Successful adjuvant treatment of recalcitrant epidermolysis bullosa acquisita with anti-CD20 antibody rituximab.
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Biomedical subjects
Publications and source records attributed to Eva-Bettina Bröcker.
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Innate and adaptive immunity have not evolved separately. In this regard, the NKG2D molecule first identified on NK cells and classified as an activating NK cell receptor is also an important receptor for CD8(+) T cells. Functional analyses of human NKG2D and its ligands, i.e. UL16 binding proteins (ULBP) and MHC class I chain-related (MIC), have so far focused on immune cell-target cell situations because of the expression of NKG2D ligands on infected, stressed or transformed cells. Here, however, we address a possible function of NKG2D/ULBP-1 during the initiation of T cell responses. ULBP-1 can be detected on mature dendritic cells both in situ in the T cell areas of lymph nodes as well as in vitro after artificial maturation. FCM analysis further demonstrated that although NKG2D is expressed to some degree on all analyzed T cell subsets from peripheral blood, in vitro stimulation of T cells results in up-regulation of NKG2D on proliferating T cells. Using the sentinel lymph nodes of primary melanoma as a model for induction of defined T cell responses in vivo, we were able to demonstrate the expression of NKG2D on melanoma-associated antigen-specific T cells. Thus, our results suggest a role for NGK2D-ULBP-1 in the induction or reactivation of T cell responses.
In Central Europe, bites from the common bed bug (Cimex lectularius) are nowadays rather uncommon. Nevertheless, infestations are sometimes observed in old framehouses and by immigration due to international travel and migration. The clinical picture of bug bites substantially varies between individuals, depending upon previous exposure and the degree of an immune response. The host immune response and potential protein antigens present in the saliva of C. lectularius or specific antibodies have not been characterized thus far. We describe a patient with bullous bite reactions after sequential contact with C. lectularius over a period of 1 year. In skin tests, we observed immediate reactions to the salivary gland solution of C. lectularius, which were followed by a pronounced partially blistering late-phase response. Immunoblot analysis of the patient's serum with salivary gland extracts and recombinant C. lectularius saliva proteins revealed specific IgE antibodies against the 32 kDa C. lectularius nitrophorin, but not to 37 kDa C. lectularius apyrase. Our data demonstrate that bullous cimicosis may be the late-phase response of an allergic IgE-mediated hypersensitivity to C. lectularius nitrophorin.
Recent results from basic and translational research on tumor genesis and progression establish the basis for future therapeutic approaches. Targeted therapeutics are tailored toward the molecular abnormalities that cause tumor progression and could potentially provide an effective, non-toxic therapeutic approach in a broad range of cancers including melanoma. Cancer is as much a (cyto)genetic disease as it is an epigenetic disease. Indeed, the fate of the cell depends on a delicate balance between expression and repression of genes. The notion that drastic changes in DNA methylation and histone modifications are present in a variety of human tumors has prompted the development and characterization of epigenetic drugs. Inhibitors of histone deacetylases and methyltransferases as well as of the proteasome are covered in this review.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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BACKGROUND: Pemphigus is a potentially life-threatening autoimmune blistering skin disease usually treated with high-dose corticosteroids in combination with immunosuppressive drugs. In a multicenter, prospectively randomized study we compared efficacy and side effects of a dexamethasone-cyclophosphamide (D/C) pulse therapy with a methylprednisolone-azathioprine (M/A) therapy in 22 patients with newly diagnosed pemphigus vulgaris and pemphigus foliaceus. PATIENTS AND METHODS: The 11 patients of the M/A group were treated with daily doses of methylprednisolone (initially 2 mg/kg body weight) and azathioprine (2-2,5 mg/kg body weight) which were subsequently tapered. D/C pulse therapy in 11 patients consisted of intravenous administration of 100 mg dexamethasone/d on 3 consecutive days along with cyclophosphamide (500 mg) on day one. Pulses were initially repeated every 2-4 weeks and then at increasing intervals. In between the pulses, oral cyclophosphamide (50 mg) was given daily for 6 months. RESULTS: Within 24 months after treatment initiation, 5/11 patients of the D/C group had a remission (complete remissions after discontinuation of therapy in 3 patients) and 6/11 patients had a progression. In the M/A group, there were remissions in 9/11 patients (complete remissions after discontinuation of therapy in 3 patients) and progression in 1/11 patients. There were more relapses in M/A therapy after remission than in D/C therapy. Side effects were more common in the M/A group. These differences were not significant (p > 0,05). CONCLUSION: Because of the high number of progressions in patients treated with D/C therapy, we can not confirm the encouraging results of earlier reports about pulse D/C therapy. Nevertheless D/C therapy seemed to be better tolerated and, in case of primary efficacy, was associated with fewer recurrences than M/A therapy.
BACKGROUND: According to guidelines of the German STD Association, appropriate treatment of extensive anogenital warts with comparable recurrence rates includes cryotherapy, surgical excision, electrosurgery, CO2- and Nd:YAG-laser vaporisation. All these procedures are associated with varying degrees of risk for bleeding, release of potentially infectious aerosol, deep thermal destruction, slow wound healing, and scarring. METHODS: Using argon-plasma coagulation anogenital warts can be removed in layers in a controlled manner. High frequency current flows through the argon plasma to the tissue, allowing well-controlled, superficial tissue destruction. RESULTS: From January 2001 to March 2003, 54 patients with extensive genital, anal or anogenital warts were treated. After one treatment, 66% of the pa- tients remained disease-free in the following 4 months. Thirteen patients (24%) showed early recurrence after 4 weeks, five patients (9%) at a later date. In these patients, further treatment, in 9 cases combined with topical imiquimod cream, were necessary for complete remission. CONCLUSION: Compared to other therapeutic procedures, argon-plasma coagulation is a better controlled, quick and low-risk option for the treatment of anogenital warts. Depending on the type of involvement and individual risk factors, postoperative treatment with topical imiquimod cream may be useful.
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A 40-year-old female patient with diabetes mellitus presented with multiple erythematous ulcerated nodules and plaques predominantly on the trunk. A few months ago her partner had a small ulcer on the penis. She was HIV negative but showed markedly elevated syphilis serology titers (TPPA titer > 1:20.480, VDRL titer 1:128). The serum glucose levels exceeded 275 mg/dl. After exclusion of neurological involvement, we made the diagnosis of "lues maligna" arising in the setting of diabetes mellitus. The patient was treated with 2.4 million units benzathine penicillin intramuscularly weekly for three weeks. Simultaneously, diabetes therapy was improved with insulin injections. The syphilitic lesions cleared rapidly. In the follow-up VDRL titer was negative. "Lues maligna" is an unusual ulcerative variant of secondary syphilis which has been observed more frequently in HIV-infected patients in the last years. The occurrence of this aggressive variant in the clinical setting of diabetes mellitus is extremely rare.
A 29-year-old patient presented with recurrent erythematous eruptions on both lower legs of 15 years' duration. Family history, along with clinical and laboratory examinations, revealed congenital hereditary spherocytosis and excluded other reasons for the erythematous eruptions of the lower legs. During two subsequent episodes, we detected increased hemolysis that disappeared concomittantly on spontanous resolution of the lesions. To our knowledge, this case is the first report showing a recurrent erythematous eruption on the lower legs in a patient with congenital hereditary spherocytosis. These eruptions might be caused by intermittent hemolysis-induced inflammation as a result of the increased osmotic fragility of the erythrocytes and may evolve to chronic leg ulcers later in life.
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The histopathological picture of many autoimmune bullous dermatoses is considered to be relatively characteristic. However, different entities may show similar histological findings. In addition, the picture depends on both the stage of the disease and prior treatment. Autoimmune bullous dermatoses are characterized by the production of autoantibodies to structural proteins of the skin. In most instances, the autoantigens have been identified and are available as recombinant proteins. Utilizing these recombinant forms, specific and sensitive assays have been developed for the detection of circulating autoantibodies in the serum. The detection of autoantibodies in skin or mucous membranes and/or serum is required for the diagnosis of autoimmune bullous dermatoses. The task of the dermatopathologist in the diagnostic process of autoimmune bullous dermatoses is to describe precisely the histopathological findings, to mention differential diagnoses and to recommend how these can be confirmed or excluded by immunopathological and immunoserological studies.
OBJECTIVES: To investigate the sensitivity of immunoblotting and enzyme-linked immunosorbent assay (ELISA) to detect autoantibodies to bullous pemphigoid antigen 180 in patients with pemphigoid gestationis and to correlate autoantibody serum levels with disease activity. METHODS: In serum samples obtained from 44 pregnant patients before initiation of therapy and from the same number of healthy blood donors, the autoantibody reactivity was assayed by immunofluorescence microscopy on human skin sections as well as Western blot analysis and 2 different ELISAs by using recombinant forms of the immunodominant domain of BP180. In addition, ELISA reactivity with this autoantigen was assayed in 6 patients during the course of the disease, and its correlation with the clinical disease activity was estimated by applying the Spearman rank correlation test. RESULTS: By indirect immunofluorescence microscopy, complement-fixing autoantibodies to the dermal-epidermal junction were found in 93% of patients' sera. By immunoblotting and ELISA, autoantibodies to bullous pemphigoid antigen 180 were detected in 93% and 86.3% of pemphigoid gestationis patients, respectively, but in none of the healthy controls. Serum levels of autoantibodies as detected by ELISA paralleled the patients' disease activity. CONCLUSIONS: Our study shows that immunoblotting and ELISA are sensitive tools for the detection of autoantibodies to bullous pemphigoid antigen 180 in patients with pemphigoid gestationis. In addition, the ELISA is useful to monitor autoantibody serum levels. LEVEL OF EVIDENCE: II-2
The occurrence of a granulomatous inflammation following herpes zoster infection is uncommon and its pathogenesis is unclear. A 74-year-old male patient developed multiple red-brown papules following a secondary generalized infection with varicella zoster virus in the same area. The patient was suffering from a chronic lymphocytic B-cell leukaemia. Histopathologically, granulomatous dermatitis with multinucleate giant cells was found. Varicella zoster virus DNA was identified by polymerase chain reaction in the tissue. After a renewed antiviral therapy, skin lesions disappeared completely.