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Biomedical subjects

V Mielke

Publications and source records attributed to V Mielke.

At least 19 recordsLinked to original sources
PubMed1995

Systemic treatment for cutaneous lymphomas.

Primary malignant T cell lymphomas of the skin form a heterogenous group. Relevant classifications were recently made to separate different entities by various criteria. This is of great importance, because one should only rely on those therapeutical trials in which patients were included according such classifications. In this paper, we will mainly focus on therapeutic modalities for mycosis fungoides, which is the most frequent cutaneous T cell lymphoma and which may serve as a model disease. In principle, local (e.g., psoralens and ultraviolet A, PUVA) and systemic therapies (e.g., interferon-alpha 2a) can be applied. Very recently, we were able to demonstrate that even in initial stages of mycosis fungoides, the T cell clone is not restricted to the skin, but rather is present in low amounts in the peripheral blood. Therefore, systemic therapeutic modalities alone or in combination with local strategies (interferon-alpha 2a and acitretin/PUVA and interferon-alpha 2a) should be more effective, which will be proven by currently running clinical trials.

Antineoplastic Agents↗
PubMed1995

[Reticular elastolytic giant cell granuloma. A variant of the annular elastolytic giant cell granuloma].

The case report presented describes a new variant of annular elastolytic giant cell granuloma. Over a period of 10 years, a 40-year-old woman had developed reticular, brown to livid, partly atrophic skin lesions on the shoulders and decolletée. The patient had no subjective symptoms. Histology revealed a patchy lymphohistiocytic infiltrate in the dermis, with many giant cells. Elastic fibres were less frequently found in these infiltrates; in a few of the giant cells and macrophages fragments of elastic fibres were demonstrated within the cytoplasm. There were no deposits of mucin. For this new variant we propose the term "reticular elastolytic giant cell granuloma."

Adult↗
PubMed1995

[Parakertosis variegata after pityriasis lichenoides et varioliformis acuta].

We report on a 34-year-old male patient who developed generalized parakeratosis variegata lesions 4 years after suffering from pityriasis lichenoides et varioliformis acuta. For further investigation of a possible interrelationship between these two diseases of the parapsoriasis group and their relationship to the T-cell type of cutaneous non-Hodgkin-lymphoma, histological, immunohistological and molecular-biological techniques were applied. We were able to demonstrate typical morphological features common to both diseases, and a polyclonal T-cell infiltrate in both. It is concluded that pityriasis lichenoides et varioliformis acuta and parakeratosis variegata are separate entities without monoclonal rearrangement or signs of malignancy.

Adult↗
PubMed1995

A subset of macrophages located along the basement membrane ("lining cells") is a characteristic histopathological feature of psoriasis.

In this paper, we describe the immunophenotype and ultrastructure of a new macrophage subpopulation present in inflamed but not in normal human skin. In biopsy material from patients with psoriasis (n = 4), atopic dermatitis (n = 4), and positive patch test reactions (n = 4), spindle-shaped macrophages located along the basement membrane were detected staining positive for CD11c (LeuM5 high, Ki-M1 low), CD68 (Ki-M6 low), and Ki-M8 (low). This subpopulation was most prominent in psoriasis, where a median of 34 macrophages neighbored 100 basal keratinocytes, thus covering about 80% of the dermoepidermal junction. The numbers of atopic and positive patch test reactions were 11 and 13, respectively, accounting for about 20% of the dermoepidermal junction. Transmission electron microscopy revealed an electron-lucent nucleus with dense deposits of chromatin along the nuclear membrane. Interruptions of the integrity of the basement membrane neighboring these cells were also seen. We repeatedly observed parts of basal keratinocytes merging through these openings and macrophages exhibiting cytoplasmic extentions directed toward the porus. Our observations suggest vigorous interactions between macrophages and basal keratinocytes and support the hypothesis that these interactions are an important regulatory event in the pathogenesis of psoriasis.

Antigens, CD↗
PubMed1994

["Granulomatous slack skin"--cutaneous elastolytic lymphoma].

The term "granulomatous slack skin" (GSS) was introduced by Ackerman for a disease first described by Convit et al. in 1973. GSS represents a rare cutaneous lymphoma characterized by localized elastolytic lesions with a granulomatous infiltrate. We recently observed two male patients with the characteristic features of this disease. Both patients responded well to therapy with interferon-alpha 2b. In one patient clinical remission was stable under long-term treatment with clofazimine. We report on common features of these two patients and give a review of the cases published in the literature.

Biopsy↗
PubMed1994

Expression of the B7/BB1 activation antigen and its ligand CD28 in T-cell-mediated skin diseases.

Interactions of CD28 (on T cells) with its recently identified ligand B7/BB1 (on antigen-presenting cells) have been shown to activate T cells via a major histocompatibility complex/Ag-independent "alternative" pathway, leading to an amplification of T-cell-mediated immune responses. The in vivo relevance of these molecules for cutaneous immunity is presently unknown. These findings prompted us to study the expression of B7/BB1 and CD28 in normal human skin and in selected T-cell-mediated inflammatory skin diseases. Biopsies were obtained from lesional skin of patients with allergic contact dermatitis, lichen planus, and, as control, from basal cell carcinoma and from healthy controls. Serial cryostat sections were stained with a panel of MoAbs directed against CD28, B7/BB1, CD3, CD1a, and KiM8 using immunohistochemistry (ABC technique). CD28 expression was observed in the majority of dermal and epidermal CD3+ T cells in contact dermatitis and lichen planus. In normal skin and basal cell carcinoma, CD28 was expressed only occasionally by perivascular T cells. In allergic contact dermatitis and lichen planus, B7/BB1-expression was found on dermal dendritic cells, on dermal macrophages, on Langerhans cells, focally on keratinocytes, and occasionally on dermal T cells. No B7/BB1 immunoreactivity was detected in normal skin and basal cell carcinoma. These findings indicate that T-cell-mediated skin diseases are accompanied by an influx of CD28+ T cells and an upregulation of B7/BB1 on cutaneous antigen-presenting cells, keratinocytes, and on some T cells. We speculate that "alternative" T cell-activation via the B7/CD28 pathway may contribute to the pathogenesis of these skin diseases.

Antibodies, Monoclonal↗
PubMed1994

Predominant usage of distinct T-cell receptor V beta regions by epidermotropic T cells in psoriasis.

To investigate the role of T cells in psoriasis, we analyzed the T-cell receptor (TCR) repertoire in peripheral blood lymphocytes (PBLs) and in skin lesions of 9 patients with chronic plaque-stage psoriasis by means of immunohistochemistry. An extended panel of monoclonal antibodies detecting 11 different V beta families was employed in this study. In the peripheral blood, no predominant TCR V beta expression was detected and interindividual differences were small. Skin-infiltrating T cells showed only marginal differences in the TCR V beta usage when compared with PBLs. However, in 3 patients the intraepidermal infiltrate comprised up to 40% of T cells expressing a TCR V beta region which was virtually absent in the peripheral blood and the dermal infiltrate. Thus, although the TCR V beta usage of skin-infiltrating T cells showed little difference compared to PBLs, several cases exhibited a significant increase of epidermotrophic T cells using one particular V beta region.

Epidermis↗
PubMed1994

Clonal disease in early cutaneous T-cell lymphoma.

Our experience with 185 cases of T-cell dominated skin infiltrates demonstrates that the PCR-based method for detection of TCR gamma chain gene rearrangement in combination with temperature gradient electrophoresis can routinely be used for the demonstration of clonal T cells in formalin-fixed and paraffin-embedded biopsies of lesional skin. In contrast to Southern blot analysis, the amplification by PCR is nonradioactive, is not time consuming (approximately 3 days), can be performed using frozen or paraffin-embedded tissue, and allows additional molecular biologic analyses, such as sequencing. Furthermore, it offers the possibility to design patient-specific primers for monitoring of the disease activity. It also has to be concluded from our study that all available clinical, histologic, cytologic, immunophenotypical, and rearrangement studies have to be considered in order to establish the correct diagnosis.

Blotting, Southern↗
PubMed1993

Cellular and molecular composition of human skin in long-term xenografts on SCID mice.

We report on the immunophenotypical characterization of adult human skin transplanted onto severe combined immunodeficient (SCID) mice. Thirty animals were followed for up to 12 months after receiving split-thickness xenografts, of which 28 were tolerated for the whole test period. Antigen mapping revealed an almost complete preservation of human cellular and extracellular tissue components in long-term transplants including skin immune cells (Langerhans-cells, macrophages, lymphocytes) and also parts of the engrafted endothelium. Hence, xenografts on SCID mice offer a versatile experimental tool for the in vivo study of both human skin immune cell function and endothelial cell-mediated interactions in an environment completely devoid of interferences by adoptive host immune response.

Animals↗
PubMed1992

Infiltration of both T cells and neutrophils in the skin is accompanied by the expression of endothelial leukocyte adhesion molecule-1 (ELAM-1): an immunohistochemical and ultrastructural study.

Various inducible adhesion molecules on human endothelial cells like the endothelial leukocyte adhesion molecule-1 (ELAM-1) seem to be the basis of mechanisms that allow peripheral blood leukocytes to enter precisely areas of inflamed tissue. Because in vitro data had shown that ELAM-1 plays a central role in neutrophil as well as memory T-cell endothelium interactions, we analyzed in vivo at the light and electron microscopic level its expression in various benign and malignant skin diseases, which differ in the composition of the cellular infiltrates. The expression of ELAM-1 on endothelial cells at different anatomical sites could be demonstrated independently from the cell type (neutrophils/memory T cells) infiltrating the surrounding tissue. On the ultrastructural level we demonstrate that the expression of ELAM-1 is restricted to certain segments of post-capillary venules exhibiting distinctive morphologic features. The ELAM-1-positive endothelia are identical to those vessels that are currently described to be the preferred sites of lymphocyte trafficking in diseased skin.

Antibodies, Monoclonal↗
PubMed1992

HTLV-1-negative pleomorphic T-cell lymphoma of the skin: the clinicopathological correlations and natural history of 15 patients.

The peripheral T-cell lymphomas represent a heterogeneous group and include, besides mycosis fungoides and Sézary syndrome, large-cell anaplastic lymphoma. We report 15 cases from our files that fulfil the histological criteria of pleomorphic T-cell lymphoma with primary skin involvement. Most of the cases were elderly with a male-to-female ratio of 1.5:1. The HTLV-1 serology was negative. The clinical features of these patients differed from those with mycosis fungoides and Sézary syndrome, in that eczematous and precursor lesions such as parapsoriasis en plaque were lacking apart from one exception. All the patients with small-cell pleomorphic T-cell lymphomas were alive, although three of the nine patients with medium-to-large tumour cells have died. Pleomorphic T-cell lymphoma should be regarded as a distinct entity among the lymphoproliferative disorders of the skin.

Adult↗
PubMed1992

Cellular localizations and processing of the two molecular forms of the Hodgkin-associated Ki-1 (CD30) antigen. The protein kinase Ki-1/57 occurs in the nucleus.

The Ki-1 antibody not only detects a Hodgkin-associated membrane molecule of 120 kd (Ki-1/120 = CD30), but also reacts with an independently synthesized molecule of 57 kd (Ki-1/57) that only occurs intracellularly. Hodgkin's disease-derived cell lines L428 and L540 contain both Ki-1-reactive antigens, whereas others, e.g., U266/Bl myeloma cells, only express the intracellular Ki-1/57. The present immunoelectronmicroscopic analysis detected the Ki-1/57 antigen of U266/Bl cells not only in the cytoplasm, but also in association with the nuclear envelope, chromatin structures, and nucleoli. This Ki-1/57-specific type of labeling also was observed in L428 and L540 cells that, in contrast to U266/Bl cells, showed an additional staining of cell membranes and cytoplasmic vesicles. These results were confirmed by two independent methods: 1) cytocentrifuge preparations of isolated nuclei of L540 cells showed a spotted Ki-1-specific labeling, 2) immunoprecipitations demonstrated that the Ki-1/57, but not the Ki-1/120 antigen, was transferred into the nuclei of L540 and U266/Bl cells, whereas the Ki-1/120 antigen with its 90-kd precursor remained in the non-nuclei fraction of L540 cells.

Antigens, CD↗
PubMed1992

Role of beta 1-integrins in epidermotropism of malignant T cells.

To better understand the molecular mechanisms of epidermotropism, we immunohistochemically analyzed the expression pattern of adhesion molecules belonging to the integrin and immunoglobulin superfamilies in cases of mycosis fungoides (MF) (n = 15), pleomorphic T cell lymphoma (n = 10), and high-grade T cell lymphoma (n = 7). The cutaneous T cell lymphomas (CTCLs) investigated were categorized into cases with or without epidermotropism. Focal neoexpression of ICAM-1 on keratinocytes was restricted to epidermotropic lymphomas. Both LFA-1 and LFA-3 were expressed on infiltrating cells in all cases investigated. In contrast, beta 1-integrins showed differential expression, most prominent in the case of VLA-1 and VLA-6: These molecules were present on infiltrating cells in most cases with epidermotropic MF and absent in most other CTCLs. We conclude that the phenomenon of epidermotropism might involve different sets of adhesion molecules in different entities of CTCL, with VLA-1 being the most influential beta 1-integrin in the case of MF.

Antibodies, Monoclonal↗
PubMed1991

Neutrophil-activating peptide 1/interleukin 8 mRNA expression and protein secretion by human monocytes: effect of cyclosporin A.

Neutrophil-activating peptide 1/interleukin 8 (NAP-1/IL-8) is a recently described cytokine with potent chemotactic activity for human neutrophil granulocytes (PMN) and T cells. In psoriasis, a chronic hyperproliferative and inflammatory skin disorder, PMN and T cells are found as prominent cells in the inflammatory infiltrate of the lesions; however, monocytes were shown to be the first cells invading a newly formed plaque. NAP-1/IL-8 was found to be present in high amounts in the skin and in scale material of psoriatic patients. Psoriasis responds well to systemic treatment with cyclosporin A (CsA), an immunosuppressive peptide. Therefore, we addressed the question of whether the clinical improvement of psoriatic patients during CsA therapy may be due to an inhibition of NAP-1/IL-8 production and secretion from monocytes. Purified human monocytes were stimulated by lipopolysaccharide in the presence or absence of various concentrations of CsA. Production of NAP-1/IL-8 was determined as expression of specific mRNA by fluorescent in situ hybridization. Secreted peptide was measured by bioassay (PMN chemotaxis) and enzyme-linked immunosorbent assay (ELISA) using specific monoclonal antibodies. The results show that CsA neither inhibited mRNA expression for NAP-1/IL-8 nor secretion of the peptide. These findings support the hypothesis that the pharmacological effect of CsA may be restricted to the inhibition of T-cell activation and proliferation.

Cyclosporins↗
PubMed1991

Cell trafficking in positive and negative patch-test reactions: demonstration of a stereotypic migration pathway.

The cellular and molecular events taking place during epidermal antigen exposure in sensitized individuals are principally well understood. Epidermal Langerhans cells (LC) are supposed to take up, process, and express a given foreign substance on their cell surface. The antigen is then recognized by T cells bearing the appropriate T-cell receptor (TCR). Because LC do not bear variable antigen (Ag)-specific binding sites, one could postulate that the epidermal exposure of any substance should activate LC and other cells of the skin immune system. To test this hypothesis, we analyzed immunophenotypically the cellular trafficking events in positive (n = 5) and negative epicutaneous patch-test reactions (n = 10), using a panel of monoclonal antibodies against CD1a, CD11c (Ki-M1, LeuM5), CD68 (Ki-M6), Ki-M8, and CD3 (Leu4). We can demonstrate that irrespective of whether or not an antigen will be responded to by the immune system (i.e., positive or negative test reaction), epidermal antigen exposure causes a decrease of LC density in the epidermis and simultaneously causes an increase of LC in the dermis. Moreover, monocytes and T cells immigrate into the dermis both in positive and negative patch-test reactions. As is to be expected, the degree of this cellular traffic is more pronounced in positive test reactions, which may be due to amplification mechanisms caused by antigen recognition of sensitized T cells. This finding demonstrates that human skin contains cell migration programs that ensure that any foreign substance will be accessible to the skin immune and phagocytic system.

Antibodies, Monoclonal↗
PubMed1991

Upper keratinocytes of psoriatic skin lesions express high levels of NAP-1/IL-8 mRNA in situ.

In order to better understand the factors regulating disease promotion and activity in psoriasis (PS), we searched for the in situ expression of mRNA for various cytokines in long-standing PS skin lesions. Specific hybridization with a NAP-1/IL-8 anti-sense RNA probe was keratinocyte associated and yielded strong and specific signals exclusively in the upper layers of the lesional epidermis, but not in uninvolved skin from psoriatic patients or normal skin from non-psoriatics. Interestingly, NAP-1/IL-8 transcripts were focally clustered in a spotty pattern predominantly between the tips of elongated papillae, but were absent in the lower epidermal region and the dermal compartment. We consistently failed to detect appreciable numbers of TNF-alpha and/or IL-6 mRNA-containing cells in psoriatic lesions. These results support the notion that IL-8, rather than IL-6, is an important disease-promoting cytokine in PS. In view of the known in vitro and in vivo effects of IL-8, it is conceivable that this substance greatly contributes to the major pathologic changes seen in psoriatic skin, i.e., keratinocyte hyperproliferation and leucocyte infiltration. In this case, local pharmacologic down-regulation of NAP-1/IL-8 activity could be a promising therapeutic strategy in PS.

Cell Adhesion Molecules↗
PubMed1991

CD4+ memory T cells in peripheral blood are not decreased in patients with atopic dermatitis.

Atopic dermatitis (AD) is a severe and chronic eczematous skin disease, to which increased IgE levels and imbalances of CD4+ T cells are related. CD4+ T cells, however, are heterogeneous and include at least two subpopulations being designated as CD4+ naive and memory T cells. They represent sequential maturational stages (naive into memory) in CD4+ T cell development differing in function and phenotype. Of these two subpopulations the CD4+ memory T cell compartment is a potent producer of gamma-interferon which suppresses IgE synthesis in B cells. Therefore, we speculated whether an inborn maturation defect of CD4+ memory T cells causes the increased IgE production in AD. In patients with AD and age- and sex-matched controls (both n = 10) we analyzed the distribution of both subpopulations in peripheral blood by two-color flow cytometry using monoclonal antibodies against the CD4, CD45RA and CD29 antigen. We provide evidence that the numerical values of CD4+ memory T cells and CD4+ naive T cells are equivalent in both groups. This supports the view that functional disturbances of lymphocytes or lymphocyte subsets are responsible for IgE excess and the pathogenesis of AD.

Adolescent↗