (117) Google ScholarImmune pathology of AD and therapy aimed at local immune modulationTacrolimus blocks this process by binding to the FK506-binding protein, a 12-kd macrophilin (Fig 1, B ). The FK506-binding protein/tacrolimus complex inhibits calcineurin and thereby the dephosphorylation of NF-ATp and expression of inflammatory T-cell cytokines, such as IL-2, IL-3, IL-4, IL-5, GM-CSF, IFN-γ, and TNF-α.12Goto T Kino T Hatanaka H et al.Discovery of FK-506, a novel immunosuppressant isolated from Streptomyces Tsukubaensis.Transplant Proc. 1987; 19: 4-8PubMed Google Scholar, 13Tocci MJ Markovich DA Collier KA et al.The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes.J Immunol. 1989; 143: 718-726PubMed Google Scholar In vitro studies have also shown that tacrolimus, through a mechanism that involves binding to the FK506-binding protein, also inhibits the release of inflammatory mediators from mast cells and basophils.14De Paulis A Stellato C Cirillo R Ciccarelli A Oriente A Marone G Anti-inflammatory effect of FK506 on human skin mast cells.J Invest Dermatol. 1992; 99: 723-728Abstract Full Text PDF PubMed Google ScholarIn the February issue of the Journal, Panhans-Groß et al15Panhans-Groß A Novak N Kraft S Bieber T. Human epidermal Langerhans cells are targets for the immunosuppressive macrolide tacrolimus (FK506).J Allergy Clin Immunol. 2001; 107: 345-352Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar showed that in vitro tacrolimus downregulated the expression of FcϵRI (Fig 1, B ), whereas betamethasone upregulated its expression. Earlier, AD was shown to be characterized by strong expression of FcϵRI on antigen-presenting epidermal dendritic cells (ie, LCs and related CD1a+ dendritic cells).11Wollenberg A Kraft S Hanau D Bieber T Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema.J Invest Dermatol. 1996; 106: 446-453Crossref PubMed Scopus (342) Google Scholar Thus the downregulation of FcϵRI by tacrolimus is of potential clinical significance in the therapy of AD. It would be of interest to assess whether the action of tacrolimus on FcϵRI depends on NF-ATp. LCs have been thought to originate from myeloid precursors; however, a recent study suggests they are more closely related to lymphoid precursors.16Anjuere F del Hoyo GM Martin P Ardavin C Langerhans cells develop from a lymphoid precursor.Blood. 2000; 96: 1633-1667PubMed Google Scholar Thus it is possible that their activation shares features in common with T-cell activation, such as dependence on calcineurin in the activation of a FcϵRI-specific transcription factor.In the present issue of the Journal, Wollenberg et al17Wollenberg A Sharma S von Bubnoff D Geiger E Haberstok J Bieber T Topical tacroilmus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen presenting dendritic cells in atopic dermatitis.J Allergy Clin Immunol. 2001; 107: 519-525Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar describe an in vivo intervention study with topical tacrolimus. An increased proportion of CD1a+ cells in the epidermis of AD lesions decreased to normal during clinical improvement with tacrolimus ointment. The CD1a+ population consisted of LCs and inflammatory dendritic epidermal cells (IDECs). An analysis of the relative proportion of these cell types showed that the decrease in CD1a+ cells was mainly caused by a decrease in IDECs. The reduction in CD1a+ cells during treatment with tacrolimus ointment was associated with downregulation of FcϵRI expression in both IDECs and LCs. The authors concluded that the CD1a+ dendritic cells could represent a target of tacrolimus in AD therapy.Is IgE central to ad and its therapy?As assessed by the proportion of patients with AD who have elevated serum IgE levels, approximately 80% have extrinsic AD, and approximately 20% have an intrinsic (non-IgE-related) form of the disease.18Werfel T Kapp A. What do we know about the etiopathology of the intrinsic type of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 29-36Google Scholar One proposed explanation for the cause of AD in patients with intrinsic AD is that enterotoxins released by Staphylococcus aureus act as superantigens, which, independently of IgE, promote the release of proinflammatory molecules, such as IL-1 and TNF-α, from monocytes and dendritic cells and activate T cells. There is also evidence indicating that allergen-specific T cells, independently of IgE, play a role in the immune pathology of intrinsic AD.18Werfel T Kapp A. What do we know about the etiopathology of the intrinsic type of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 29-36Google Scholar, 19Akdis CA Akdis M Simon D et al.Role of T cells and cytokines in the intrinsic form of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 37-44Google Scholar T cells are equally important in extrinsic AD. Increased IL-13 expression by T cells from lesions of patients with extrinsic AD is considered to account for increased IgE production through stimulation of B cells.19Akdis CA Akdis M Simon D et al.Role of T cells and cytokines in the intrinsic form of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 37-44Google Scholar It seems feasible that allergen-specific T cells can serve as a triggering factor in extrinsic, as well as intrinsic, AD.Fig. 2A 27-year-old patient who was insensitive to topical corticosteroid therapy quickly responded to 0.03% tacrolimus ointment. Left, Before treatment with 0.03% tacrolimus; right, 48 hours after application of 0.03% tacrolimus.View Large Image Figure ViewerDownload Hi-res image Download (PPT)There remains the question of what came first, the chicken or the egg. FcϵRI and IgE certainly play an important role in the immune pathology of AD in that they are required for optimal activation of T cells, but do they represent the principal anomaly in AD? The fact that AD can persist without apparent involvement of IgE (eg, in intrinsic AD) and that antigen processing by LCs seems not to be essential for T-cell activation (eg, in S aureus superantigen-induced T-cell proliferation) suggests that other possibilities should be considered. This is an exciting area of research, with research into the mechanism of action of tacrolimus perhaps leading to important discoveries about the immune pathology of AD and, more importantly, improved treatment for this common and debilitating skin disease. Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease in which both inherited and environmental factors play a role in maintaining and exacerbating the condition.1Leung DYM Atopic dermatitis: new insights and opportunities for therapeutic intervention.J Allergy Clin Immunol. 2000; 105: 860-876Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar Treatment options are few, with topical corticosteroids being the principal treatment for acute episodes. Secondary treatments with UV light irradiation or immune suppressive drugs generally do not replace topical corticosteroids but rather act as steroid-sparing therapies. The development of new corticosteroid preparations, with an aim to reduce side effects, has not significantly changed the benefit-risk ratio. The side effects of topical cortico-steroids relate to the wide distribution of steroid-responsive elements in various cells and tissues. In general, the most clinically relevant are atrophogenicity, growth retardation in children, poor long-term control of AD, and, in some patients, therapeutic resistance. Tacrolimus ointment, which recently received marketing approval in the United States under the trade name Protopic, offers the first new therapy for AD. Clinical studies performed in Europe, Japan, and the United States have shown short- and long-term therapy with tacrolimus ointment to be effective and safe for adults and children with moderate-to-severe AD.2Nakagawa H Etoh T Ishibashi Y et al.Tacrolimus ointment for atopic dermatitis.Lancet. 1994; 344: 883Abstract PubMed Scopus (222) Google Scholar, 3Boguniewicz M Fiedler VC Raimer S Lawrence ID Leung DY Hanifin JM A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children.J Allergy Clin Immunol. 1998; 102: 637-644Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 4Ruzicka T Bieber T Schöpf E et al.A short-term trial of tacrolimus ointment for atopic dermatitis.N Engl J Med. 1997; 337: 816-821Crossref PubMed Scopus (508) Google Scholar, 5Reitamo S Wollenberg A Schöpf E et al.Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis.Arch Dermatol. 2000; 136: 999-1006Crossref PubMed Scopus (365) Google Scholar A major advantage over topical corticosteroid therapy is that skin atrophy does not occur.6Reitamo S Rissanen J Remitz A et al.Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial.J Invest Dermatol. 1998; 111: 396-398Crossref PubMed Scopus (251) Google Scholar Tacrolimus ointment targets the local immune pathology of AD. The absence of a systemic effect is supported by minimal systemic exposure and by clinical findings that show no apparent increased risk of cutaneous or systemic infections.4Ruzicka T Bieber T Schöpf E et al.A short-term trial of tacrolimus ointment for atopic dermatitis.N Engl J Med. 1997; 337: 816-821Crossref PubMed Scopus (508) Google Scholar, 5Reitamo S Wollenberg A Schöpf E et al.Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis.Arch Dermatol. 2000; 136: 999-1006Crossref PubMed Scopus (365) Google Scholar, 7Alaiti S Kang S Fiedler C et al.Tacrolimus (FK506) 0.3% ointment for atopic dermatitis: a phase I study in adults and children.J Am Acad Dermatol. 1998; 38: 9-76Abstract Full Text Full Text PDF Scopus (189) Google Scholar It is also of interest to note that long-term use of tacrolimus ointment in adult patients with AD did not reduce cell-mediated immunity, as assessed in the Recall Antigen Test,5Reitamo S Wollenberg A Schöpf E et al.Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis.Arch Dermatol. 2000; 136: 999-1006Crossref PubMed Scopus (365) Google Scholar and was associated with a decrease in staphylococcal colonization.8Remitz A Kyllönen H Granlund H Reitamo S. Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions.J Allergy Clin Immunol. 2001; 107 ([letter]): 196Abstract Full Text PDF PubMed Scopus (117) Google Scholar Immune pathology of AD and therapy aimed at local immune modulationTacrolimus blocks this process by binding to the FK506-binding protein, a 12-kd macrophilin (Fig 1, B ). The FK506-binding protein/tacrolimus complex inhibits calcineurin and thereby the dephosphorylation of NF-ATp and expression of inflammatory T-cell cytokines, such as IL-2, IL-3, IL-4, IL-5, GM-CSF, IFN-γ, and TNF-α.12Goto T Kino T Hatanaka H et al.Discovery of FK-506, a novel immunosuppressant isolated from Streptomyces Tsukubaensis.Transplant Proc. 1987; 19: 4-8PubMed Google Scholar, 13Tocci MJ Markovich DA Collier KA et al.The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes.J Immunol. 1989; 143: 718-726PubMed Google Scholar In vitro studies have also shown that tacrolimus, through a mechanism that involves binding to the FK506-binding protein, also inhibits the release of inflammatory mediators from mast cells and basophils.14De Paulis A Stellato C Cirillo R Ciccarelli A Oriente A Marone G Anti-inflammatory effect of FK506 on human skin mast cells.J Invest Dermatol. 1992; 99: 723-728Abstract Full Text PDF PubMed Google ScholarIn the February issue of the Journal, Panhans-Groß et al15Panhans-Groß A Novak N Kraft S Bieber T. Human epidermal Langerhans cells are targets for the immunosuppressive macrolide tacrolimus (FK506).J Allergy Clin Immunol. 2001; 107: 345-352Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar showed that in vitro tacrolimus downregulated the expression of FcϵRI (Fig 1, B ), whereas betamethasone upregulated its expression. Earlier, AD was shown to be characterized by strong expression of FcϵRI on antigen-presenting epidermal dendritic cells (ie, LCs and related CD1a+ dendritic cells).11Wollenberg A Kraft S Hanau D Bieber T Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema.J Invest Dermatol. 1996; 106: 446-453Crossref PubMed Scopus (342) Google Scholar Thus the downregulation of FcϵRI by tacrolimus is of potential clinical significance in the therapy of AD. It would be of interest to assess whether the action of tacrolimus on FcϵRI depends on NF-ATp. LCs have been thought to originate from myeloid precursors; however, a recent study suggests they are more closely related to lymphoid precursors.16Anjuere F del Hoyo GM Martin P Ardavin C Langerhans cells develop from a lymphoid precursor.Blood. 2000; 96: 1633-1667PubMed Google Scholar Thus it is possible that their activation shares features in common with T-cell activation, such as dependence on calcineurin in the activation of a FcϵRI-specific transcription factor.In the present issue of the Journal, Wollenberg et al17Wollenberg A Sharma S von Bubnoff D Geiger E Haberstok J Bieber T Topical tacroilmus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen presenting dendritic cells in atopic dermatitis.J Allergy Clin Immunol. 2001; 107: 519-525Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar describe an in vivo intervention study with topical tacrolimus. An increased proportion of CD1a+ cells in the epidermis of AD lesions decreased to normal during clinical improvement with tacrolimus ointment. The CD1a+ population consisted of LCs and inflammatory dendritic epidermal cells (IDECs). An analysis of the relative proportion of these cell types showed that the decrease in CD1a+ cells was mainly caused by a decrease in IDECs. The reduction in CD1a+ cells during treatment with tacrolimus ointment was associated with downregulation of FcϵRI expression in both IDECs and LCs. The authors concluded that the CD1a+ dendritic cells could represent a target of tacrolimus in AD therapy. Tacrolimus blocks this process by binding to the FK506-binding protein, a 12-kd macrophilin (Fig 1, B ). The FK506-binding protein/tacrolimus complex inhibits calcineurin and thereby the dephosphorylation of NF-ATp and expression of inflammatory T-cell cytokines, such as IL-2, IL-3, IL-4, IL-5, GM-CSF, IFN-γ, and TNF-α.12Goto T Kino T Hatanaka H et al.Discovery of FK-506, a novel immunosuppressant isolated from Streptomyces Tsukubaensis.Transplant Proc. 1987; 19: 4-8PubMed Google Scholar, 13Tocci MJ Markovich DA Collier KA et al.The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes.J Immunol. 1989; 143: 718-726PubMed Google Scholar In vitro studies have also shown that tacrolimus, through a mechanism that involves binding to the FK506-binding protein, also inhibits the release of inflammatory mediators from mast cells and basophils.14De Paulis A Stellato C Cirillo R Ciccarelli A Oriente A Marone G Anti-inflammatory effect of FK506 on human skin mast cells.J Invest Dermatol. 1992; 99: 723-728Abstract Full Text PDF PubMed Google Scholar In the February issue of the Journal, Panhans-Groß et al15Panhans-Groß A Novak N Kraft S Bieber T. Human epidermal Langerhans cells are targets for the immunosuppressive macrolide tacrolimus (FK506).J Allergy Clin Immunol. 2001; 107: 345-352Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar showed that in vitro tacrolimus downregulated the expression of FcϵRI (Fig 1, B ), whereas betamethasone upregulated its expression. Earlier, AD was shown to be characterized by strong expression of FcϵRI on antigen-presenting epidermal dendritic cells (ie, LCs and related CD1a+ dendritic cells).11Wollenberg A Kraft S Hanau D Bieber T Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema.J Invest Dermatol. 1996; 106: 446-453Crossref PubMed Scopus (342) Google Scholar Thus the downregulation of FcϵRI by tacrolimus is of potential clinical significance in the therapy of AD. It would be of interest to assess whether the action of tacrolimus on FcϵRI depends on NF-ATp. LCs have been thought to originate from myeloid precursors; however, a recent study suggests they are more closely related to lymphoid precursors.16Anjuere F del Hoyo GM Martin P Ardavin C Langerhans cells develop from a lymphoid precursor.Blood. 2000; 96: 1633-1667PubMed Google Scholar Thus it is possible that their activation shares features in common with T-cell activation, such as dependence on calcineurin in the activation of a FcϵRI-specific transcription factor. In the present issue of the Journal, Wollenberg et al17Wollenberg A Sharma S von Bubnoff D Geiger E Haberstok J Bieber T Topical tacroilmus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen presenting dendritic cells in atopic dermatitis.J Allergy Clin Immunol. 2001; 107: 519-525Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar describe an in vivo intervention study with topical tacrolimus. An increased proportion of CD1a+ cells in the epidermis of AD lesions decreased to normal during clinical improvement with tacrolimus ointment. The CD1a+ population consisted of LCs and inflammatory dendritic epidermal cells (IDECs). An analysis of the relative proportion of these cell types showed that the decrease in CD1a+ cells was mainly caused by a decrease in IDECs. The reduction in CD1a+ cells during treatment with tacrolimus ointment was associated with downregulation of FcϵRI expression in both IDECs and LCs. The authors concluded that the CD1a+ dendritic cells could represent a target of tacrolimus in AD therapy. Is IgE central to ad and its therapy?As assessed by the proportion of patients with AD who have elevated serum IgE levels, approximately 80% have extrinsic AD, and approximately 20% have an intrinsic (non-IgE-related) form of the disease.18Werfel T Kapp A. What do we know about the etiopathology of the intrinsic type of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 29-36Google Scholar One proposed explanation for the cause of AD in patients with intrinsic AD is that enterotoxins released by Staphylococcus aureus act as superantigens, which, independently of IgE, promote the release of proinflammatory molecules, such as IL-1 and TNF-α, from monocytes and dendritic cells and activate T cells. There is also evidence indicating that allergen-specific T cells, independently of IgE, play a role in the immune pathology of intrinsic AD.18Werfel T Kapp A. What do we know about the etiopathology of the intrinsic type of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 29-36Google Scholar, 19Akdis CA Akdis M Simon D et al.Role of T cells and cytokines in the intrinsic form of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 37-44Google Scholar T cells are equally important in extrinsic AD. Increased IL-13 expression by T cells from lesions of patients with extrinsic AD is considered to account for increased IgE production through stimulation of B cells.19Akdis CA Akdis M Simon D et al.Role of T cells and cytokines in the intrinsic form of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 37-44Google Scholar It seems feasible that allergen-specific T cells can serve as a triggering factor in extrinsic, as well as intrinsic, AD.There remains the question of what came first, the chicken or the egg. FcϵRI and IgE certainly play an important role in the immune pathology of AD in that they are required for optimal activation of T cells, but do they represent the principal anomaly in AD? The fact that AD can persist without apparent involvement of IgE (eg, in intrinsic AD) and that antigen processing by LCs seems not to be essential for T-cell activation (eg, in S aureus superantigen-induced T-cell proliferation) suggests that other possibilities should be considered. This is an exciting area of research, with research into the mechanism of action of tacrolimus perhaps leading to important discoveries about the immune pathology of AD and, more importantly, improved treatment for this common and debilitating skin disease. As assessed by the proportion of patients with AD who have elevated serum IgE levels, approximately 80% have extrinsic AD, and approximately 20% have an intrinsic (non-IgE-related) form of the disease.18Werfel T Kapp A. What do we know about the etiopathology of the intrinsic type of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 29-36Google Scholar One proposed explanation for the cause of AD in patients with intrinsic AD is that enterotoxins released by Staphylococcus aureus act as superantigens, which, independently of IgE, promote the release of proinflammatory molecules, such as IL-1 and TNF-α, from monocytes and dendritic cells and activate T cells. There is also evidence indicating that allergen-specific T cells, independently of IgE, play a role in the immune pathology of intrinsic AD.18Werfel T Kapp A. What do we know about the etiopathology of the intrinsic type of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 29-36Google Scholar, 19Akdis CA Akdis M Simon D et al.Role of T cells and cytokines in the intrinsic form of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 37-44Google Scholar T cells are equally important in extrinsic AD. Increased IL-13 expression by T cells from lesions of patients with extrinsic AD is considered to account for increased IgE production through stimulation of B cells.19Akdis CA Akdis M Simon D et al.Role of T cells and cytokines in the intrinsic form of atopic dermatitis.in: The atopy syndrome in the third millennium. Karger, Basel1999: 37-44Google Scholar It seems feasible that allergen-specific T cells can serve as a triggering factor in extrinsic, as well as intrinsic, AD. There remains the question of what came first, the chicken or the egg. FcϵRI and IgE certainly play an important role in the immune pathology of AD in that they are required for optimal activation of T cells, but do they represent the principal anomaly in AD? The fact that AD can persist without apparent involvement of IgE (eg, in intrinsic AD) and that antigen processing by LCs seems not to be essential for T-cell activation (eg, in S aureus superantigen-induced T-cell proliferation) suggests that other possibilities should be considered. This is an exciting area of research, with research into the mechanism of action of tacrolimus perhaps leading to important discoveries about the immune pathology of AD and, more importantly, improved treatment for this common and debilitating skin disease.