Joerg Wenzel

Loss-of-Function Mutations in the Keratin 5 Gene Lead to Dowling-Degos Disease

Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation of the flexures. We performed a genomewide linkage analysis of two German families and mapped DDD to chromosome 12q, with a total LOD score of 4.42 ( theta =0.0) for marker D12S368. This region includes the keratin gene cluster, which we screened for mutations. We identified loss-of-function mutations in the keratin 5 gene (KRT5) in all affected family members and in six unrelated patients with DDD. These represent the first identified mutations that lead to haploinsufficiency in a keratin gene. The identification of loss-of-function mutations, along with the results from additional functional studies, suggest a crucial role for keratins in the organization of cell adhesion, melanosome uptake, organelle transport, and nuclear anchorage.

Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus

Recent studies have suggested that type I interferons (IFN) play a role in the pathogenesis of lupus erythematosus (LE), an autoimmune disease of unknown aetiology. Natural interferon‐producing plasmacytoid cells have been demonstrated in cutaneous LE (CLE) lesions, along with elevated levels of IFN‐α mRNA. The hypothesis in the current study was that local production of type I IFNs in CLE induces Th1‐biased inflammation via induction of IFN‐inducible chemokines such as IP10/CXCL10 leading to the recruitment of chemokine receptor CXCR3 expressing T‐cells into skin lesions. Skin biopsies from 21 patients suffering from different types of active cutaneous LE were analysed for the expression of MxA, a protein specifically induced by type I interferons, the IFN‐inducible protein IP10/CXCL10, and the chemokine receptor CXCR3, characteristic for Th1 cells, by immunohistochemistry. Additionally, peripheral CD4+ and CD8+ T‐cells were investigated for the expression of MxA and CXCR3 by flow cytometry. Cutaneous LE lesions were characterized by strong expression of MxA indicating the induction of localized type I IFN signalling in the skin. Large numbers of infiltrating CXCR3 positive lymphocytes were detected in CLE skin lesions, and correlated closely with lesional MxA expression (epidermis: Spearmans ρ = 0.56, p < 0.001; dermis: ρ = 0.82, p < 0.001). Intracellular MxA levels of circulating CD4+ and CD8+ T‐cells were significantly enhanced in patients with active CLE lesions. The percentage of peripheral T‐cells expressing CXCR3 was significantly decreased in specific CLE subtypes. Expression of IP10/CXCL10 in the epidermis links type I IFN signalling and recruitment of CXCR3+ T cells. These results suggest an important role for type I interferon signalling in the pathogenesis of cutaneous lupus erythematosus. It is proposed that type I IFNs induce a Th1‐biased inflammatory immune response, with recruitment of CXCR3‐expressing T‐lymphocytes into the skin. Copyright

Distribution of Langerhans cells and mast cells within the human oral mucosa: new application sites of allergens in sublingual immunotherapy?

Background:  Sublingual immunotherapy (SLIT) represents an alternative to subcutaneous immunotherapy. While antigen‐presenting cells such as Langerhans cells (LCs) are thought to contribute to the effectiveness of SLIT, mast cells (MCs) most likely account for adverse reactions such as sublingual edema. As little is known about LCs and MCs within the oral cavity, we investigated their distribution in search for mucosal sites with highest LCs and lowest MCs density.

Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin‐homing cytotoxic lymphocytes associated with strong expression of the type I interferon‐induced protein MxA

Background  Infiltrating T lymphocytes are considered to play a major pathological role in skin lesions of cutaneous lupus erythematosus (CLE), a cutaneous autoimmune disease of unknown aetiology. Earlier histological studies revealed that the inflammatory infiltrate in CLE skin lesions is predominantly composed of T lymphocytes, with a slight predominance of CD4+ over CD8+ T cells, but failed to explain the development of scarring skin lesions, characteristic for chronic discoid lupus erythematosus (CDLE). Because recent investigations have highlighted the relevance of cytotoxic lymphocytes in autoimmune tissue destruction, we hypothesized that the scarring CDLE lesions might be caused by cytotoxic T lymphocytes.

Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis.

Background.  Dermatomyositis (DM) is an autoimmune disease of unknown origin affecting skin and muscles. Infiltrating autoreactive T lymphocytes are thought to play an important pathogenetic role, but it is unclear which mechanisms are involved in the recruitment of these cells. Recent studies provided evidence that a type I interferon (IFN)‐driven immune response, including the recruitment of T cells via IP10/CXCR3 interactions, might be important for the generation of skin lesions of cutaneous lupus erythematosus (CLE), an autoimmune disease that shares some clinical and histopathological features with DM. We hypothesized that a similar mechanism might also be involved in the pathogenesis of DM skin lesions.

IL-21R is essential for epicutaneous sensitization and allergic skin inflammation in humans and mice

Atopic dermatitis (AD) is a common allergic inflammatory skin disease caused by a combination of intense pruritus, scratching, and epicutaneous (e.c.) sensitization with allergens. To explore the roles of IL-21 and IL-21 receptor (IL-21R) in AD, we examined skin lesions from patients with AD and used a mouse model of allergic skin inflammation. IL-21 and IL-21R expression was upregulated in acute skin lesions of AD patients and in mouse skin subjected to tape stripping, a surrogate for scratching. The importance of this finding was highlighted by the fact that both Il21r-/- mice and WT mice treated with soluble IL-21R-IgG2aFc fusion protein failed to develop skin inflammation after e.c. sensitization of tape-stripped skin. Adoptively transferred OVA-specific WT CD4+ T cells accumulated poorly in draining LNs (DLNs) of e.c. sensitized Il21r-/- mice. This was likely caused by both DC-intrinsic and nonintrinsic effects, because trafficking of skin DCs to DLNs was defective in Il21r-/- mice and, to a lesser extent, in WT mice reconstituted with Il21r-/- BM. More insight into this defect was provided by the observation that skin DCs from tape-stripped WT mice, but not Il21r-/- mice, upregulated CCR7 and migrated toward CCR7 ligands. Treatment of epidermal and dermal cells with IL-21 activated MMP2, which has been implicated in trafficking of skin DCs. These results suggest an important role for IL-21R in the mobilization of skin DCs to DLNs and the subsequent allergic response to e.c. introduced antigen.

Circulating clonal CLA(+) and CD4(+) T cells in Sezary syndrome express the skin-homing chemokine receptors CCR4 and CCR10 as well as the lymph node-homing chemokine receptor CCR7.

Background  Adhesion molecules and chemokine receptors are involved in tissue‐specific homing of T cells to the skin and play an important role in the pathophysiology of cutaneous lymphoma. It has recently been reported that the chemokine CCL27 expressed by keratinocytes attracts lymphocytes bearing the chemokine receptor CCR10.

Type I interferon-associated cytotoxic inflammation in lichen planus

Introduction:  Lichen planus (LP) is an inflammatory autoimmune skin disease of unknown origin. Evidence has accumulated that autoreactive cytotoxic CD8+ T lymphocytes cause destruction of keratinocytes. Recent studies suggested that type I interferons (IFNs) play a central role in cytotoxic skin inflammation by increasing the expression of IP10/CXCR10 and recruiting effector cells via CXCR3. Here, we investigated whether type I IFNs are also involved in the pathogenesis of LP.

Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients

Background  The therapy of cutaneous lupus erythematosus (CLE) is often challenging, especially in patients resistant to topical treatment and established first‐line systemic drugs such as antimalarials. Systemic corticosteroids are effective, but their use is limited due to well‐known side‐effects, especially in long‐term treatment. In recent years several other immunosuppressive agents have been successfully applied in CLE. However, there are no large studies or explicit guidelines on the use of these drugs in CLE.

Role of granulocyte elastase and interleukin-6 in the diagnosis of male genital tract inflammation.

Chronic genital tract inflammations are a frequent cause or at least a concomitant factor of male fertility disturbances. The diagnosis is difficult because of the mostly asymptomatic course of the disease. Therefore, determination of biochemical markers of inflammation in addition to the number of leucocytes in the seminal plasma has been recommended. The aim of the study was to find out whether determination of granulocyte elastase and interleukin‐6 provide comparable and reliable results with regard to diagnosis of genital tract inflammation; in addition, the association between genital tract inflammation and semen quality should be evaluated with special focus on potentially disturbed sperm functions like sperm motility and DNA integrity. In a prospective study, the concentrations of interleukin‐6 (IL‐6) and granulocyte elastase were determined in seminal plasma samples from 340 patients to investigate the relationship with other parameters of genital tract inflammation such as the number of peroxidase‐positive cells and conventional semen parameters. Microbiological investigations were included. As post‐testicular inflammatory influences may cause sperm DNA damage, the correlation between IL‐6 and elastase and DNA integrity was evaluated by the sperm chromatin structure assay. IL‐6 and elastase were significantly correlated both with each other (P < 0.01) and the number of peroxidase‐positive cells (P < 0.01). IL‐6 showed a highly significant negative correlation with sperm vitality (P < 0.01) and a significant negative correlation with sperm motility (P < 0.05). Elastase concentrations were highly significantly associated with the number of peroxidase‐positive cells (P < 0.01) and negatively correlated with sperm vitality (P < 0.01). Moreover, there were significantly negative correlations with sperm motility (P < 0.05), progressive motility according to WHO a quality (P < 0.05) as well as sperm morphology (P < 0.05). In addition, a significant negative correlation was observed between elastase concentrations and percentage of spermatozoa with intact DNA, which may suggest the use of anti‐inflammatory treatment. It can be concluded that both IL‐6 and granulocyte elastase are useful and suitable as markers for silent genital tract inflammation; in contrast to previous contributions there were clear correlations of IL‐6 and granulocyte elastase with sperm parameters, the relationship of elastase with semen quality being more marked. Moreover, the results of the study confirm the need for a change of the threshold value of peroxidase‐positive cells according to WHO definition to lower levels for definition of silent genital tract inflammation.