T.J. Stoof

Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation

Recruitment of activated T‐cells to the skin is a common feature in a wide variety of inflammatory skin diseases. As CXCR3 activating chemokines CXCL10 (IP‐10), CXCL9 (Mig), and CXCL11 (IP‐9/I‐TAC) specifically attract activated T‐cells, this study addressed the question of whether differences in the expression of these chemokines correlate with the site and cellular composition of the skin infiltrates in different types of inflammatory skin disease. Skin biopsies from lichen planus, chronic discoid lupus erythematosus, allergic patch test reactions, psoriasis, and Jessners lymphocytic infiltration of the skin were investigated for chemokine expression using RNA in situ hybridization, and for the expression of CXCR3 using immunohistochemistry. The results showed differential expression of CXCL10, CXCL9, and CXCL11, which correlated with differences in the localization and cellular composition of the infiltrates. Whereas CXCL10 and CXCL11 were mainly expressed by basal keratinoctyes, CXCL9 mRNA expression was located predominantly in the dermal infiltrates. Correlation with immunohistochemical data suggested that macrophages and activated keratinocytes were the main producers of these chemokines. CXCR3 was expressed by a majority of both CD4+ and CD8+ infiltrating T‐cells, suggesting a functional interaction between locally produced chemokines and CXCR3‐expressing T‐cells. In conclusion, these findings indicate that these CXCR3 activating chemokines play a significant role in the recruitment and maintenance of T‐cell infiltrates in the inflammatory skin diseases studied. Copyright

Follicular and epidermal alterations in patients treated with ZD1839 (Iressa), an inhibitor of the epidermal growth factor receptor

We report the cutaneous side‐effects of ZD1839 (Iressa), a new anticancer agent that acts by inhibiting epidermal growth factor (EGF) receptor signal transduction. Three patients receiving ZD1839 developed an eruption consisting of follicular papules and pustules in an acneiform distribution as well as diffuse fine scaling of the skin. Additionally, hair growth abnormalities were noted in two patients. Histologically, a superficial purulent folliculitis and disordered differentiation with focal parakeratosis were seen. The follicular eruption appeared to respond favourably to treatment with tretinoin cream and minocycline. The cutaneous adverse effects of ZD1839 are similar to those of other EGF receptor‐targeted agents and result from direct interference with the functions of EGF receptor signalling in the skin.

The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells.

Background The effectiveness of systemic treatment of psoriasis with fumaric acid esters has been proven, but their mode of action at the cellular and molecular level has not yet been fully elucidated.

Successful treatment of erosive vulvovaginal lichen planus with topical tacrolimus

SIR, The ichthyoses are a heterogeneous group of skin disorders of epidermal differentiation, with both inherited and acquired forms. This cornification disorder may be found isolated or in association with other genetic defects. In 1998, five siblings with congenital ichthyosis, follicular atrophoderma, hypotrichosis and hypohidrosis were described as a new genodermatosis by Lestringant et al. We report a 17-year-old Turkish patient with ichthyosis vulgaris, follicular atrophoderma, woolly hair and hypotrichosis as a second report on this syndrome. A 17-year-old-girl was admitted to our hospital because of woolly hair, sparse eyelashes and eyebrows, and a very dry skin. She was born at term after an uncomplicated pregnancy. Ichthyosis and baldness were present at birth, but there was no history of a collodion baby. She had almost no scalp hair until she was 4 months old. In the early childhood period, funnel-shaped round follicular depressions had appeared on the dorsal aspects of the hands. She stated that her scalp hair had improved and straightened with age. The patient was otherwise healthy and detailed ophthalmological, neurological and audiometric examinations were normal. There was no history of atopy. There was no family history of similar skin problems. Both her parents and paternal grandparents were first cousins. There was no maternal history of drug intake during pregnancy. On examination, there was diffuse ichthyosiform scaling sparing the major flexures and face as in ichthyosis vulgaris (Fig. 1). The ichthyotic skin was hypohydrotic but the axilla, palms and soles sweated normally. Follicular atrophoderma was observed on the backs of her hands (Fig. 2). She had diffuse and patchy non-scarring hypotrichosis with a receding frontal hairline. Her hair was normal in length, but was light brown in colour, coarse, curly and unruly, in contrast to the straight black hair of the rest of her family. Eyelashes and particularly eyebrows were sparse (Figs 3–4). Routine haematological, biochemical, immunological, thyroid and radiological investigations were normal. Osteopoikilosis was not present on the X-rays. Echocardiography and ECG were normal. Hair microscopy was normal apart from curling. Biopsy from ichthyotic skin showed orthokeratosis with focal hypogranulosis (Fig. 5). Electron microcopy showed normal tonofilaments. Based on clinical and laboratory findings a diagnosis of ichthyosis vulgaris associated with follicular atrophoderma, hypotrichosis and woolly hair was made. The patient was prescribed 10% urea cream and salicylic acid ointments. The ichthyotic lesions resolved within a few weeks. Ichthyosis is a feature of several genetic disorders. These are rare disorders and the associated ichthyosis may be mild. The following syndromes with ichthyosis may be considered

Chemokine IP-10 expression in cultured human keratinocytes

Abstract IP-10, a member of the CXC family of chemokines, is considered to play an important role in inflammation via its T-cell chemotactic and adhesion-promoting properties. Elevated IP-10 levels in the epidermis of psoriasis, delayed-type hypersensitivity reactions, cutaneous T-cell lymphoma and fixed drug eruptions prompted us to study its expression in keratinocytes. IP-10 mRNA could be detected using the sensitive RT-PCR method, but not by Northern blotting in RNA preparations from unstimulated normal cultured keratinocytes, indicating a low steady-state level of IP-10 mRNA. Upon stimulation with IFN-γ, IP-10 mRNA was found to accumulate in high amounts in a time- and dose-dependent manner. Superexpression was found with the combination of IFN-γ and TNF-α or IL-1, although these latter cytokines by themselves did not induce accumulation of IP-10 mRNA. Nuclear run-on experiments performed to investigate the regulation of IP-10 mRNA expression, showed a very high constitutive transcriptional activity of the IP-10 gene in unstimulated keratinocytes, which was not affected by stimulation with IFN-γ, TNF-α, or a combination of IFN-γ and TNF-α. Protein kinase C (PKC) was shown to be involved in IP-10 mRNA expression since the PKC inhibitor H7 decreased IP-10 mRNA accumulation. A protein was isolated from culture supernatants of stimulated keratinocytes using HPLC techniques and, by sequence analysis, was found to be identical to IP-10. The dynamics of secretion of IP-10 protein as monitored by ELISA was shown to parallel the mRNA expression.

Increased CCL27-CCR10 expression in allergic contact dermatitis: implications for local skin memory

Allergic contact dermatitis (ACD) is a T‐cell‐mediated disease in which expression of a distinct repertoire of chemokines results in the recruitment of effector T cells into the skin. While it is becoming clear which chemokines and receptors determine the development of ACD, the mechanisms involved in the retention of T cells in the skin after resolution of inflammation are still unknown. Unravelling these mechanisms will help us to understand local skin memory as observed in retest reactivity and flare‐up reactions. This study was designed to evaluate the role of chemokine–chemokine receptor interactions in local T‐cell retention. The results show that expression of the CCR10 targeting ligand CCL27 is not only increased during inflammation, but also remains increased several weeks after clinical responsiveness to patch testing. In parallel with increased CCL27 expression, an increased number of infiltrating cells could still be detected in skin that, clinically, had returned to normal 21 days after patch testing. These persisting cells were characterized as CD4+ cells expressing CCR10, while no CD8+ CCR10+ cells could be detected. The presence of these cells is most likely an allergen‐mediated effect, as increased levels of CCL27 and CCR10 could not be detected 21 days after initiating an irritant contact dermatitis reaction. In contrast to CCL27, increased expression of CXCL9, CXCL10, and CXCL11 could only be observed during the clinically inflammatory phase of ACD. In conclusion, local CCL27‐mediated retention of CCR10+ CD4+ T cells in sites previously challenged by ACD could be responsible for phenomena such as local skin memory observed in retest reactions and flare‐up reactions in which the presence of persisting T cells results in an accelerated inflammatory response upon renewed allergen challenge. Copyright

Nickel-responding T cells are CD4+ CLA+ CD45RO+ and express chemokine receptors CXCR3, CCR4 and CCR10

Background  Whereas T lymphocytes are widely accepted as effector cells determining the pathogenesis of allergic contact dermatitis, contradictory results have been found regarding the roles of different T‐cell subsets. The use of various experimental models, involving long‐term cultured T‐cell lines or clones, may explain these contradictory results.

Human growth factor (huGRO), interleukin-8 (IL-8) and interferon-γ-inducible protein (γ-IP-10) gene expression in cultured normal human keratinocytes

HuGRO, IL-8 and γ-IP-10 belong to a recently described superfamily of genes encoding a group of cytokines with inflammatory, growth regulating and/or leukocyte chemotactic properties (chemokines). We studied huGRO, IL-8 and γ-IP-10 gene expression in unstimulated and stimulated (TNFα, INFγ, TNFα + IFNγ, IL-1Β, PMA and LPS) normal human keratinocytes by Northern blot analysis. The mRNA for none of the three chemokines was detectable in unstimulated keratinocytes, but considerably elevated levels of huGRO and IL-8 mRNA, but not of γ-IP-10 mRNA, were found in the presence of cycloheximide, indicating that huGRO and IL-8 mRNA, but not γ-IP-10 mRNA, are constitutively produced. γ-IP-10 mRNA was exclusively induced by IFNγ, with a strong and transient rise between 8 and 18 h, and superinduced by the combination of IFNγ and TNFα, indicating marked synergism. Both huGRO and IL-8 mRNA were induced by TNFα and PMA (a strong and transient rise between 2 and 8 h), but not by IFNγ or LPS. The combination of TNFα and IFNγ did not show a synergistic effect. In addition, IL-1Β transiently upregulated huGRO mRNA but failed to induce IL-8 mRNA. Using specific oligonucleotides for α, Β and γ huGRO, TNFα was found to induce all three forms, α and Β to an equal extent and γ to a lesser extent. Our results indicate that there is stimulus-specific transcription of these early response genes which may have important implications for the modulation of cutaneous inflammatory processes.

Differential suppression of dendritic cell cytokine production by anti-inflammatory drugs

Background  Various anti‐inflammatory drugs are available for the treatment of skin disorders. In these diseases, untoward immune responses to endogenous and/or environmental antigens are initiated by maturation and polarization of dendritic cells (DC).

The expression of interleukin-8 receptor in untreated and treated psoriasis

The expression of IL-8 in psoriasis has been clearly shown with the use of immunocytochemical, RT-PCR and in situ hybridization methods. The presence of its ligand, the IL-8 receptor, has been demonstrated by the RT-PCR technique. We report here a study of the expression of both IL-8 type A and B receptors by immunohistochemical techniques, using one polyclonal and four monoclonal antibodies. By this technique, we found that the neutrophilic granulocytes express the IL-8 type A receptor, whereas the IL-8 type B receptor was present on the keratinocytes. The type B receptor on the keratinocytes was localized in the suprabasal layers of the epidermis. Following therapy, the expression of the IL-8 type B receptor on the keratinocytes was reduced. This could suggest that IL-8 in psoriasis is involved in the disturbed differentiation rather than in proliferation, probably via an autocrine loop.