{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:42:04Z","timestamp":1768506124277,"version":"3.49.0"},"posted":{"date-parts":[[2023,2,28]]},"group-title":"Molecular Biology","reference-count":67,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,2,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>A subgroup of atopic dermatitis (AD) patients suffer from recurrent, disseminated herpes simplex virus (HSV) skin infections, termed eczema herpeticum (EH), which can be life-threatening and contribute to AD morbidity. The pathobiology underlying ADEH is unknown.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>To determine transcriptional mechanisms of skin and immune system pathobiology that underlie ADEH disease.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    We performed whole transcriptome RNA-sequencing of non-lesional skin samples (epidermis, dermis) of AD patients with (ADEH\n                    <jats:sup>+<\/jats:sup>\n                    , n=15) and without (ADEH\n                    <jats:sup>-<\/jats:sup>\n                    , n=13) recurrent EH history, and healthy controls (HC, n=15). We also performed RNA-sequencing on plasmacytoid dendritic cells (pDCs) collected from these participants and infected\n                    <jats:italic>in vitro<\/jats:italic>\n                    with HSV-1. Differential expression, gene set enrichment, and endotyping analyses were performed.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    ADEH\n                    <jats:sup>+<\/jats:sup>\n                    disease was characterized by dysregulation in skin gene expression, which was limited in dermis (differentially expressed genes [DEGs]=14) and widespread in epidermis (DEGs=129). ADEH\n                    <jats:sup>+<\/jats:sup>\n                    -upregulated epidermal DEGs were enriched in type 2 cytokine (T2) (\n                    <jats:italic>IL4R, CCL22, CRLF2, IL7R<\/jats:italic>\n                    ), interferon (\n                    <jats:italic>CXCL10, ICAM1, IFI44<\/jats:italic>\n                    , and\n                    <jats:italic>IRF7)<\/jats:italic>\n                    , and IL-36\u03b3 (\n                    <jats:italic>IL36G<\/jats:italic>\n                    ) inflammatory pathway genes. At a person-level, all ADEH\n                    <jats:sup>+<\/jats:sup>\n                    participants exhibited T2 and interferon endotypes and 87% were IL36G-high. In contrast, these endotypes were more variably expressed among ADEH\n                    <jats:sup>-<\/jats:sup>\n                    participants. ADEH\n                    <jats:sup>+<\/jats:sup>\n                    patient skin also exhibited dysregulation in epidermal differentiation complex (EDC) genes within the\n                    <jats:italic>LCE, S100<\/jats:italic>\n                    , and\n                    <jats:italic>SPRR<\/jats:italic>\n                    families, which are involved in skin barrier function, inflammation, and antimicrobial activities. pDC transcriptional responses to HSV-1 infection were not altered by ADEH status.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>\n                    ADEH\n                    <jats:sup>+<\/jats:sup>\n                    pathobiology is characterized by a unique, multi-faceted epidermal inflammation that accompanies dysregulation in the expression of EDC genes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Messages<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>AD patients with a history of recurrent EH exhibit molecular skin pathobiology that is similar in form, but more severe in degree, than in AD patients without this complication.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Non-lesional skin of ADEH\n                        <jats:sup>+<\/jats:sup>\n                        patients concurrently exhibits excessive type 2 cytokine, interferon, and IL-36\u03b3-driven epidermal inflammation.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Expression of these inflammatory skin endotypes among ADEH\n                        <jats:sup>+<\/jats:sup>\n                        patients is associated with dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Capsule Summary<\/jats:title>\n                  <jats:p>AD patients with a history of recurrent disseminated HSV-1 skin infections form a unique molecular skin endotype group that concurrently exhibits type 2 cytokine, interferon, and IL-36\u03b3-driven skin inflammation, accompanied by dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity.<\/jats:p>\n                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