High recurrence rate of eczema herpeticum in moderate/severe atopic dermatitis -TREATgermany registry analysis.

BACKGROUND: Eczema herpeticum (EH) is a disseminated skin infection caused by herpes simplex virus in atopic dermatitis (AD) patients. The frequency of EH and the clinical features of EH patients have not yet been investigated in a larger cohort. METHODS: We sought to investigate the TREATgermany cohort, a multicenter, non-interventional clinical registry of moderately to severely affected AD patients in Germany. Baseline characteristics of patients included between December 2017 and April 2021 were compared between patients without, single, and multiple EH. RESULTS: Of the 893 patients, 195 (21.8%) had at least one EH. Of the 195 patients with EH, 107 had multiple EH (54.9%), representing 12.0% of the total study population. While there were no differences in demographic characteristics, previous treatment, and disease scores at enrollment (itch, IGA, oSCORAD, EASI), patients with EH had more frequent atopic comorbidities and sensitizations to house dust mite, food, and mold. DISCUSSION: TREATgermany registry data suggest a high prevalence and recurrence rate of EH, while there appears to be no specific clinical phenotype, besides an increase in allergies, to identify EH patients in the daily routine.

Autoallergy in atopic dermatitis.

The term autoallergy denotes autoimmunity accompanying an atopic disease, with antigen-specific IgE as a hallmark. This phenomenon is discussed to contribute to a chronification of the disease and to shape the immune response in chronic atopic dermatitis (AD). In this review, we highlight recent insights into the autoallergic inflammation in AD. Different mechanisms underlying the allergenicity of autoallergens are discussed at the moment: intrinsic functions modulating the immune system as well as molecular mimicry may influence the allergenic potential of these proteins. Finally, the role of specific T cells is discussed. Cite this as: Hradetzky S, Werfel T, Roesner LM. Autoallergy in atopic dermatitis. Allergo J Int 2015; 24:16-22 DOI: 10.1007/s40629-015-0037-5.

RAC1 in keratinocytes regulates crosstalk to immune cells by Arp2/3-dependent control of STAT1.

Crosstalk between keratinocytes and immune cells is crucial for the immunological barrier function of the skin, and aberrant crosstalk contributes to inflammatory skin diseases. Using mice with a keratinocyte-restricted deletion of the RAC1 gene we found that RAC1 in keratinocytes plays an important role in modulating the interferon (IFN) response in skin. These RAC1 mutant mice showed increased sensitivity in an irritant contact dermatitis model, abnormal keratinocyte differentiation, and increased expression of immune response genes including the IFN signal transducer STAT1. Loss of RAC1 in keratinocytes decreased actin polymerization in vivo and in vitro and caused Arp2/3-dependent expression of STAT1, increased interferon sensitivity and upregulation of aberrant keratinocyte differentiation markers. This can be inhibited by the AP-1 inhibitor tanshinone IIA. Loss of RAC1 makes keratinocytes hypersensitive to inflammatory stimuli both in vitro and in vivo, suggesting a major role for RAC1 in regulating the crosstalk between the epidermis and the immune system.

XRCC4 controls nuclear import and distribution of Ligase IV and exchanges faster at damaged DNA in complex with Ligase IV.

Non-homologous end-joining (NHEJ) is one major pathway for the repair of double-stranded DNA breaks in mammals. Following break recognition, alignment and processing, broken DNA ends are finally rejoined by the essential DNA Ligase IV. In the cell, Ligase IV is unable to function without its constitutive interaction partner XRCC4 and becomes unstable when it is missing, and it has been assumed that XRCC4 may also be required for recruitment of Ligase IV to repair sites. To investigate the function of complex formation between both proteins directly in the living cell, we stably expressed them as bio-fluorescent fusion proteins in human HT-1080 cell clones. Ligase IV or XRCC4 were expressed either alone or both were co-expressed at a roughly equimolar ratio. Labelled proteins were overexpressed manifold in comparison to endogenously expressed proteins. We show that over-expressed Ligase IV was only partially imported into the nucleus and showed a diffuse distribution there, whereas XRCC4 expressed alone was entirely nuclear with a distinct exclusion from nucleoli. When Ligase IV was co-expressed with XRCC4, both proteins formed the natural complex, and Ligase IV was not only efficiently imported but also resembled the sub-nuclear distribution of XRCC4. In addition, Ligase IV, when in complex with XRCC4, acquired a delayed nuclear reimport after mitotic cell division of XRCC4. We further determined by photobleaching the kinetics with which the proteins exchange at UVA laser-irradiated nuclear sites between damage-bound and diffusing states. We found that the dynamic exchange rate of the Ligase IV/XRCC4 complex at micro-irradiated sites was faster than that of XRCC4 expressed alone. In summary, our findings demonstrate a novel function of XRCC4 in controlling nuclear import and sub-nuclear distribution of Ligase IV, and they suggest that XRCC4 modulates the dynamic interaction of the Ligase IV/XRCC4 complex with the NHEJ machinery at double-stranded DNA breaks.