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ZusammenfassungDieser Beitrag beleuchtet die fast 150 Jahre lange Geschichte der Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie des Universitätsklinikums Würzburg und ihrer Vorgängerinstitutionen von der Gründung bis zur Gegenwart. Dargestellt werden die wichtigsten Entwicklungsschritte von den ersten dermatologischen Vorlesungsinhalten im späten 18. Jahrhundert über die erste eigene Abteilung für Hautkrankheiten in Würzburg im Jahre 1872, die mit dem 1921 erfolgten Bezug des Luitpoldkrankenhauses verbundene Erweiterung des Fachgebiets, die Wirren in der Zeit des Nationalsozialismus und die Modernisierungen in der Nachkriegszeit bis hin zum aktuellen Stand als Klinik der universitären Maximalversorgung mit krankheitsorientierter molekularbiologischer und immunologischer Forschung und Lehre.

BACKGROUND: Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. METHODS: We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3-9, 10-30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (

Dendritic cell (DC) vaccination, albeit still in an early stage, is a promising strategy to induce immunity to cancer. We explored whether DC can expand Ag-specific CD8+ T cells even in far-advanced stage IV melanoma patients. We found that three to five biweekly vaccinations of mature, monocyte-derived DC (three vaccinations of 6 × 106 s.c. followed by two i.v. ones of 6 and 12 × 106, respectively) pulsed with Mage-3A2.1 tumor and influenza matrix A2.1-positive control peptides as well as the recall Ag tetanus toxoid (in three of eight patients) generated in all eight patients Ag-specific effector CD8+ T cells that were detectable in blood directly ex vivo. This is the first time that active, melanoma peptide-specific, IFN-γ-producing, effector CD8+ T cells have been reliably observed in patients vaccinated with melanoma Ags. Therefore, our DC vaccination strategy performs an adjuvant role and encourages further optimization of this new immunization approach.

Background. There are myriads of potentially irritant agents causing acute irritant contact dermatitis. In the large majority of cases, dermatitis is mild to moderate, and patients do not need hospitalization. However, some agents or special circumstances may cause severe dermatitis requiring more intensive therapy. Objectives. The aim of this study was to evaluate causative agents of severe acute irritant contact dermatitis requiring hospitalization. Methods. In this single-centre observational cohort study, we included 54 consecutive patients presenting with signs and symptoms of acute irritant contact dermatitis for which hospitalization was necessary. The severity of dermatitis was graded (grade I-IV) according to intensity, and details related to the skin irritation (irritant agent, area of exposure, time interval to onset of symptoms, and duration of hospitalization) were determined. Results. All cases with severe ulcerative dermatitis (grade IV) were caused by wet cement, owing to prolonged skin contact. These cement burns are clearly associated with amateur work, younger age, male preponderance, and leg localization. Conclusions. The study data provide clear-cut evidence that wet cement is a severely irritant substance that regularly causes the most severe form of acute irritant contact dermatitis. The main causative prerequisite for these cement burns is do-it-yourself work with poor protective measures. Language: en

Background Knowledge about the risk for recurrence and secondary cutaneous melanoma (CM) is an important basis for patient counseling and planning of follow-up examinations. Objectives This study aimed to analyze stage- and time-dependent hazard rates (HR) and discusses current surveillance recommendations. Methods Follow-up data of 33,384 patients with incident CM in stages I to III (American Joint Committee on Cancer 2002) were recorded by the German Central Malignant Melanoma Registry in 1976 through 2007. Survival was based on Kaplan-Meier estimates and HRs were calculated. Results Recurrences were recorded in 4999 patients (stage I, 7.1%; stage II, 32.8%; and stage III, 51.0%). Ten-year recurrence-free survival was 78.9% (95% confidence interval 73.1-90.5); in stage I, 89.0%; stage II, 56.9%; and stage III, 36.0%. Whereas HR for recurrent CM showed a constantly low level less than or equal to 1:125 per year for stage IA, clearly higher HRs of greater than or equal to 1:40 were recorded in stage IB for the first 3 years and generally in stages II to III. Of all patients 2.3% developed secondary melanomas, with a consistently low HR of less than 1:220 per year. Limitations As German recommendations discontinued regular follow-up examinations after 10 years, no information can be given beyond this time point. Follow-up data of longer than 5 years were available in 41.4% of patients. Conclusion For patients at stage IA with thin melanoma and low HR for recurrent CM the need for surveillance remains questionable. For patients with higher HR greater than 1:40 per year, intensified surveillance strategies should be taken into account.

Das Muir-Torre-Syndrom (MTS) ist ein seltenes autosomal-dominant vererbtes Tumorsyndrom, gekennzeichnet durch Auftreten von Talgdrusentumoren und/oder multiplen Keratoakanthomen in Kombination mit internen Neoplasien. An der Haut kommen neben Talgdrusenadenomen und Sebazeomen v. a. Talgdrusenkarzinome vor, die in uber 50% mit kolorektalen Karzinomen, seltener mit Karzinomen des ubrigen Gastrointestinal- oder Urogenitaltrakts assoziiert sind. Pathogenetisch liegt ein Defekt des DNA-Mismatch-Repair-Systems zugrunde, wodurch Mikrosatelliteninstabilitat im Tumorgewebe resultiert.

Apoptosis of single keratinocytes (KC) is a characteristic feature of spongiosis formation, the histopathologic hallmark of acute eczematous dermatitis. In acute eczema, activated dermis-infiltrating T cells secrete several proinflammatory cytokines which might be decisive for KC apoptosis or survival. We analyzed the role of tumor necrosis factor alpha (TNF-α) in the determination of KC fate during spongiosis formation in acute eczematous dermatitis. Supernatants of activated human CD4(+) T cells induced apoptosis in primary KC, which could be fully inhibited by individual blockade of interferon-γ (IFN-γ) and CD95 but not by neutralization of TNF-α activity. As compared to CD95-triggering alone, synchronous CD95 and TNF receptor cross-linking in the presence of IFN-γ only marginally enhanced KC apoptosis. Importantly, pre-treatment of KC with TNF-α followed by CD95 stimulation, but not vice versa, significantly amplified KC apoptosis as compared to CD95 stimulation alone. This TNF-α-mediated sensitization to CD95-induced KC cell death could be abrogated by blocking TNF receptor 1 (TNF-R1) but not TNF-R2 mAb. In eczematous dermatitis, the CD95 receptor was expressed throughout the epidermis, whereas immunohistological detection of TNF-R1 was rather restricted to KC around spongiotic vesicle formation. Thus, TNF-α primes KC for CD95-mediated signals which results in an increased susceptibility to apoptosis. TNF-R1 expression and spatial action of TNF-α restricted to spongiotic vesicles promote both CD95-induced KC apoptosis and limitation of spreading KC damage.

To cite this article: Seitz CS, Brocker E-B, Trautmann A. Diagnosis of drug hypersensitivity in children and adolescents: Discrepancy between physician-based assessment and results of testing. Pediatric Allergy Immunology 2011; 22: 405–410. Abstract Background: Diagnosis of drug hypersensitivity is often based on history alone. But such a vague diagnosis may cause limitations of therapeutic options in the future. To confirm or rule out drug hypersensitivity, skin testing, in vitro studies, and challenge tests are necessary. However, the diagnostic value of this complex and time-consuming allergologic work-up, especially in children, remains controversial. Objective: Aim of this retrospective analysis was to compare the results of diagnostic testing in children and adolescents with drug hypersensitivity diagnosed on clinical grounds, i.e., temporal relationship and observation of symptoms alone. Methods: We studied 43 children and adolescents (23 females, 20 males, mean age 13) with a history of immediate or delayed hypersensitivity symptoms in temporal relation to drug treatment using standardized skin testing followed by oral challenges. Patients with suspected penicillin hypersensitivity were further evaluated with in vitro tests. Results: Drug hypersensitivity was excluded in 40 patients by tolerated oral challenge tests with the incriminated drug. In two patients, positive challenge tests confirmed non-steroidal anti-inflammatory drug hypersensitivity. One patient with amoxicillin-associated exanthema developed positive late skin test reactions to aminopenicillins. Conclusion: In childhood and adolescence, allergologic testing in cases of suspected drug hypersensitivity is of importance both to establish a correct diagnosis and to prevent unjustified withholding of a drug or class of drugs.

Basal cell carcinoma (BCC) is the most common neoplasm in the Caucasian population. Only a fraction of BCC exhibits pigmentation. Lack of melanocyte colonization has been suggested to be due to p53-inactivating mutations in the BCC cells interfering with the p53-proopiomelanocortin pathway and the production of alpha melanocyte-stimulating hormone in the tumor. To evaluate this, we determined tumor pigmentation as well as expression of melan-A and of p53 in 49 BCC tissues by means of immunohistochemistry. As expected, we observed a positive relation between tumor pigmentation and melan-A positive intra-tumoral melanocytes. Melanocyte colonization and, to a lesser extent, p53 overexpression showed intraindividual heterogeneity in larger tumors. p53 overexpression, which is indicative of p53 mutations, was not correlated to melanocyte colonization of BCC. Sequencing of exon 5–8 of the p53 gene in selected BCC cases revealed that colonization by melanocytes and BCC pigmentation is neither ablated by p53 mutations nor generally present in BCCs with wild-type p53.

Chelation therapy with (RS)-2,3-Bis(sulfonyl)propane-1-sulfonic acid (DMPS) after an occupational lead exposure led to the development of a severe bullous drug eruption. Skin tests and histology/immunohistology of the test reactions indicated a T-cell-mediated immune response against DMPS. Metal-binding thiol groups as in DMPS are chemically highly reactive and therefore effectively mediate the development of immunogenic hapten (DMPS)-protein complexes. Therefore, the pharmacological effects and sensitization potential of dithiols are tightly connected. Cross-reactivity of DMPS to other chelators like D-penicillamine is possible; the indications for chelation therapy should be weighed carefully.

Summary. Phaeohyphomycotic cysts developed on the right knee of a 72-year-old woman undergoing immunosuppressive treatment for ulcerative colitis 6 years after accidental inoculation of soil in a bicycle accident. The lesions were red, firm, slightly raised, 0.5–1 cm in size and completely asymptomatic. The diagnosis was made by histo-pathological examination of three excised cysts and by repeated isolation of Exophiala jeanselmei in pure culture. The excised cyst walls contained large numbers of dematiaceous fungal elements in the form of hyphae, yeast-like cells and some cells dividing internally by a transverse septum. The patient was treated with 200 mg of itraconazole daily, but the treatment had to be stopped because of severe side-effects after 6 weeks. Histologically the cysts were cleared of dematiaceous elements, but E. jeanselmei could still be isolated from one of two skin biopsies 1 month after the end of therapy. Zusammenfassung. Bei einer 72-jahrigen Frau, die wegen einer Colitis ulcerosa mit Kortiko-steroiden behandelt wurde, entwickelten sich 6 Jahre nach einem Fahrradunfall und einer leichten Verletzung im Bereich des rechten Knies phaeo hyphomykotische Zysten. Die Hautveranderungen waren rot, fest in der Beschaffenheit, leicht erha-ben, ungefahr 0.5–1 cm gros und vollkommen asymptomatisch. Die Diagnose konnte erst nach histopathologischer Untersuchung und wiederhol-ter Isolierung von Exophiala jeanselmei in Reinkultur gestellt werden. Im Bereich der Zystenwande fanden sich grose Mengen an pigmentierten Pilz-elementen in Form von Hyphen, hefeartigen Zellen und einigen Zellen, welche sich mit einem transversen Septum teilten. Nach Diagnosesstel-lung wurde eine Therapie mit Itraconazol 200 mg pro Tag oral begonnen. Aufgrund von Nebenwir-kungen muste die Behandlung nach 6 Wochen abgesetzt werden. Bei der histologischen Untersuchung fanden sich keine Pilzelemente mehr, aber E. jeanselmei konnte aus einem von zwei Hautbiop-saten einen Monat nach Therapieende isoliert werden.

Pilomatricomas are benign skin tumors originating from hair follicle matrix cells. In 2% to 3.5% of cases they occur in multiplicity and then may be associated with genetic diseases, such as myotonic dystrophy Curschmann-Steinert, familial adenomatous polyposis (Gardner syndrome), and Rubinstein-Taybi syndrome. A 15-year-old boy treated with temozolomide and oxcarbazepine for gliomatosis cerebri with symptomatic epilepsy developed four firm cutaneous nodules on his face and right upper arm in the course of 1 year. All four tumors were excised under local anesthesia. Histological examination confirmed the clinical diagnosis of pilomatricomas. This is the first published case of a patient suffering from gliomatosis cerebri and developing multiple pilomatricomas. Whether this observation represents a new association or is a mere coincidence cannot be clarified at present.

PURPOSE: 31 P MR spectroscopy (MRS) allows the noninvasive assessment of metabolic alterations in tumors. Due to physical as well as technical limitations, mostly large and single voxels are used. We used a spatially resolved 31 P MRS technique to characterize metabolic abnormalities inside and adjacent to liver metastases of patients with uvea melanoma. MATERIALS AND METHODS: Optimization of 3D chemical shift imaging (3D CSI) was performed in healthy volunteers (n = 19; voxel size 25 ml). Patients (n = 8) with liver metastases were then examined. Cross sectional imaging was available for all patients. RESULTS: Compared to healthy volunteers, the PME/PDE ratios of patients with liver metastasis were significantly higher (0.56 ± 0.30 vs. 0.39 ± 0.21; p < 0.05). A trend towards increased PME/beta ATP ratios (2.07 ± 1.83 vs. 1.02 ± 0.45; p = 0.12) and decreased Pi/PME ratios (0.57 ± 0.29 vs. 1.06 ± 0.58; p = 0.06) was also observed. Patients with metastases ≥ 5 cm showed significantly higher PME/PDE ratios (0.68 ± 0.17 vs. 0.45 ± 0.03; p < 0.05). Liver parenchyma adjacent to metastases did not show any significant changes compared to non-diseased tissue. CONCLUSION: 3D CSI allows the simultaneous analysis of metabolic alterations in diseased as well as in healthy human liver. Metastases show significant metabolic alterations. Thus, 31 P MRS opens new possibilities for therapeutic monitoring.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. The incidence of this rare tumor is increasing rapidly; the American Cancer Society estimates for 2008 almost 1500 new cases in the U.S. Thus, the incidence of MCC will exceed the incidence of cutaneous T-cell lymphoma. Moreover, the mortality rate of MCC with 33% is considerably higher than that of cutaneous melanoma. These clinical observations are especially disturbing as we are only recently beginning to understand the pathogenesis of MCC. For the same reason, the therapeutic approach is often unclear; reliable data are only available for the therapy of locoregional disease.

This study analysed the changes of excision margins in correlation with tumour thickness as recorded over the last three decades in Germany. The study also evaluated surgical management in different geographical regions and treatment options for metastasized melanoma. A total of 42 625 patients with invasive primary cutaneous melanoma, recorded by the German Central Malignant Melanoma Registry between 1976 and 2005 were included. Multiple linear regression analysis was used to investigate time trends of excision margins adjusted for tumour thickness. Excision margins of 5.0 cm were widely used in the late 1970s but since then have been replaced by smaller margins that are dependent on tumour thickness. In the case of primary melanoma, one-step surgery dominated until 1985 and was mostly replaced by two-step excisions since the early 1990s. In eastern Germany, one-step management remained common until the late 1990s. During the last three decades loco-regional metastases were predominantly treated by surgery (up to 80%), whereas systemic therapy decreased. The primary treatment of distant metastases has consistently been systemic chemotherapy. This descriptive retrospective study revealed a significant decrease in excision margins to a maximum of 2.00 cm. A significant trend towards two-step excisions in primary cutaneous melanoma was observed throughout Germany. Management of metastasized melanoma showed a tendency towards surgical procedures in limited disease and an ongoing trend to systemic treatment in advanced disease.

Thirty-three patients with malignant melanoma and regional lymph node metastases who underwent lymph node dissection were additionally given polychemotherapy with carmustine, hydroxycarbamide and dacarbazine immediately before surgery and up to five times postoperatively. Twenty-nine patients were only treated surgically. These two groups were comparable as regards prognostic criteria, in particular tumour size, ulceration and the number of lymph nodes affected, although the individual follow-up periods varied considerably. The group given chemotherapy showed better results than the control group undergoing surgery alone. The log rank test yielded a significant difference (P less than 0.05) with respect to the probability of relapse-free survival but not as regards probability of survival time. Patients with ulcerated primary melanomas and with a large number of affected lymph nodes had a less favourable prognosis. The major side effects of chemotherapy were transient nausea and bone marrow depression.

Contrast material is generally well tolerated although approximately 1% of patients who receive low-osmolar nonionic contrast material will develop anaphylaxis symptoms. Because most anaphylactic reactions are mild and nonallergic, clinically mimicking immunoglobulin E (IgE)-mediated allergy, diagnostic skin testing has been discussed controversially in the past and prophylactic pretreatment drug regimens are recommended instead. In the past 6 years, all patients with contrast material-induced anaphylaxis have been subjected to allergologic diagnostic procedures to clearly differentiate allergic and nonallergic anaphylaxis. Thus the purpose of our study was to identify and differentiate IgE-mediated allergy and nonallergic contrast material-induced hypersensitivity. Furthermore, the objective of our diagnostic procedures was not only to identify the culprit contrast material but also to find alternative contrast material for future radiologic interventions.We evaluated 96 patients with anaphylaxis symptoms after contrast material application using standardized intradermal skin testing. In patients with positive skin tests, the IgE-mediated allergy was further evaluated with in vitro and challenge tests.In four patients (suffering from anaphylaxis grades 2 and 3) out of the 96 (4.2%), skin tests and basophil activation tests strongly suggested IgE-mediated allergy to the contrast materials iopromide (two patients), iomeprol, and iopentol. In two patients with allergies to iopromide and iomeprol, alternative nonionic monomer contrast materials were tolerated, as identified in controlled challenge tests with iopamidol and iopromide, respectively.The evaluation of patients with contrast material-induced anaphylaxis (at least those with anaphylaxisor = grade 2) should always include appropriate skin tests ensuring that patients with an IgE-mediated allergy are not missed. Moreover, allergologic testing may identify a contrast material of the group of nonionic monomers that will be tolerated in future radiologic interventions.

Behcet's disease is a chronic relapsing systemic vasculitis of unknown etiology, affecting predominantly oral and genital mucocutaneous tissues and also the eyes. The disease is spread worldwide with a higher prevalence rate in countries along the ancient Silk Route, but it is rare (1-10/100,000) in Central and Northern Europe. Genetic, environmental, immunologic, inflammatory and rheologic factors are involved in the pathogenesis and the course of the disease. Any vascularized organ may be affected. Eye involvement is frequent, and may eventually result in loss of vision. Further important complications are cerebral manifestations, thrombotic syndromes, and arterial aneurysms with a high risk of rupture. Diagnosis and therapy of Behcet's disease are best managed by an interdisciplinary team. Skin lesions may be controlled by systemic treatment with colchicine, alternatively with dapsone, and in severe cases with thalidomide. Active systemic disease should be treated more aggressively using immunosuppressants. Despite advances in treatment relapses are still frequent, and systemic disease remains associated with an adverse prognosis.

Transient aquagenic palmar hyperwrinkling (TAPH) is a rarely reported cutaneous condition clinically characterized by swelling and hyperwrinkling of the palms, and associated with burning sensations after briefly immersing the hands in water. Upon the withdrawal of water, the symptoms rapidly disappear. We report on a 10-year-old boy with type I diabetes, who developed the typical symptoms of TAPH concomitantly with the onset of palmar hyperhidrosis. Determination of the sodium chloride concentration of the sweat revealed elevated levels. Subsequent screening for the most common mutations of the gene responsible for cystic fibrosis (CF) was negative. Review of the literature shows that TAPH may develop in conditions of increased water absorption due to an increased sweat quantity, such as hyperhidrosis, or an increased sweat electrolyte concentration, such as CF. In the majority of reported cases TAPH has been associated with CF; therefore, it is a cutaneous sign, which should be recognized by dermatologists, and patients should be referred for evaluation of the sodium chloride concentration of the sweat.

Received 3 December 2006; returned 26 February 2007; revised 20 March 2007; accepted 18 April 2007Objectives: Aminopenicillin-induced exanthema poses a problem in the management of infectious dis-eases. Due to theoretically possible immunological cross-reactivity, all b-lactam drugs, i.e. penicillins,penicillin derivatives and cephalosporins, are usually avoided. The available alternative antibiotics(macrolides, quinolones and glycopeptides) may be less effective, have more side effects, and theiruse increases medical costs. Moreover, their use contributes to the increasing bacterial resistance toantibiotics. The aim of the study is to demonstrate that patients with aminopenicillin-inducedexanthema may receive specific b-lactams for future antibiotic therapy.Methods: Skin testing followed by oral challenges to identify b-lactams that are tolerated by patientsdespite confirmed delayed-type non-immunoglobulin E (IgE)-mediated allergic hypersensitivity to ami-nopenicillins.Results: Sixty-nine out of 71 patients (97.2%) with non-IgE-mediated allergic hypersensitivity to amino-penicillins tolerate cephalosporins without an aminobenzyl side chain such as cefpodoxime or cefix-ime and 51 patients (71.8%) also tolerate phenoxymethyl penicillin.Conclusions: The majority of patients with non-IgE-mediated allergic hypersensitivity to aminopenicil-lins do not cross-react to certain cephalosporins or phenoxymethyl penicillin. Skin and drug challengetests can be helpful to determine individual cross-reactivity.Keywords: drug challenge, drug provocation, non-IgE-mediated allergic hypersensitivity, skin tests

To scrutinize published data from small mono-centric studies and case reports which implicated high response rates and promising survival times for a combination therapy consisting of epifocal dinitrochlorobenzene (DNCB) and dacarbazine (DTIC) for metastasized melanoma. This therapy merges the effects of an allergic contact dermatitis elicited at the site of a cutaneous metastasis, and systemic chemotherapy. We performed a retrospective survey with nine German centers and evaluated 72 patients treated from 1993 to 2005. The objective response rate in stage III melanoma (n = 39) was 62%. In contrast, only 9% objective responses were observed in 33 stage IV patients. Interestingly, more than half of patients with objective remissions remained progression-free for more than 1 year irrespective of the stage of disease. Epifocal DNCB combined with DTIC is effective in patients with regionally metastasized melanoma not amenable to surgery or isolated limb perfusion, whereas in stage IV disease in spite of few durable remissions the addition of DNCB does not improve the therapeutic efficacy of DTIC.

Ein 70-jahriger Patient stellte sich mit einer seit 6 Monaten bestehenden, ausgedehnten, grosenprogredienten perianalen Erosion vor. Daruber hinaus fanden sich einige kleinere Erosionen mit umgebender weislich retikularer Zeichnung am Penis. Die klinische Diagnose eines erosiven Lichen ruber wurde histologisch bestatigt. Nach Versagen mehrerer topischer Therapien und Absetzen des β-Blockers konnte der Befund durch 3 Zyklen einer Dexamethason-Pulstherapie (100 mg Dexamethason i.v. an 3 aufeinanderfolgenden Tagen in 4-wochigen Abstanden) zur langfristigen Abheilung gebracht werden.

Background: Successful allergen-specific immunotherapy (SIT) is associated with reduced Th2 cytokine production and the induction of IL-10-producing regulatory T cells. To improve treatment efficacy, we investigated the impact of an IL-4/IL-13 inhibitor during SIT. Methods: BALB/c mice were sensitized intranasally with ovalbumin (OVA) for 4 weeks. Subsequently, they were subjected to intranasal SIT, with OVA being administered at doses increasing from 1 µg to 1 mg over 3 weeks with or without an IL-4/IL-13 inhibitor. Serum OVA-specific antibodies were measured and bronchoalveolar lavage (BAL) fluids were checked for airway eosinophilia. Subsequently, lung tissue was examined histologically for inflammatory infiltrates. Cytokines were detected in BAL fluids and spleen cell cultures. Furthermore, CD4 CD25 double-positive spleen T cells were checked for intracellular IL-10 production by flow cytometry. Results: OVA sensitization resulted in persistent IgE synthesis and an eosinophil-rich allergic airway inflammation combined with increased IL-4 and IL-5 levels. Therefore, intranasal SIT could efficiently reverse the allergic phenotype. This was associated with decreased IL-4 and IL-5 levels, and increased IL-10 levels in BAL fluids as well as increased amounts of IL-10-producing CD25+ regulatory T cells. However, mice treated with the IL-4/IL-13 inhibitor during SIT did not produce significantly different results . Conclusion: The use of an IL-4/IL-13 inhibitor as an adjuvant for SIT did not enhance anti-allergic effects. Thus, the observed reversal of Th2 responses during SIT may not be the keystone for successful therapy, but rather other factors, e.g. IL-10-producing regulatory T cells, may be crucial.

Background No data are available on the incidence and immunoreactivity of autoimmune subepidermal blistering skin diseases in East Africa. Methods All patients with frank blisters/erosions on the skin and/or mucous membranes that attended the Department of Dermatology at Mbarara University, Uganda, from May 2000 to June 2002, were investigated. The diagnosis was based on the clinical presentation and on the presence of circulating autoantibodies detected by indirect immunofluorescence microscopy on 1 m NaCl-split human skin and by Western blotting of recombinant and cell-derived forms of BP180, BP230, and type VII collagen. Results Twenty-two patients with autoimmune subepidermal blistering skin disorders were identified, including nine with bullous pemphigoid (41%), four with linear immunoglobulin A (IgA) disease (18%), three with mucous membrane pemphigoid (14%), two with linear IgG/IgA bullous dermatosis (9%), and one each with cicatricial pemphigoid and epidermolysis bullosa acquisita (5%). In addition, two patients with immunoreactivity to both the epidermal and dermal side of salt-split skin by indirect immunofluorescence microscopy, who were unreactive to type VII collagen, were provisionally diagnosed as “mixed pemphigoid” (9%). In patients with subepidermal blistering diseases, IgG reactivity correlated significantly with old age, whereas younger patients preferentially developed IgA autoantibodies (P = 0.024). Conclusions The age of patients with autoimmune subepidermal blistering diseases appears to influence the immunoglobulin class of autoantibodies. The high frequency of IgA autoantibodies in Ugandan patients may be explained by the age distribution of the Ugandan population.

Treatment of autoimmune blistering diseases consists of systemic glucocorticosteroids usually in combination with additional immunosuppressants such as azathioprine and mycophenolate mofetil or immunomodulators such as dapsone, antibiotics, intravenous immunoglobulins, and immunoadsorption. In some patients, these treatment regimens are not sufficient to control disease activity and/or lead to intolerable adverse events. Rituximab, originally developed for the treatment of non-Hodgkin's lymphoma, is an anti-CD20 humanized monoclonal antibody leading to transitory B-cell depletion. For this indication, rituximab is widely employed, and severe side-effects rarely observed. Subsequently, the B-cell-depleting effect of rituximab has been exploited successfully in various autoimmune disorders, including autoimmune blistering diseases. Here, we review the effect of rituximab in such diseases. To date, application of rituximab has been reported in 26 treatment-resistant patients with the vulgaris, foliaceus, and paraneoplastic variants of pemphigus as well as in bullous pemphigoid and epidermolysis bullosa acquisita. All but a single patient showed clinical improvement with reduction of lesion formation. In about a third, a clinical remission requiring further immunsuppressive medication was achieved, and in about a quarter, complete remission was induced. In addition, the mode of action and adverse events of rituximab as well as adjuvant immunosuppressive treatments, and the effect on levels of circulating autoantibodies in these patients are discussed.

Ein 40-jahriger Mann mit einer seit 3 Jahren bekannten Thrombozytopenie stellte sich wegen retikularer und gesprenkelter Hyper- und Hypopigmentierungen besonders im Bereich des Thorax und der oberen Extremitaten vor. Die Mehrzahl der Finger- und Fusnagel fehlte oder war dystroph. Hinzu kamen ein weitgehender Verlust der Zahne sowie multiple Leukoplakien an Zunge und Mundschleimhaut. Weiterhin zeigte sich eine Atresie der Tranenkanale. Aufgrund der typischen Befundkonstellation stellten wir die Diagnose einer X-chromosomal vererbten Dyskeratosis congenita (Zinsser-Engman-Cole-Syndrom, OMIM #305000), die durch Sequenzierung des Gendefekts [Punktmutation im Exon 11 des Dyskerin 1 (DKC1)-Gens] bestatigt werden konnte.

We report on a 24-year-old, male Ugandan patient with a 2-week history of itchy papules, vesicles, erosions, and crusts distributed on the entire body, accompanied by minor erosions on the palate, tongue, and lower lip. Conjunctivae and genital mucosa were not involved. Circulating IgG and IgA autoantibodies were found against recombinant full-length BP180, BP180 4575, and the C-terminus of BP230. In addition, IgG reactivity was observed against the 16th noncollagenous region of the BP180 ectodomain, the cell-derived soluble ectodomain of BP180 (linear IgA disease antigen 1), and the alpha3 and gamma2 chains of laminin 5. No reactivity was detected with type VII collagen, alpha6beta4 integrin, and the p200 protein. Oral prednisolone and dapsone led to clearance of lesions that mostly healed with scarring and milia formation. Here, we describe a scarring mucocutaneous variant of an autoimmune blistering skin disorder that extends the current clinical and immunopathologic spectrum of this group of diseases.

Summary A 70-year-old patient presented erosions on the oral mucosa and skin, predominantly in perianal and inguinal areas. Histopathologically, subepidermal blistering was observed. By direct immunofluorescence microscopy, linear deposits of IgG and C3 were seen at the dermal-epidermal junction. By indirect immunofluorescence microscopy, binding of IgG autoantibodies to the dermal side of NaCl-split skin was detected. These autoantibodies were shown to target both the non-processed and processed α3- as well as the β3-subunit of laminin 5 by immunoblot analysis using extracellular matrix of cultured human keratinocytes. Based on these results, the diagnosis of an anti-laminin 5 mucous membrane pemphigoid was established. Oral treatment with dapsone, combined with intravenous dexamethasone pulse therapy, led to rapid improvement. Zusammenfassung Ein 70-jahriger Patient litt an einer ausgepragten ulzerosen Stomatitis sowie Erosionen der Haut, vorwiegend perianal und inguinal. Die Histologie zeigte eine subepitheliale Spaltbildung, die direkte Immunfluoreszenz lineare Ablagerungen von IgG und C3 an der dermo-epidermalen Junktionszone. In der indirekten Immunfluoreszenz auf NaCl-separierter humaner Spalthaut fanden sich IgG-Autoantikorper, die am Boden der artifiziellen Blase banden. Im Immunoblot mit extrazellularer Matrix kultivierter humaner Keratinozyten erkannten diese die prozessierte und nicht prozessierte α3-Kette sowie die β3-Untereinheit von Laminin 5. In Zusammenschau dieser Befunde diagnostizierten wir ein Schleimhautpemphigoid vom anti-Laminin 5-Typ. Unter oraler Gabe von Dapson und intravenoser Pulstherapie mit Dexamethason konnte eine rasche Besserung erzielt werden.

Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different susceptibility to ultraviolet light.We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas.We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89 percent accuracy. Eighty-one percent of melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway.The genetic alterations identified in melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.

Zusammenfassung Die von der grundlagenwissenschaftlichen und translationalen Forschung erarbeiteten Erkenntnisse uber die Ursachen und Mechanismen der Melanomentstehung und -progression werden sich in den nachsten Jahren auf die Therapie auswirken. Die zunehmende Aufklarung der molekularen Pathogenese maligner Erkrankungen und die differenzierte Analyse der verschiedenen Signal- und Regulationswege innerhalb und auserhalb der malignen Zelle fuhrte zu neuen, relativ spezifischen Ansatzpunkten, um in den malignen Prozess einzugreifen. Diese Interventionen zielen auf einzelne Molekule ab, welche mit der malignen Grunderkrankung assoziiert sind oder sie sogar induzieren, weshalb diese Interventionen auch als „targeted therapy” bezeichnet werden. Diese Arbeit gibt eine kurze Ubersicht uber therapeutische Moglichkeiten, welche auf einer Modulation der Ras/MAPK- und des PI3K/AKT-Signaltransduktionsweges abzielen. Summary Recent results from basic and translational research on the causes and mechanisms of melanoma genesis and progression will impact on future therapeutic approaches. The increasing understanding of the molecular pathology of malignant disease and the detailed analysis of the signal transduction pathways involved allows specific intervention with these oncogenic events. These interventions address the molecules associated with or responsible for the malignant transformation and have therefore been termed “targeted therapy”. The present review focuses on the therapeutic options involving modulation of the Ras/MAPK- and PI3K/AKT-signal transduction pathways.

Background Recently, it has been shown that UVB phototherapy may be more effective than UVA in the treatment of vitiligo. Currently, however, no studies have compared the efficacy of UVB311 nm and broad-band UVB therapy. Calcipotriol has recently been reported to be effective adjunctive treatment for vitiligo, enhancing the efficacy of 8-methoxypsoralen plus UVA (PUVA) therapy. Methods Ten patients were enrolled in the study; nine completed the 12 months of therapy. The upper part of the body was treated twice weekly with UVB311 nm and the lower part with broad-band UVB. Calcipotriol was applied onto the vitiligo lesions of the right side of the body and placebo on the left side. Repigmentation was documented by photography, planimetry, and Vitiligo Disease Activity (VIDA) score. The quality of life was measured by the Dermatology Life Quality Index (DLQI). Results After 7–16 weeks, six of the nine patients showed initial repigmentation on the side treated with UVB311 nm. After 6 months of treatment, none of the patients showed repigmentation on the areas treated with broad-band UVB, which prompted us to apply UVB311 nm all over the body. At the end of 12 months, two patients showed > 75% repigmentation, two showed 51–75%, two showed 26–50%, and three showed 0–25%. In all patients with progressive vitiligo (seven of the nine patients), disease activity was stopped. Remarkably, vitiligo lesions treated with calcipotriol initially showed delayed repigmentation compared with control areas; however, there was no therapeutic difference between calcipotriol and placebo, both in combination with UVB311 nm, by the end of the study. The DLQI score improved significantly by an average of 28%. Conclusion UVB311 nm therapy was effective in the treatment of vitiligo, whereas broad-band UVB had no effect. Combination with calcipotriol ointment was not superior to UVB311 nm monotherapy. The quality of life significantly improved with narrow-band UVB311 nm phototherapy.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with circulating autoantibodies to the hemidesmosomal antigens BP180 and BP230. We report two cases of therapy-refractory BP adjuvantly treated by tryptophan immunoadsorption. In both patients, this treatment was associated with rapid clinical improvement and reduction in the required corticosteroid dosage. In addition, levels of circulating anti-BP180 autoantibodies decreased markedly. Antibodies that were eluted from the tryptophan matrix bound to BP180 and induced dermal-epidermal separation in cryosections of human skin. Our observations suggest that immunoadsorption may be a helpful adjuvant treatment in severe BP.

Matrix metalloproteinases (MMPs) are essential for tumor progression, invasion and metastases formation. Expression of these proteinases is not only restricted to the tumor cells themselves, but also is found in normal stromal cells. Moreover, immunohistochemistry suggests stromal cells as the major source. To scrutinize this hypothesis we established a slowly growing, syngeneic tumor model using the B16-melanoma cell line B78D14. In vitro analysis demonstrated that B78D14 cells secreted MMP-2, MT1-MMP, and to a lesser degree MMP-9; in addition they expressed both MT1-MMP and EMMPRIN on their surface. In subcutaneous (s.c.) tumors of these cells MMP-2 expression was predominantly present at the tumor-stroma border indicating stromal cells as primary source for this protease in vivo. Indeed, double staining experiments and in situ zymography confirmed that tumor adjacent stromal cells at the invasive front expressed MMP-2 and only at this site activated MMP-2 was detectable. Notably, in an experimental pulmonary metastases model neither tumor nor stromal cells expressed MMP-2, suggesting that the capacity of stromal cells is largely dependent on the surrounding microenvironment.

Morphological plasticity of Candida albicans is a major virulence factor. Using pH-dependent dimorphism we show, that human dendritic cells (DC) recognize filamentous forms and blastoconidia of a virulent C. albicans isolate (strain SC5314). Heat inactivated and viable blastoconidia are rapidly phagocytosed by human DC. However, viable yeast cells start to filament inside the DC at later stages of infection, leading to penetration and loss of cellular integrity. The cytokine burst of human DC induced upon contact with Candida is dominated by the granulocyte-activating, chemotactic factor IL-8 and the proinflammatory mediator TNF-alpha. Blastoconidia induce markedly lower cytokine levels than filamentous forms. Whereas IL-8 secretion is mainly cell mass dependent, release of TNF-alpha, a major proinflammatory cytokine, is clearly dependent on the morphology of Candida.

Cutaneous melanomas are notorious for their tendency to metastasize. Essential steps in this process are the degradation of basement membranes and remodeling of the extracellular matrix (ECM) by proteolytic enzymes such as matrix metalloproteinases (MMPs), which are regulated by their tissue inhibitors (TIMPs). An MMP expression is not restricted to tumor cells but is also found in stromal cells, indicating that stroma-derived proteases may contribute to melanoma progression. The MMPs have been shown to interact with a broad range of non-matrix proteins including adhesion molecules, growth factors and mediators of angiogenesis and apoptosis. In this review, we evaluate new insights into the interplay of MMPs and their molecular partners in melanoma progression.

Delayed-type hypersensitivity to subcutaneously injected heparin is relatively common. Particularly, extensive cross-reactivity between different heparins and heparinoids often occurs. Delayed-type hypersensitivity to heparin implies the risk of a generalized eczema when heparin is administered intravenously. However, case reports demonstrated a tolerance to intravenous heparin in patients with delayed-type hypersensitivity to subcutaneous heparin, but prospective studies have not been performed. Our study group, of 28 patients with a proven delayed-type hypersensitivity to subcutaneous heparin, was challenged with intravenous heparin, which was well tolerated in all 28 patients. Therefore, in case of therapeutic necessity, the shift from subcutaneous to intravenous heparin administration is justified.

Prognosis of disseminated melanoma remains gloomy as neither chemotherapeutic nor unspecific immune modulatory approaches were able to improve the overall survival of these patients. Hence, specific immunotherapy has received increasing attention. Disappointing clinical results, however, indicate that the choice of suitable antigens is of special importance. To this end, the inhibitor of apoptosis (IAP) protein survivin, which is over-expressed in several tumours but is largely undetectable in adult tissues, appears to be a promising target for vaccination purposes, since down-regulation or loss of expression is associated with impaired tumour progression. Consequently, five heavily pretreated stage IV melanoma patients were vaccinated with the HLA-A2 restricted survivin96–104 epitope presented by autologous dendritic cells (DCs) in a compassionate use setting. Four of these patients mounted strong T cell responses to this epitope as measured by ELISPOT assay. Furthermore, in situ peptide/HLA-A2 multimer staining confirmed that these survivin reactive cells infiltrated both visceral and soft tissue metastases.