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Biomedical subjects

Dieter Metze

Publications and source records attributed to Dieter Metze.

At least 19 recordsLinked to original sources
PubMed2006

Junctional basement membrane anomalies of skin and mucosa in lipoid proteinosis (hyalinosis cutis et mucosae).

BACKGROUND: Excessive basement membrane (BM) deposition in skin and mucosa is characteristic for lipoid proteinosis (LP; hyalinosis cutis et mucosae), an inherited disease caused by extracellular matrix protein 1 (ECM1) mutations. According to ultrastructure there are striking differences between junctional and microvascular BM. OBJECTIVE: Distinct analysis of the junctional zone in epidermis and oral mucosa, contrasting concentric BM arrays in the microvasculature; evaluation of impact on epithelial histogenesis and differentiation, and specifically on adhesion structures to BM (hemidesmosomes). METHODS: LP-epithelia were analyzed for alterations in differentiation, BM composition and texture, and hemidesmosomal components by indirect immunofluorescence (IIF), electron microscopy (EM), and immunoelectron microscopy (ImEM). RESULTS: Most striking was the irregular deposition of collagen IV and VII, BM-laminin, and laminin-5 at the junctional zone, accompanied by lamellate or punctuated structures below BM (IIF), whereas integrin alpha6beta4 and bullous pemphigoid antigen-1 and -2 (BPAG-1/-2) were regularly aligned. Also integrins alpha2beta1 and alpha3beta1 remained restricted to the epidermal basal layer, while the tissue-specific differentiation markers keratin K1/10 (mucosa, additionally K4/13) appeared delayed indicating mild hyperplasia, further confirmed by focal K6/16 expression. Ultrastructure (EM) disclosed abundance of extended basal cell protrusions and junctional aberrations like exfoliating excessive BM material. Hemidesmosomes were complete, but ImEM indicated weakened interactions between their components (BPAG-1, -2, and HD1). Confirming IIF, collagen IV and VII, and laminin-5 appeared extensively scattered, the latter two probably remaining associated. CONCLUSIONS: Subtle defects in anchorage assembly, spanning the entire BM zone, apparently compromise epithelial-matrix adhesion, which may provoke (mechanical stress-induced) erroneous BM repair.

Adult↗
PubMed2006

Vascular anomalies in lipoid proteinosis (hyalinosis cutis et mucosae): basement membrane components and ultrastructure.

BACKGROUND: In lipoid proteinosis (LP) vascular anomalies represent severe functional defects caused by excessive deposition of basement membrane (BM)-like matrix, particularly around small subepithelial blood vessels. OBJECTIVE: Correlation of microvascular anomalies in morphology and ultrastructure with extracellular matrix composition and cell interactions for elucidating vascular involvement in LP-pathophysiology. METHODS: Biopsies from non-related LP-patients were analyzed by indirect immunofluorescence (IIF), electron microscopy (EM), and immune-EM (ImEM). RESULTS: In LP-skin and mucosa the thickened vessel walls stained strongly for the BM-components type IV collagen, laminin, perlecan, and nidogen (IIF). Integrin alpha6beta4 was regularly collocated with endothelial surface markers such as PECAM (CD31). Ultrastructure (EM) revealed highly ordered matrix deposits around microvessels, with frequently collapsed lumina, functionally compensated by increased vascular density (histology, IIF). Pericytes were trapped between these concentric BM-layers at varying distances towards the periphery (EM), contrasting their regularly close endothelial apposition. Periodic type IV collagen patterns (ImEM) corroborated the multiple BM-leaflet structure and the lack of a common 'fused' endothelial-pericyte BM, seen normally. Presumptive secretory vesicles, abundant in both cell types, implied an equal contribution to BM-synthesis, but also indicated partial loss of endothelial polarity. CONCLUSIONS: In LP thickened vessel walls, composed of multiple BM, profoundly alter microvascular properties, also by interference with endothelial-pericyte interactions. The increased microvascular density reflects compensatory restoration for disabled function. Most remarkable was the exaggerated secretory activity (also at luminal surfaces) underlining the regulatory key role of extracellular matrix protein 1 (ECM1; mutated in LP) in export or turnover of all major BM-components.

Adult↗
PubMed2006

Immune response modifiers--mode of action.

The innate immune system governs the interconnecting pathways of microbial recognition, inflammation, microbial clearance, and cell death. A family of evolutionarily conserved receptors, known as the Toll-like receptors (TLRs), is crucial in early host defense against invading pathogens. Upon TLR stimulation, nuclear factor-kappaB activation and the interferon (IFN)-regulatory factor 3 pathway initiate production of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha, and production of type I IFNs (IFN-alpha and IFN-beta), respectively. The innate immunity thereby offers diverse targets for highly selective therapeutics, such as small molecular synthetic compounds that modify innate immune responses. The notion that activation of the innate immune system is a prerequisite for the induction of acquired immunity raised interest in these immune response modifiers as potential therapeutics for viral infections and various tumors. A scenario of dermal events following skin cancer treatment with imiquimod presumably comprises (i) an initial low amount of pro-inflammatory cytokine secretion by macrophages and dermal dendritic cells (DCs), thereby (ii) attracting an increasing number type I IFN-producing plasmacytoid DCs (pDCs) from the blood; (iii) Langerhans cells migrate into draining lymph nodes, leading to an increased presentation of tumor antigen in the draining lymph node, and (iv) consequently an increased generation of tumor-specific T cells and finally (v) an accumulation of tumoricidal effector cells in the treated skin area. The induction of predominately T helper (Th)1-type cytokine profiles by TLR agonists such as imiquimod might have further benefits by shifting the dominant Th2-type response in atopic diseases such as asthma and atopic dermatitis to a more potent Th1 response.

Adjuvants, Immunologic↗
PubMed2005

Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients.

In the new World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification of cutaneous lymphomas, large B-cell lymphomas (LBCLs) are divided into 3 groups: LBCL, leg-type (LBCLLT); follicle center lymphoma, diffuse type (FCLDT); and LBCL, others (LBCLO). We studied a large number of primary cutaneous LBCLs to test the validity of the classification and to identify prognostic factors for these patients. Ninety-three cases of primary cutaneous LBCL were analyzed for clinicopathologic features, expression of several markers including Bcl-2, Bcl-6, MUM-1, and FOX-P1, in situ hybridization for Epstein-Barr virus, and molecular analyses of IGH gene rearrangement and of Borrelia burgdorferi and human herpesvirus 8 DNA. Patients were classified into the following categories: FCLDT, 44 cases; LBCLLT, 40 cases; and LBCLO, 9 cases. Statistical analyses showed that the LBCLLT and FCLDT groups were clearly distinct in terms of clinicopathologic features and survival. The LBCLO group had features in between those of LBCLLT and FCLDT. Our study shows that accurate morphologic and phenotypic analyses allow us to stratify most patients into the prognostically different categories of LBCLLT and FCLDT. The definition of a third category of LBCLO requires further studies to clarify whether these cases indeed show distinct clinicopathologic features.

Adult↗
PubMed2005

Surgical treatment of persistent macrocheilia in patients with Melkersson-Rosenthal syndrome and cheilitis granulomatosa.

BACKGROUND: Various conservative methods for treatment of labial swelling in patients with cheilitis granulomatosa have been attempted, often with only moderate success and sometimes with persistent disfiguring lip swelling. Severe macrocheilia can produce an unaesthetic facial deformity associated with functional disturbances. In patients with persistent macrocheilia, reduction cheiloplasty with excision of excess tissue may be indicated when conservative treatment has proven ineffective in reducing swelling but may have been successful in stabilizing disease. OBJECTIVE: To evaluate long-term results after reduction cheiloplasty in patients with macrocheilia caused by Melkersson-Rosenthal syndrome or cheilitis granulomatosa. DESIGN: Follow-up study in 7 patients with severe persisting macrocheilia, including 3 patients with Melkersson-Rosenthal syndrome and 4 patients with cheilitis granulomatosa in a stable state of disease, treated by reduction cheiloplasty at our hospital between January 1, 1987, and December 31, 2002. Preoperative and postoperative medical histories were obtained, and criteria for the success of surgical treatment were evaluated by clinical examination. Different techniques of reduction cheiloplasty are described and demonstrated in representative cases of severe macrocheilia. RESULTS: Surgical treatment in all 7 patients showed satisfying aesthetic and functional outcomes that persisted throughout follow-up (median follow-up, 6.5 years). CONCLUSIONS: Reduction cheiloplasty is an effective method to correct persistent macrocheilia and improve lip aesthetics in patients with Melkersson-Rosenthal syndrome or granulomatous cheilitis in the persistent state of disease. With careful planning, proper sequencing of treatment, and proficiency in the various surgical techniques, optimal results can be achieved.

Adolescent↗
PubMed2005

The expression of the 27-kd heat shock protein in keratinization disorders: an immunohistological study.

In human skin, the 27-kd heat shock protein (hsp27), a member of the small hsp family, is expressed mainly in the upper epidermal layers. Hsp27 functions as a molecular chaperone and is involved in the regulation of cell growth and differentiation. According to experimental evidence, epidermal hsp27, through its chaperone function, might play a role in the assembly of keratin filaments and the cornified cell envelope. This study was conducted to assess the expression pattern of hsp27 in a panel of different ichthyoses. Twelve hereditary and acquired skin diseases associated with an ichthyotic phenotype and 2 corresponding mouse models were investigated by immunohistochemistry on formalin-fixed paraffin-embedded tissue, using a monoclonal antibody specific for hsp27. In ichthyosis vulgaris, lamellar ichthyosis, Sjögren-Larsson syndrome, Netherton syndrome, and acquired ichthyosiform skin condition, the pattern of hsp27 expression resembles healthy human skin. Hsp27 expression was reduced in bullous ichthyosiform erythroderma and annular epidermolytic ichthyosis, and absent in X-linked recessive ichthyosis (1/3 patients) and congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome (1/1). In X-linked dominant chondrodysplasia, 3 small samples are completely negative and 2 larger samples show a pattern resembling random X inactivation. In the mouse models, tattered and bare patches, representing the murine analogues to X-linked dominant chondrodysplasia and congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome, expression of hsp25 (the murine homologue of hsp27) also showed lyonization, demonstrating a clear-cut link between hsp27 expression and underlying molecular pathology. Our results show that loss of hsp27 is a rare event in human epidermis that is associated with specific genetic defects. Among the cases described here, these defects are either in suprabasal keratins or in enzymes involved in cholesterol biosynthesis. The expression and chaperone function of hsp27 might be modified by low/absent epidermal cholesterol and aberrant substrates (ie, keratins) resulting in protein misfolding, dyskeratosis, and thus contribute to the ichthyotic phenotype.

Animals↗
PubMed2005

Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin.

BACKGROUND: Cannabinoid receptors mediate the psychopharmacological action of marijuana and have been localized in the central and peripheral nervous system as well as on cells of the immune system. OBJECTIVE: Up to now, two cannabinoid receptors (CB1 and CB2) have been cloned and recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in the skin. METHODS: In the present immunohistochemical investigation we determined the precise localization of CB1 and CB2 in sections of human skin and in one case of mastocytosis. RESULTS: CB1 and CB2 immunoreactivity was observed in cutaneous nerve fiber bundles, mast cells, macrophages, epidermal keratinocytes, and the epithelial cells of hair follicles, sebocytes and eccrine sweat glands. In epidermal keratinocytes, hair follicle and sebaceous glands, CB1 and CB2 were distributed in a complementary fashion. Double-immunostaining with an anti-CGRP antibody suggested the presence of cannabinoid receptors on small afferent peptidergic nerves. CONCLUSION: The abundant distribution of cannabinoid receptors on skin nerve fibers and mast cells provides implications for an anti-inflammatory, anti-nociceptive action of cannabinoid receptor agonists and suggests their putatively broad therapeutic potential.

Animals↗
PubMed2005

Indeterminate cell histiocytosis: fact or fiction?

Indeterminate cell histiocytosis is a rare disorder, in which the predominant cells have the characteristics of both Langerhans cells and macrophages. We, in this study, describe 18 patients and compare them with those previously published. Most patients were adults with either solitary or multiple red-brown papules or nodules. While most lesions were confined to the skin, both conjunctival and bony involvement was seen. Histologically, the lesions showed patterns resembling those described for xanthogranulomas, with predominantly oncocytic (nine patients), spindled (five patients), scalloped (two patients) or vacuolated (two patients) macrophages. The accompanying infiltrate was mainly lymphocytic, although eosinophils and occasionally plasma cells were seen. All lesions were positive for macrophage markers, such as KP1 (CD68) and Ki-M1p, as well as for S-100 protein and showed variable reactivity for CD1a. No Birbeck granules were seen ultrastructurally in one patient. Some patients shared features with sinus histiocytosis with massive lymphadenopathy. It is unclear whether this disorder is a separate entity or represents various macrophage disorders identified at various time points in the inflammatory response. Ratzinger G, Burgdorf WHC, Metze D, Zelger BG, Zelger B. Indeterminate cell histiocytosis: fact or fiction? A clinicopathological series of 18 patients.

Adult↗
PubMed2005

Early activation of cutaneous vessels and epithelial cells is characteristic of acute systemic onset juvenile idiopathic arthritis.

In biopsies of 16 patients (mean: 5.2 years) with acute systemic onset juvenile idiopathic arthritis (SOJIA), we analysed the initial cellular events during the characteristic cutaneous rash for composition of the infiltrate and for expression of activation markers on epithelial and endothelial cells. Despite the fleeting nature of the rash, there was a characteristic infiltration of neutrophils and monocytes, accompanied by a marked expression of endothelial adhesion receptors. In addition, we found a general activation of the cutaneous epithelium reflected by the expression of the pro-inflammatory S100-proteins - myeloid-related protein 8 (MRP8) and MRP14. In responders to therapy, follow-up biopsies showed a complete normalization of these inflammatory parameters, whereas non-responders presented with continuous signs of activation. In conjunction with the high level of epithelial activation, we detected an infiltrate of leucocytes within epithelium of sweat gland ducts during active SOJIA. Such a pattern has not been described for other inflammatory skin diseases nor did we find it in biopsies from nine patients with acute urticaria. It was accompanied by exclusive expression of MRP8, but not MRP14 by the secretory cells of sweat glands. Because MRP8 and MRP14, released by epithelial cells, exhibit pro-inflammatory effects on endothelial cells and leucocytes, the particular expression pattern of MRP8 and MRP14 in SOJIA is likely to represent a decisive early constitutive component in this inflammatory disease. Their differential expression further points to distinct roles of the individual molecules in inflammatory processes.

Arthritis, Juvenile↗
PubMed2005

[Erythrokeratodermia variabilis (EKV)--a disorder due to altered epidermal expression of gap junction proteins].

Erythrokeratodermia variabilis (EKV) is a rare autosomal dominant genodermatosis with disturbed epidermal differentiation. Its clinical picture varies from transient, fast moving erythema to persistent brown hyperkeratoses. The gene defect in EKV was recently located on the short arm of chromosome 1 encoding the gap junction protein connexin 31. We report on a 48-year-old patient with sharply circumscribed, scaling erythema on the extremities, buttocks and trunk starting since 30 years of age. Histological investigation showed orthokeratotic hyperkeratosis with focal parakeratosis overlying an acanthotic epidermis. Immunohistochemistry revealed a decreased expression of the gap junction protein connexin 31 as well as increased expression of connexin 43. At the ultrastructural level, widened intercellular spaces in the upper epidermis were present with regular desmosomes, adherens junctions and gap junctions. Epidermal cell proliferation and differentiation are regulated by gap junctions. The mutation in connexin 31 is regarded therefore as causal for the clinical picture of the EKV. The unique upregulation of connexin 43 may occur as a consequence of the Cx31 mutation and temporarily compensate for this defect.

Acitretin↗
PubMed2004

Solar-simulated ultraviolet radiation-induced upregulation of the melanocortin-1 receptor, proopiomelanocortin, and alpha-melanocyte-stimulating hormone in human epidermis in vivo.

Ultraviolet light is one of the most crucial environmental factors with regard to its capacity to induce skin cancer, premature aging of the skin, and immunosuppression. Although ultraviolet directly affects the function of epidermal cells, many of these effects are mediated by induction of cytokines, growth factors, and neuropeptides, such as alpha-melanocyte-stimulating hormone. Recently, in addition to its well-known pigmentation inducing activity, a strong anti-inflammatory as well as an immunomodulatory potential of alpha-melanocyte-stimulating hormone has been recognized. The aim of this study was to determine, whether ultraviolet irradiation affects the expression of both alpha-melanocyte-stimulating hormone and the melanocortin-1 receptor in human epidermis in vivo. The volar aspects of the forearms were exposed to twice the minimal erythema dose of solar-simulating radiation. Three, 6, and 24 h after irradiation, the proopiomelanocortin and interleukin-10 mRNA levels in suction blister induced epidermal sheets were considerably upregulated as detected by semiquantitative reverse transcription-polymerase chain reaction. Furthermore, alpha-melanocyte-stimulating hormone and interleukin-10 protein levels in blister fluids were significantly increased 24 h after ultraviolet irradiation, an effect that could be abolished by application of the broad-spectrum sunscreen Anthélios XL prior to ultraviolet (solar-simulating radiation) exposure. In addition, enhanced melanocortin-1 receptor mRNA and receptor protein expression upon solar-simulating radiation was ascertained by reverse transcription-polymerase chain reaction and immunohistochemistry of the epidermal sheets, respectively. Proopiomelanocortin-derived neuropeptides, such as alpha-melanocyte-stimulating hormone may therefore play an important part in modulating ultraviolet-induced inflammation.

Adolescent↗
PubMed2004

Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients.

A new group of subcutaneous, natural killer (NK), NK/T-cell, and other cytotoxic T-cell lymphomas of the skin has been recently described, and some have been included as distinct clinicopathologic entities in the classification of hematologic malignancies recently proposed by the World Health Organization. In the European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas, they would be classified either as CD30- large T-cell lymphoma, small/medium pleomorphic T-cell lymphoma, or subcutaneous T-cell lymphoma. Precise clinicopathologic and prognostic features of all of them have not yet been well characterized. We studied retrospectively 81 biopsies from 50 patients with subcutaneous, blastic natural killer (NK), NK/T-cell, or other non-mycosis fungoides cytotoxic T-cell lymphomas of the skin. Clinical, morphologic, phenotypical, and genetic features and data on Epstein-Barr virus association allowed us to classify our cases according to the following 7 categories: a) subcutaneous "panniculitis-like" T-cell lymphoma (SPTCL): 10 cases (estimated 5-year survival: 80%); b) blastic NK-cell lymphoma: 12 cases (estimated 5-year survival: 0%); c) nasal-type extranodal NK/T-cell lymphoma: 5 patients (estimated 5-year survival: 0%); d) epidermotropic CD8+ T-cell lymphoma: 5 cases (estimated 5-year survival: 0%); e) cutaneous gamma/delta T-cell lymphoma: 8 cases (estimated 5-year survival: 0%); f) cutaneous alpha/beta pleomorphic T-cell lymphoma: 8 cases (estimated 5-year survival: 0%); and g) cutaneous medium/large pleomorphic T-cell lymphoma, not otherwise specified: 2 cases. Our study shows that these cutaneous lymphomas can be classified according to precise diagnostic categories. With the exception of SPTCL, analysis of follow-up data from our patients showed that these groups of lymphomas are characterized by an aggressive course, regardless of the diagnostic category.

Adult↗
PubMed2004

Expression of SOCS-1, suppressor of cytokine signalling-1, in human melanoma.

Cytokine resistance is a well-established feature of melanoma cell progression and represents also a major obstacle in immunotherapy of patients with metastatic melanoma. To check whether suppressors of cytokine signalling (SOCS) play a role in cytokine resistance and tumor progression of melanoma, we investigated the expression and regulation of SOCS-1, an established negative regulator of interleukin-6 (IL-6) and interferon (IFN) signalling. In vitro SOCS-1 transcripts were detectable by RT-PCR in 8 out of 8 human melanoma cell lines derived from different tumor stages. Normal human melanocytes also expressed SOCS-1 mRNA in the presence or absence of artificial growth factors. Both IL-6 and alpha-IFN induced rapid and transient SOCS-1 mRNA expression in WM35 and WM9 melanoma cells. At the protein level, SOCS-1 was undetectable in normal human melanocytes whereas uniformly expressed in all tested melanoma cell lines. The aberrant SOCS-1 protein expression in melanoma cells was recapitalized in situ as shown by immunohistochemical analysis. SOCS-1 immunoreactivity was closely related to tumor invasion (Clark level), tumor thickness according to Breslow, and stage of the disease. In contrast, melanocytes in normal skin or melanocytic nevi lacked SOCS-1 protein expression. Our findings show that melanoma cells express a member of the SOCS family, SOCS-1, in vitro and in situ. SOCS-1 is a progression marker of human melanoma and may downregulate biological responses by endogenous and/or therapeutically administered cytokines.

Antineoplastic Agents↗
PubMed2004

Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures.

The vanilloid receptor subtype 1 (VR1)/(TRPV1), binding capsaicin, is a non-selective cation channel that recently has been shown in human keratinocytes in vitro and in vivo. However, a description of VR1 localization in other cutaneous compartments in particular cutaneous nerve fibers is still lacking. We therefore investigated VR1 immunoreactivity as well as mRNA and protein expression in a series (n = 26) of normal (n = 7), diseased (n = 13) [prurigo nodularis (PN) (n = 10), generalized pruritus (n = 1), and mastocytosis (n = 2)], and capsaicin-treated human skin (n = 6). VR1 immunoreactivity could be observed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands. Upon reverse transcriptase-polymerase chain reaction and Western blot analysis, VR1 was detected in mast cells and keratinocytes from human skin. In pruritic skin of PN, VR1 expression was highly increased in epidermal keratinocytes and nerve fibers, which was normalized after capsaicin application. During capsaicin therapy, a reduction of neuropeptides (substance P, calcitonin gene-related peptide) was observed. After cessation of capsaicin therapy, neuropeptides re-accumulated in skin nerves. In conclusion, VR1 is widely distributed in the skin, suggesting a major role for this receptor, e.g. in nociception and neurogenic inflammation.

Adolescent↗