[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.

Skin test to assess immunity against cottontail rabbit papillomavirus antigens in rabbits with progressing papillomas or after papilloma regression.

This study analyzed in vivo antiviral cellular immune reactions in the Shope rabbit papilloma-carcinoma model. Antigens studied in experimentally infected domestic rabbits were cottontail rabbit papillomavirus particles produced with the athymic (nu/nu) mouse xenograft system and bacterial fusion proteins containing the major or minor capsid protein. Recall reactions to antigens were tested by classic intracutaneous tests. Positive reactions had a biphasic course. Histopathology of skin test biopsy specimens showed infiltrating polymorphonuclear cells during the early stages. Later they were replaced by predominantly perivascular infiltrates composed of mononuclear cells. Time course of swelling and infiltrates resembled a delayed-type hypersensitivity reaction. Ten of 11 regressor rabbits (p = 0.00006) and 10 of 20 progressors (p = 0.009) had positive skin tests with intact and/or denaturated virus particles and individual capsid proteins also could elicit specific skin reactions. Skin reactivity to the cottontail rabbit papillomavirus particles was also greater (p = 0.042) in regressor rabbits (8 of 11) when compared to progressors (7 of 20). Recall reactions remained detectable at post-regression times, ranging from several months up to more than 2 years. We conclude that specific skin reactions against the cottontail rabbit papillomavirus in infected domestic rabbits exist, and are strongly positive to intact particles of this papillomavirus in animals (regressors) clinically free of disease.

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).

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.

Rejection, after a slightly prolonged survival time, of Langerhans cell-free allogeneic cultured epidermis used for wound coverage in humans.

Autologous cultured epidermis (CE) grown from small skin biopsies in vitro has been successfully applied for wound grafting in humans. Since it has been reported recently that allogeneic CE might be tolerated as permanent wound cover, we investigated the properties of CE and its use as autologous and allogeneic grafts. Except for some differences, such as the absence of Langerhans cells and the lack of a stratum corneum, CE resembled its natural analogue. Autologous CE applied for grafting of leg ulcers and various surgical skin defects adhered firmly and permanently to the wound bed within 2 weeks, became regularly stratified, and formed a stratum corneum. Langerhans cells gradually entered the grafts; the dermis contained no inflammatory infiltrate. Allogeneic CE unmatched for MHC and blood group antigens used to partially cover tangentially excised third-degree burns, donor sites of split-thickness skin, and a defect after tumor excision initially survived well like the autografts. However, they were completely rejected after 10-22 (mean, 14.5) days, which is 4-5 days later than reported for split-thickness skin allografts. Clinically, rejection presented as "melting" of the graft. (Immuno)histologically, we found a dense mononuclear dermal infiltrate consisting predominantly of activated T cells, vacuolization, and single-cell necrosis of keratinocytes, as well as HLA-DR expression on keratinocytes, and finally separation and lysis of the epidermis. Limiting dilution analysis in 2 out of 4 allograft recipients revealed a considerable increase of circulating donor-specific cytotoxic T cell precursors during graft rejection. We conclude that grafting of allogeneic CE does not lead to permanent but to slightly prolonged graft survival.

Leukocyte proliferation in vitro against cottontail rabbit papillomavirus in rabbits with persisting papillomas/cancer or after regression.

Leukocyte proliferation responses to cotton-tail rabbit papillomavirus (CRPV) were measured in vitro with fresh whole blood as well as with ammonium chloride lysis-separated leukocytes. The antigens used were (1) CRPV particles produced in the athymic( (nu/nu) mouse xenograft system and (2) purified bacterial fusion proteins of the CRPV major and minor capsid proteins L1 and L2. CRPV-infected domestic rabbits with persistent papillomas or after papilloma regression, as well as uninfected controls were studied. There was a clearcut difference between infected and uninfected animals. We demonstrated antigen-specific leukocyte proliferation to at least one CRPV antigen in 12 of 21 infected rabbits but there was no positivity in 9 control animals (P = 0.004). There was whole-blood reactivity preferentially to intact CRPV particles in regressors. Specific but weak leukocyte proliferation against CRPV particles was detected in 6 of 9 regressor rabbits (66%) but only in 1 of 12 progressors (8%; P = 0.0158). This trend of greater reactivity to intact CRPV particles in regressors as compared with progressors was not seen with peripheral blood leukocytes isolated by ammonium chloride lysis. We conclude that specific leukoproliferative responses against capsid CRPV proteins exist in rabbits experimentally infected with CRPV.

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.

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.

[Benign prostatic hyperplasia: a stromal disease]. / Benigne Prostatahyperplasie: Eine stromale Erkrankung.

Morphometric studies show that benign human prostatic hyperplasia is a stromal disease caused by the activation of smooth muscle cells. This activation manifests itself in increased amounts of cytoplasmic organelles, which are preferably localized in the perinuclear region. Moreover, marked vesicular activity is present. Besides considerable overproduction of type I and III collagens, the architecture of the extracellular matrix is altered distinctly. In spite of strong evidence that androgens and estrogens regulate the growth of epithelial and stromal cells in the prostate and the induction of fibromuscular overgrowth in various animal models, the exact role of steroids in the pathogenesis of benign prostatic hyperplasia still remains to be elucidated.

[Specific serologic studies with a novel authentic HPV antigen (virus-like particles) for HPV-6 antibodies in gynecologic patient samples]. / Spezifische serologische Untersuchungen mit einem neuartigen authentischen HPV-Antigen (Virus-like Particles) auf HPV-6 Antikörper bei gynäkologischen Patientenkollektiven.

OBJECTIVE: A serological assay for genital HPV infection would provide important additional information to HPV DNA diagnostic methods, since it would evaluate prior exposure to the viruses, detect significant systemic immunologic response to virus infection, and could be performed in most clinical laboratories. METHODS: Serum samples from three groups of patients attending a gynecology clinic were analysed by direct ELISA for specific IgG antibodies to baculovirus-expressed HPV-6 and BPV-1-L1-VLPs. RESULTS: Positive IgG reactivity to HPV-6-L1-VLPs were 4/72 (6%) in a control group, 28/73 (38%) in a condyloma group and 17/62 (17%) in cervical intraepithelial neoplasia patients. Individual IgG ELISA values of condyloma and CIN patients for HPV-6-L1-VLPs demonstrated no correlation to results with BPV-1-L1-VLPs. CONCLUSIONS: These data show that HPV-6-L1-VLPs are effective antigens for serological studies and can detect species specific antibodies with important implications for diagnosis, epidemiology, insights to natural course of disease, prognosis and evaluation of vaccination.

"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.

[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.