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. 2022 Jun 15;23(12):6682. doi: 10.3390/ijms23126682

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© 2022 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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(a). Schematic illustration of non-lesioned skin and the positive-reaction site of atopy patch test in IgE-allergic AD. In non-lesioned skin, IgE-expressing LCs are regularly arranged in preparation for allergen/antigen invasion of the epidermis, and both Th2 (IL-4– or IL-13-expressing) and Th1 (INF-γ-expressing) cells and T cytotoxic (INF-γ-expressing CD8+) cells are increased among dermal infiltrating cells. IDECs are not found in the epidermis, and inflammatory DCs expressing IgE are almost undetectable in the dermis. Allergens such as HDMs are rarely observed in the dermis and epidermis by histopathological analysis. In the APT-positive reaction site for allergens (e.g., HDMs and pollens), spongiotic dermatitis is observed as a characteristic finding. Therefore, this characteristic has been used in pathological analysis as a prototype of acute AD lesions that reflect IgE-mediated delayed-type hypersensitivity. Considering the APT for HDM antigens in IgE-allergic AD, the following characteristics have been revealed: HDM antigens are initially captured primarily by IgE+ LCs; at 48 h after application, spongiosis formation in the epidermis and infiltration of lymphocytes and macrophages accompanied by basophils and eosinophils in the upper dermis are observed; keratinocytes secrete TSLP and induce the production of the Th2 cytokine CCL17 by DCs (probably LCs); penetrated HDM antigens are also captured by MCs, eosinophils, and macrophages, and the activated macrophages secrete IL-12, which induces the recruitment of Th1 cells; IgE+ IDECs become apparent in the upper dermis and aggregate inside the spongiosis lesion; in early spongiosis, both HDM antigen-capturing IgE+ IDECs and IgE+ LCs are seen in the epidermal DC aggregates; infiltrating lymphocytes are primarily CD4+ T cells, but some are CD4+ CD25+ FOXP3+ T cells with regulatory functions; and keratinocyte apoptosis possibly induced by IFN-γ-secreting Th1 cells and the Fas/FasL system is the key reaction in spongiosis formation. (b). Schematic illustration of areas of spongiotic dermatitis and non-spongiotic dermatitis in lichenified eczema of IgE-allergic AD. Lichenified eczema develops as a chronic inflammatory skin lesion caused by the interaction between cytokine/chemokine activation by innate immunity and allergic inflammation. In this state, to prepare for capturing allergens invading through the impaired epidermal barrier, IgE+ LCs are present in the middle to upper epidermis, and IgE+ IDECs are present in the lower epidermis, and IgE+ LCs primarily react to the allergens (non-spongiotic epidermis; both outer parts of the schematic). Following the introduction of several inducing factors, spongiosis dermatitis reflecting IgE-mediated delayed-type hypersensitivity may occur as an acute lesion in lichenified eczema (spongiotic epidermis; central part of the schematic illustration). The following pathomechanism is possible: IgE+ LCs and IgE+ IDECs that capture allergens (e.g., HDMs) become activated, and the IgE+ IDECs gather in the central area of the spongiosis lesion and form an epidermal DC aggregate; the IgE+ epidermal DCs (i.e., LCs and IDECs) induce the infiltration of allergen-specific CD4+ T cells in the spongiotic epidermis; the Fas/FasL system is induced by the interactions between the IgE+ epidermal DCs, activated CD4+ T cells, and keratinocytes to induce the expression of TNF-α, INF-γ, Fas ligand, and Fas receptor (CD95); cell-mediated cytotoxicity is also induced by perforin and granzyme B, which are primarily released by CD8+ T cells; keratinocyte apoptosis is the key reaction in the development of spongiosis lesions and progresses to completion under control of the Fas/FasL system, cell-mediated cytotoxicity, and T cells with regulatory function. Abbreviations: AD, atopic dermatitis; APT, atopy patch test; CD, cluster of differentiation; DC, dendritic cell; DDC, dermal dendritic cell; DIDC, dermal inflammatory dendritic cell; FasL, Fas-ligand; FcεRI, high-affinity IgE receptor; FOXP3, Forkhead box protein P3; HDMs, house dust mites; IDEC, inflammatory dendritic epidermal cell; IgE, immunoglobulin E; IL, interleukin; IFN, interferon; LC, Langerhans cell; MC, mast cell; MHC, major histocompatibility complex; S. aureus, Staphylococcus aureus; Th, T helper; TNF, tumor necrosis factor; and TSLP, thymic stromal lymphopoietin.

(a). Schematic illustration of non-lesioned skin and the positive-reaction site of atopy patch test in IgE-allergic AD. In non-lesioned skin, IgE-expressing LCs are regularly arranged in preparation for allergen/antigen invasion of the epidermis, and both Th2 (IL-4– or IL-13-expressing) and Th1 (INF-γ-expressing) cells and T cytotoxic (INF-γ-expressing CD8+) cells are increased among dermal infiltrating cells. IDECs are not found in the epidermis, and inflammatory DCs expressing IgE are almost undetectable in the dermis. Allergens such as HDMs are rarely observed in the dermis and epidermis by histopathological analysis. In the APT-positive reaction site for allergens (e.g., HDMs and pollens), spongiotic dermatitis is observed as a characteristic finding. Therefore, this characteristic has been used in pathological analysis as a prototype of acute AD lesions that reflect IgE-mediated delayed-type hypersensitivity. Considering the APT for HDM antigens in IgE-allergic AD, the following characteristics have been revealed: HDM antigens are initially captured primarily by IgE+ LCs; at 48 h after application, spongiosis formation in the epidermis and infiltration of lymphocytes and macrophages accompanied by basophils and eosinophils in the upper dermis are observed; keratinocytes secrete TSLP and induce the production of the Th2 cytokine CCL17 by DCs (probably LCs); penetrated HDM antigens are also captured by MCs, eosinophils, and macrophages, and the activated macrophages secrete IL-12, which induces the recruitment of Th1 cells; IgE+ IDECs become apparent in the upper dermis and aggregate inside the spongiosis lesion; in early spongiosis, both HDM antigen-capturing IgE+ IDECs and IgE+ LCs are seen in the epidermal DC aggregates; infiltrating lymphocytes are primarily CD4+ T cells, but some are CD4+ CD25+ FOXP3+ T cells with regulatory functions; and keratinocyte apoptosis possibly induced by IFN-γ-secreting Th1 cells and the Fas/FasL system is the key reaction in spongiosis formation. (b). Schematic illustration of areas of spongiotic dermatitis and non-spongiotic dermatitis in lichenified eczema of IgE-allergic AD. Lichenified eczema develops as a chronic inflammatory skin lesion caused by the interaction between cytokine/chemokine activation by innate immunity and allergic inflammation. In this state, to prepare for capturing allergens invading through the impaired epidermal barrier, IgE+ LCs are present in the middle to upper epidermis, and IgE+ IDECs are present in the lower epidermis, and IgE+ LCs primarily react to the allergens (non-spongiotic epidermis; both outer parts of the schematic). Following the introduction of several inducing factors, spongiosis dermatitis reflecting IgE-mediated delayed-type hypersensitivity may occur as an acute lesion in lichenified eczema (spongiotic epidermis; central part of the schematic illustration). The following pathomechanism is possible: IgE+ LCs and IgE+ IDECs that capture allergens (e.g., HDMs) become activated, and the IgE+ IDECs gather in the central area of the spongiosis lesion and form an epidermal DC aggregate; the IgE+ epidermal DCs (i.e., LCs and IDECs) induce the infiltration of allergen-specific CD4+ T cells in the spongiotic epidermis; the Fas/FasL system is induced by the interactions between the IgE+ epidermal DCs, activated CD4+ T cells, and keratinocytes to induce the expression of TNF-α, INF-γ, Fas ligand, and Fas receptor (CD95); cell-mediated cytotoxicity is also induced by perforin and granzyme B, which are primarily released by CD8+ T cells; keratinocyte apoptosis is the key reaction in the development of spongiosis lesions and progresses to completion under control of the Fas/FasL system, cell-mediated cytotoxicity, and T cells with regulatory function. Abbreviations: AD, atopic dermatitis; APT, atopy patch test; CD, cluster of differentiation; DC, dendritic cell; DDC, dermal dendritic cell; DIDC, dermal inflammatory dendritic cell; FasL, Fas-ligand; FcεRI, high-affinity IgE receptor; FOXP3, Forkhead box protein P3; HDMs, house dust mites; IDEC, inflammatory dendritic epidermal cell; IgE, immunoglobulin E; IL, interleukin; IFN, interferon; LC, Langerhans cell; MC, mast cell; MHC, major histocompatibility complex; S. aureus, Staphylococcus aureus; Th, T helper; TNF, tumor necrosis factor; and TSLP, thymic stromal lymphopoietin.