[Pityriasis amiantacea and folliculitis decalvans : An unusual manifestation associated with antitumor necrosis factor-α therapy]. / Pityriasis amiantacea und Folliculitis decalvans : Eine ungewöhnliche Erscheinung, assoziiert mit Anti-Tumor-Nekrose-Faktor-α-Therapie.

We report on a 21-year-old woman with a 3-year history of crusts and erosions on her scalp that had appeared after starting treatment with adalimumab due to Crohn's disease. By clinicopathological correlation pityriasis amiantacea with underlying folliculitis decalvans was diagnosed. Topical and systemic antibiotic treatment showed rapid response. The occurrence of pityriasis amiantacea in folliculitis decalvans associated with tumor necrosis factor (TNF)-α inhibitor therapy is remarkable and highlights the ambivalent role of TNF-α in diseases with immunological dysfunctions in combination with infections.

Nail psoriasis masqueraded by secondary infection with Rhodotorula mucilaginosa.

A 38-year-old man presented with whitish nail changes on all fingers as the sole symptom. The condition had developed within a few days and led to dystrophy of the proximal part of the nail plates. As microscopic examination of nail scrapings demonstrated budding hyphae and the patient working as a teacher reported frequent use of a wet sponge, antifungal therapy was initiated. Subsequent cultures and molecular typing identified Rhodotorula mucilaginosa (formerly R. rubra). This environmental yeast was repeatedly isolated despite of therapy with itraconazole. As no improvement was achieved and testing of the biological activity of the fungus revealed only marginal keratolytic activity, it was considered as a coloniser of a destructed nail matrix. Finally, a biopsy of the nail bed confirmed the diagnosis of nail psoriasis, which rapidly responded to treatment with acitretin and topical calcipotriol/betamethasone cream. Fungal growth in destructed nails masqueraded the underlying disease and may have triggered the psoriatic nail reaction.

"Recreational" drug abuse associated with failure to mount a proper antibody response after a generalised orthopoxvirus infection.

Infections with orthopoxviruses usually lead to cross-protection among all species of the family. This has been a prerequisite for successful eradication of smallpox. Here we report the rare case of a 17-year-old male, who survived a generalised cowpox virus infection of unusual severity but surprisingly did not show a proper seroconversion. Only a very weak antibody production was observed in early and late serum samples, which initially appeared to be cowpox virus specific in immunofluorescence. No neutralising antibodies were detected and in Western blotting antibody specificity was restricted to the orthopoxvirus H3L protein only. The patient had been hospitalised for alcohol and cannabis intoxication 2 months prior to the orthopoxvirus infection and high levels of cannabinoids have been found repeatedly in the urine and upon one occasion also benzodiazepines. As these substances are known to interfere with antibody production and no immunodeficiencies were detected, drug-induced immunosuppression can be suspected as the most likely cause. Therefore a possible link between "soft" drug use and sufficient immunosuppression to warrant alterations in vaccine policies using live virus vaccines like smallpox vaccine should be further studied.

Significance of the cytokine interferon gamma in clinical dermatology.

Interferon (IFN)-gamma is considered a key cytokine of innate and adaptive immunity playing pivotal roles in host defence against microbial pathogens and tumours, and exerts profound antiproliferative and antifibrotic effects. In this review we discuss applications and perspectives of IFN-gamma in clinical dermatology, such as papillomavirus and bacterial infections, tumours, atopic dermatitis, and fibrotic conditions such as scleroderma and postradiation fibrosis. Moreover, we give a summary of the pharmacologic properties including main side effects and potential risk factors of IFN-gamma therapy. Although former enthusiasm for IFN-gamma (e.g. in atopic dermatitis) has subsided, this cytokine might remain a promising tool (and target) in clinical dermatology, due to its central immunobiologic functions, better characterization of its kinetics in diseases facilitating optimized treatment schedules, and successful applications in fibrotic conditions such as scleroderma, idiopathic pulmonary and skin postradiation fibrosis.

Tolerability and efficacy of N-chlorotaurine in comparison with chloramine T for the treatment of chronic leg ulcers with a purulent coating: a randomized phase II study.

BACKGROUND: The well-known active chlorine compound chloramine T (CAT) with broad-spectrum antimicrobial activity is in common therapeutic use for leg ulcers with purulent coatings; however, this treatment is painful. The tolerability of the less aggressive N-chlorotaurine (NCT), an endogenous compound also produced in vivo by stimulated human granulocytes, could be superior. OBJECTIVES: To assess the tolerability and efficacy of NCT in the cleaning of purulent coatings in chronic leg ulcers in comparison with CAT. METHODS: In a double-blind, randomized phase IIb clinical study 40 patients were treated for a median of 7 days (range 3-14) with a 1% aqueous solution of either NCT (20 subjects) or CAT (20 subjects) by twice-daily application of dressings soaked in the test solutions. Criteria for evaluation of tolerability were intensity and duration of pain caused by the ulcer therapy and scores of tissue toxicity (necrosis, granulation tissue and re-epithelialization). Therapeutic efficacy was graded as scores of intensity of purulent coating of the ulcers. RESULTS: The concentration tolerated in vitro by human epidermoid carcinoma cells was at least 10-fold higher for NCT (0.01%) compared with CAT (0.0001-0.001%). There was significantly less pain caused by NCT compared with CAT (P < 0.05) on days 1 and 4 and a trend for a shorter duration of pain (P = 0.093). The scores of intensity of coating improved without difference in both treatment groups, whereas granulation and re-epithelialization appeared earlier in the NCT group (P < 0.05). Non-quantitative microbiological cultures from ulcer smears revealed persistence of colonization by bacterial species in approximately half of both treatment groups. CONCLUSIONS: Both active chlorine compounds were helpful in reducing purulent coatings. Because of its lower toxicity and better tolerability, NCT is of advantage in the treatment of leg ulcers.

Spontaneous regression of CIN and delayed-type hypersensitivity to HPV-16 oncoprotein E7.

We investigated delayed-type hypersensitivity to human papillomavirus (HPV) in women with cervical dysplasia or cancer. Women were challenged by skin tests with synthetic HPV-16 E7 oncoprotein peptides. 11 women were regressors (cleared disease without treatment) and 37 were progressors (required surgery). Antibodies to early antigens (markers for progression) were detectable in a higher proportion of cancer patients than all other patients, particularly progressors with cervical intraepithelial neoplasia (CIN). By contrast, cellular immunity to HPV-16 E7, measured by skin test, was significantly (p=0.0001) associated with clinical and cytological resolution of HPV-induced CIN, indicating that E7-specific T-helper cells have a role in control of HPV.

Specific serum IgG, IgM and IgA antibodies to human papillomavirus types 6, 11, 16, 18 and 31 virus-like particles in human immunodeficiency virus-seropositive women.

To evaluate the humoral immune response to human papillomavirus (HPV) in women infected with human immunodeficiency virus (HIV), serum samples of 83 HIV-positive individuals were analysed by ELISA for specific antibodies of the isotypes IgG, IgA and IgM recognizing HPV-6, -11, -16, -18 and -31 L1 virus-like particles (VLPs). Papillomavirus-related lesions were present in 30 of 83 HIV-positive women. Twenty-one women (25%) presented with high-/intermediate-grade anogenital squamous intraepithelial lesions. PCR analysis and sequencing for HPV typing was done from biopsy specimens of 18 women; PCR-positive results were obtained in 90% of cases. In addition, HPV DNA hybrid capture assays were performed from cervical swabs of 58 HIV-positive women, 53% of whom had a positive result for high-risk HPV. Overall, positive IgG reactivity to HPV-6/-11 and HPV-16/-18/-31 was seen in 19%/31% and 49%/30%/24% of HIV-positive women, respectively. HPV-seropositivity was even higher than in 48 HIV-negative cervical intraepithelial neoplasia/cancer patients with percentages as follows: 8%/2% and 31%/15%/15%. This difference was significant for HPV-16 (P=0.046). IgA responses were comparable to IgG. IgM responses were low. The extraordinarily high rate of antibodies to the capsid protein L1 of high-risk HPVs (HPV-16, -18 and/or -31) in 58% of HIV-positive women compared to 19% (P=0.00001) of 102 healthy HIV-negative control women suggests a high lifetime cumulative exposure to HPV and increased expression of capsid proteins due to cellular immunodeficiency in HIV-infected women.

Multiple blue nevi of the vagina. A case report.

BACKGROUND: Melanotic lesions of the vagina are very rare; clinically, most are suspected to be malignant melanomas. Occasional benign cases, however, require differential diagnostic consideration. We report a case of multiple (benign) blue nevi of the vagina. CASE: A 51-year-old woman presented with bluish black macules irregularly distributed throughout the vagina. Biopsies revealed pigmented cells in the dermis that proved to be melanocytes. The patient received no therapy. The lesions remained unchanged in the follow-up period. CONCLUSION: Multiple blue nevi could be a differential diagnosis for malignant melanoma of the vagina. Our patient showed no malignant transformation over a 29-year period. Therapy for blue nevi in the vagina does not require complete excision.

High prevalence of a variety of epidermodysplasia verruciformis-associated human papillomaviruses in psoriatic skin of patients treated or not treated with PUVA.

Epidermodysplasia verruciformis-associated human papillomaviruses and in particular human papillomavirus type 5 were recently shown to be highly prevalent in psoriatic skin. We have analyzed lesional skin from 54 psoriasis patients for infections with genital-specific and epidermodysplasia verruciformis-specific human papillomaviruses to define the spectrum of involved human papillomavirus types and to test if it is influenced by psoralen ultraviolet A therapy. Using polymerase chain reaction analysis we could detect human papillomavirus sequences in skin lesions of 83% of the tested patients. In contrast, human papillomavirus-DNA was only demonstrated in 19% of skin samples from 42 dermatologically healthy, immunocompetent individuals. Sequence analysis of the polymerase chain reaction amplimers revealed 14 human papillomavirus types, all belonging to the epidermodysplasia verruciformis or epidermodysplasia verruciformis-related papillomaviruses. Only in one case we identified sequences related to those of genital viruses, which, however, represented a putatively new human papillomavirus type. The most prevalent human papillomavirus type in our patient series was human papillomavirus type 36, found in 62% of the patients positive for human papillomavirus-DNA, followed by human papillomavirus type 5 (38%) and human papillomavirus type 38 (24%). Multiple infections with two to five different human papillomavirus types could be detected in skin samples of 63% of the analyzed patients. The overall human papillomavirus detection rate did not differ significantly between patients which have been subjected to psoralen ultraviolet A photochemotherapy or solely treated with topical preparations (77 vs 89%). Human papillomavirus type 5, however, could be detected significantly more frequent in lesions of psoralen ultraviolet A-treated patients (p < 0.001). Our data strongly argue for infections with epidermodysplasia verruciformis-specific papillomaviruses being an almost consistent feature of the lesional psoriatic skin and substantiate the importance of further studies to elucidate a possible involvement of human papillomaviruses in psoriasis pathology.

Detection of new human papillomavirus sequences in skin lesions of a renal transplant recipient and characterization of one complete genome related to epidermodysplasia verruciformis-associated types.

Human papillomavirus (HPV) DNA, originally isolated from patients suffering from the skin disease epidermodysplasia verruciformis (EV), and a growing number of related sequences have recently been detected in a high percentage of benign and malignant skin lesions of both immunosuppressed and immunocompetent people. HPV L1 DNA fragments (374-389 bp long) from a solar keratosis and a squamous cell carcinoma (SCC) of a renal transplant recipient were amplified, cloned and sequenced. In 54 clones, six different HPV sequences were identified. One of these six corresponded to the known type HPV-8 and two (RTRX3 and RTRX7) have been described previously in cutaneous lesions of immunosuppressed patients. The remaining three sequences were different from all known HPV types: an HPV-9-related sequence (77.4% identity), an RTRX2-related sequence (82.6% identity), and an HPV-22-related sequence (83.7% identity). These three sequences, representing putatively new HPV types, were named RTRX8, RTRX9 and RTRX10, respectively. RTRX7 was found in the majority of clones from both lesions. The complete genome of RTRX7 (7731 bp) was cloned as six overlapping subgenomic fragments, generated by nested PCR with DNA extracts from the SCC. RTRX7 showed a genome organization typical of HPVs associated with EV. The L1 DNA sequence differed by 15% from the corresponding region of its closest known relative, HPV-12; thus, RTRX7 can be regarded as a new HPV type. RTRX7 DNA could not be detected by Southern blot hybridization with the homologous probe, indicating that the DNA concentration was below one copy per 10 cells in the investigated SCC.

Spontaneous or interferon-gamma-induced T-cell infiltration, HLA-DR and ICAM-1 expression in genitoanal warts are associated with TH1 or mixed TH1/TH2 cytokine mRNA expression profiles.

The purpose of the study was to investigate the cytokine gene expression patterns and immunohistochemical characteristics of genitoanal warts in order to obtain a clue as to the immunological mechanisms possibly relevant for wart regression or persistence. We analysed surgically removed warts from 11 patients, 2 of whom were immunosuppressed. Lesions of five of the nine otherwise healthy individuals were additionally treated with intralesional interferon-gamma (IFN gamma) prior to surgery. Invasion of CD4+ T cells into the papillomas and HLA-DR and ICAM-1 expression on keratinocytes were found in two otherwise healthy patients and were intensified by intralesional IFN gamma in four of five patients. The mRNA expression patterns in seven of eight non-recurrent warts were compatible with a predominant TH1 or mixed TH1/TH2 cytokine profile. In contrast, in recalcitrant warts of three patients (one healthy, two immunocompromised) histological signs of immunore-activity and TH1-like cytokine mRNA expression were not detected. In recurrent warts of a renal transplant patient, IL-4 and IL-5 mRNA expression was repeatedly found suggesting a predominant TH2 response. In conclusion, immunoreactivity to genitoanal warts such as T-cell infiltration, HLA-DR and ICAM-1 expression was associated with a predominant TH1 or mixed TH1/ TH2 cytokine mRNA expression profile.

Presentation of tetanus toxoid to autologous T cells by dendritic cells generated from human blood. Improved specificity with dendritic cells generated without fetal calf serum.

Dendritic cells (DC) are highly specialised to initiate primary immune responses and may therefore serve as natural adjuvant in future strategies for specific immunotherapy, e. g. with tumor antigens. The originally developed culture system to generate DC from peripheral human blood with GM-CSF and IL-4 was dependent on the use of fetal calf serum. We employed such DC as antigen presenting cells in a modified lymphocyte proliferation assay to measure the response of autologous T cells to tetanus toxoid. However, a substantial proliferative response of T cells was also observed in control wells without antigen, i.e. in the setting of a syngeneic mixed leukocyte reaction. This makes it difficult, if not impossible, to monitor antigen-specific responses in vitro. In a recently developed improved method fetal calf serum was replaced by 1% autologous human plasma. Using such DC in our lymphocyte proliferation assay background proliferation was markedly reduced. T cell responses to tetanus toxoid were strongest when the antigen was added to DC three days before cocultivation with T cells. We conclude that DC cultured in FCS-free autologous systems, suitable for clinical use, can process and present tetanus protein to autologous T cells. Using such DC in a lymphocyte proliferation assay may facilitate the measurement of antigen-specific T cell responses.

Human papillomavirus DNA in non-melanoma skin cancers of a renal transplant recipient: detection of a new sequence related to epidermodysplasia verruciformis associated types.

The detection of human papillomavirus (HPV) types originally isolated from patients with epidermodysplasia verruciformis (EV) in skin tumors of transplant recipients may point to a role of this HPV subgroup in non-melanoma skin cancer in immunosuppressed people. We analyzed 17 formalin-fixed, paraffin-embedded biopsies of benign or malignant skin tumors of a renal transplant patient with unusually widespread cutaneous carcinomas. Using a nested polymerase chain reaction (PCR), HPV-specific DNA was demonstrated in 11 specimens (65%). Analysis of nine PCR amplification products revealed four different sequences related to EV-associated HPVs. Three sequences occurred only in one lesion. In six samples identical sequences were found that differed from all HPV sequences published to date and may therefore represent a novel EV-HPV type, preliminarily labeled RTRX7. RTRX7 was found in benign, premalignant, and malignant skin lesions. Alignments identified HPV12 as the closest relative of RTRX7, both in the DNA (81% homology) and in the amino acid sequence (84% homology).

[Immunologic aspects of infections with papillomaviruses. Prospects for a vaccine]. / Immunologische Aspekte bei Infektionen mit Papillomviren. Aussichten auf einen Impfstoff.

Human papillomaviruses induce benign or malignant epithelial proliferations in both skin or mucosa and are involved in the development of anogenital cancer. One can consider two approaches towards vaccine development: prevention of infection by prophylactic induction of virus neutralizing antibodies or therapeutic vaccination which would lead to regression of already existing lesions. Neutralizing antibodies are directed against 3-dimensional structures on intact virions. Such antibodies which are protective in model systems can be induced safely by DNA-free "virus-like-particles". These constructs are candidates for a prophylactic vaccine. A further approach to optimize the vaccination strategy concentrates on immunotherapy of precancerous or malignant lesions by induction of a specific cell-mediated immune response. Hypothetically the transforming papillomavirus proteins which are expressed in basal layers of the epidermis could be used as a therapeutic vaccine in the form of synthetic peptides.