Adhesion molecules on the human mast cell line HMC-1 are upregulated during cell activation.
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Binding Sites↗
Biomedical subjects
B M Czarnetzki
Publications and source records attributed to B M Czarnetzki.
Mast cells in melanocytic tumours.
The importance of mast cells in local homeostasis, inflammation and tumour surveillance is supported by many studies, and the association of mast cells with various neoplasms has been known for a long time. The functional significance of mast cells surrounding tumours is currently unclear. In the present histopathological study, 16 naevi and 44 primary malignant melanomas were analysed. The follow-up time after primary surgery of malignant melanoma patients was almost 10 years, during which time half of the tumours had metastasized. The numbers of mast cells surrounding pigmented lesions were determined. The mast cells were visualized using a modified toluidine blue staining (pH 0.5; 24 h). Significantly different numbers of mast cells were found in naevi compared to melanomas (P = 0.0013), but no significant correlation could be identified regarding prognostic parameters including tumour thickness and clinical outcome.
Adult↗
Substance P stimulates murine epidermal keratinocyte proliferation and dermal mast cell degranulation in situ.
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Animals↗
Phenotypic characterization of skin lesions in urticaria pigmentosa and mastocytomas.
In order to identify possible cellular abnormalities in human mastocytosis, sections from 13 urticaria pigmentosa lesions and 5 mastocytomas were compared with 5 normal skin specimens using histochemical, enzyme histochemical and immunohistochemical techniques. All toluidine blue-positive mast cells also reacted with Fc epsilon RI and c-kit antibodies, almost all stained for tryptase, many for chymase and the myeloid workshop mast cell antibodies, few for Fc epsilon RII and none for the proliferation marker Ki-67. Urticaria pigmentosa lesions contained fewer epidermal Langerhans cells and a lower percentage of avidin-positive mast cells than mastocytomas and normal skin. Mastocytomas exhibited generally weaker staining for mast cell markers and mostly lacked Fc epsilon RI-bound IgE on mast cells and Langerhans cells, although the receptor was able to bind IgE in tissue sections. Most of the mast cell antibodies also reacted with other cell types. Only toluidine blue, avidin, tryptase and chymase stains were mast cell specific. Mast cells in mastocytosis thus differed only to a minor degree from normal mast cells, although distinct pathomechanisms may play a role in urticaria pigmentosa and mastocytosis.
Adolescent↗
Comparative immunoreactivity of the eosinophil constituents MBP and ECP in different types of urticaria.
In order to elucidate the role of eosinophil constituents in urticaria, we investigated major basic protein expression immunohistologically in comparison with that of eosinophilic cationic protein and the low-affinity IgE receptor in lesional and uninvolved skin of different types of urticaria. Eosinophil activation was studied with the markers EG1 and EG2. Different eosinophil constituents were found in all urticarial lesions except those of urticaria pigmentosa. MBP staining tended to be distributed diffusely throughout the tissue, whereas EG1 and EG2 antibodies were located at or close to individual cells. Staining with the low affinity IgE receptor antibody was rare. In uninvolved skin, major basic protein and particularly eosinophilic cationic protein reactivity was found in chronic recurrent urticaria, delayed pressure urticaria and, to a minor degree, in cholinergic urticaria. No correlation was found between antibody reactivity and eosinophil counts. Reactivity with either of the eosinophil constituents is thus a better marker for eosinophil involvement than routine H&E staining of the cells. The demonstration of eosinophil constituents in non-lesional skin of some urticaria patients suggests generalized eosinophil activation in certain subtypes of the disease.
Biopsy↗
[Rudolf Virchow (1821-1902) and his contributions to dermatology].
The contribution of Rudolf Virchow to dermatology seems to have been forgotten, or present-day dermatologists are not aware of it. The present historical review is intended to show that Virchow's thoughts and the terminology created by him are still alive. The report encompasses a short biography, including Virchow's nonmedical activities. It starts with early experimental publications, which laid to the foundation for his fame, and with dermatological studies of his early period. This is followed by a detailed description of his contributions pertaining to dermatology in his largest work, "Cellular-pathology". Special mention is made of Virchow's lasting contributions to medical, and particularly dermatological, terminology. Finally, his historical studies, his later small publications on topics in dermatology, his pupils and scientific friends, and the social-political and anthropological activities of later years are discussed. Thus, a multifaceted picture is painted of a still modern pathologist who has influenced dermatology in multiple ways.
Dermatology↗
[Annular elastolytic giant cell granuloma with a spontaneous healing tendency].
Annular elastolytic giant cell granuloma is mostly found in middle aged women in skin areas exposed to sunlight. Our 17-year-old female patient had a widespread reddish-brown lesion on the abdomen that met the histological criteria for annular elastolytic giant cell granuloma. However, the clinical findings and the localization were uncommon. UV light was excluded as a trigger. Other, still unknown, factors that might change antigenicity of elastic fibres must be considered. Spontaneous resolution suggests a transient influence of such factors. Differential diagnosis includes skin disorders with elastolysis; discrimination especially from mid-dermal elastolysis is not well defined.
Adolescent↗
[Interleukin 7 in dermatology. Molecular, immunologic and preclinical aspects].
The vast body of knowledge on interleukin-7 (IL-7) that has accumulated over the last few years, i.e. since its discovery in 1988, is of increasing relevance for dermatologists. Because of its particular immunological effects, IL-7 is of particular interest in two areas of dermatology. First, IL-7 can be a valuable addition to immunotherapeutic approaches to the treatment of malignant melanoma. A first pilot study of IL-7 gene-modified autologous tumour cells in the treatment of metastatic melanoma is therefore currently being initiated by the authors. Then, keratinocytes are efficient IL-7-secreting cells and there is evidence that IL-7 can modulate the presence and proliferation of normal and malignant lymphopoietic cells in the dermis. In addition, IL-7 is presently the most potent growth factor for in vitro cultivation of Sézary cells and for the establishment of Sézary cell lines. This report reviews molecular, immunological and preclinical properties of IL-7, with special reference to the possible therapeutic efficacy of this cytokine in dermatology.
Genetic Therapy↗
[Chronic urticaria and hepatitis A].
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Chronic Disease↗
Nuclear proto-oncogene products transactivate the human papillomavirus type 16 promoter.
Human papillomavirus (HPV) type 16 and 18 viral genomes are frequently detected in cervical and penile cancer biopsies. Although this strongly suggests a prominent role for HPV infection in the development of genital cancer, other genetic or environmental factors are also involved. Genital cancer is postulated to result from loss of cellular control functions, which leads to an unregulated expression of HPV oncogenic proteins. In our study, we determined the trans-activating properties of nuclear proto-oncogene proteins c-Fos, c-Jun and c-Myc on P97 enhancer/promoter activity of HPV16. Using a CAT-reporter construct containing the HPV16 enhancer/promoter element, we investigated the trans-activating effects of c-Fos, c-Jun, c-Myc, and E2 in cervical HT-3 cells. c-Fos and c-Jun overexpression resulted in a 3.3- and 3.1-fold up-regulation of CAT activity. Only 2-fold induction was determined by co-transfection with c-myc and the viral transcription factor E2. Based on these findings, we investigated the expression of HPV DNA (16 and 18) as well as nuclear proto-oncogenes (c-fos, c-jun and c-myc) in nine cervical cancers by in situ hybridisation. In six out of nine carcinomas, HPV16 and/or HPV18 DNA was detectable. All tumours showed an intense and homogeneous expression of c-fos and c-jun mRNA, while the signal for c-myc was detectable only in four specimens. These data suggest that deregulation of nuclear proto-oncogene expression may contribute to an overexpression of HPV-derived oncogenic proteins (E6 and E7), which is generally hypothesised to be an important step in the malignant transformation of HPV-associated tumours.
Base Sequence↗
Serum manganese superoxide dismutase is a new tumour marker for malignant melanoma.
Malignant melanoma in its disseminated stage is incurable. The most widely accepted criteria for the prognostic evaluation of melanoma are histopathological and clinical parameters, and the identification of additional simple, serological tumour markers is thus of paramount importance. Manganese-containing superoxide dismutase (MnSOD) belongs to a family of metalloproteins that catalyse the metabolization of oxygen radicals in order to protect these cells from radical damage. In patients with epithelial ovarian carcinomas, serum MnSOD levels have been shown to be elevated in accordance with the progression of their clinical disease. Recently, an overexpression of MnSOD was shown to suppress the malignant phenotype of human malignant melanoma cells. Therefore, we determined serum MnSOD concentrations in 33 patients with malignant melanoma at different clinical stages. Whereas MnSOD serum levels in normal subjects (n = 11) and in dermatological patients with type I allergies (n = 10) or chronic non-allergic urticaria (n = 7) were below 200 ng/ml, the MnSOD serum concentrations in melanoma patients were statistically elevated in all clinical stages compared with normal (p < 0.005). These data suggest that elevated MnSOD serum concentrations correspond to tumour load and correlate with progression of malignant melanoma. Measurement of MnSOD serum levels might therefore provide a sensitive tool for monitoring the clinical course of melanoma.
Adult↗
Glutathione and related enzymes in tumor progression and metastases of human melanoma.
We have shown previously that overexpression of p-170 glycoprotein-mediated multidrug resistance plays only a minor role in conferring chemoresistance to human melanoma cells. In addition to membrane transporters like p-170, metabolizing enzyme systems have been implicated in altered drug sensitivity. Recently, glutathione and associated enzymes have been associated with resistance to alkylating substances, particularly in gastrointestinal and gynecologic cancers. In this study, we investigated whether increased levels of glutathione and related enzymes may play a role in chemoresistance in melanoma. Levels of glutathione, glutathione S-transferase (GST), glutathione reductase, and gamma-glutamyl transpeptidase were analyzed in melanoma and non-melanoma cell lines. In addition, 18 melanoma metastases derived from skin and lymph nodes were examined. Levels of gamma-glutamyl transpeptidase were statistically different in cells derived from melanocytic tumors compared with non-melanoma cell lines and normal cells. In addition, GST levels in metastases derived from skin or lymph nodes were significantly lower than those in permanent cell lines. However, levels of glutathione and related enzymes in metastases and cell lines fluctuated over a wide range, up to 40-fold, regardless of treatment status or origin of metastases. In a second part of the study, the expression of GST isoenzymes alpha, mu, and pi was studied by immunohistology in 10 benign nevi, 29 primary melanomas, and 39 melanoma metastases before and during chemotherapy. Expression of GST isoenzymes was increased with tumor progression, and GST pi was the strongest isoform expressed. However, no correlation was found between GST levels by immunohistochemistry and the course of tumor progression, between GST levels in metastases obtained before or during chemotherapy, or between GST levels and clinical response. These data suggest that alterations in glutathione metabolism and the expression of GST do not play a major role in resistance to chemotherapeutic drugs in melanoma.
Glutathione↗
Beta 2-integrins in different forms of urticaria.
As urticarial lesions involve tissue invasion by inflammatory cells, and as beta 2-integrins play a central part in adhesion of leucocytes to endothelia, allowing their migration into the tissues, we have explored the distribution and sequential expression of these molecules in tissue sections from different forms of urticaria. Prick test weals (of 10 min duration) to common inhalant allergens showed only a minor increase of CD18, whereas in a case of cold urticaria CD11b and CD18 molecules were increasingly upregulated within the first 30 min after elicitation of the lesions. Skin test sites in delayed pressure urticaria, and urticarial lesions (> 6 h duration) of acute and chronic recurrent urticaria also showed marked upregulation of CD11b and CD18, and to a lesser extent of CD11a, but this did not strongly correlate with the intensity of the mixed cellular infiltrate. Non-lesional skin showed expression of beta 2-integrins in chronic urticaria, delayed pressure urticaria, and less so in acute urticaria, suggesting generalized leucocyte activation. This analysis of integrins thus suggests an early and extensive involvement of these molecules in the pathological events associated with the evolution of urticarial lesions.
Acute Disease↗
Expression of stem cell factor in cutaneous mastocytosis.
Stem cell factor has recently been identified as a potent growth factor for bone marrow stem cells, melanocytes and mast cells. In order to evaluate its possible role in human mastocytosis, skin lesions from 13 patients with urticaria pigmentosa and five patients with mastocytomas, and normal skin specimens from five healthy donors were studied by immunohistochemistry, using polyclonal and monoclonal (hkl-12) antibodies against stem cell factor, and a monoclonal antibody (YB5.B8) against its receptor, the c-kit proto-oncogene product. Stem cell factor expression was noted in all sections studied, with an equal distribution pattern for both antibodies, but a weaker intensity with the hkl-12 reagent. Cytoplasmic staining was noted in keratinocytes, Langerhans cells, sweat gland ductal lining cells, mast cells, endothelial cells and spindle-shaped dermal stromal cells. An intense, diffusely granular reaction pattern was noted in all cells, except for a sparse, coarsely granular pattern in mast cells and stromal cells. In urticaria pigmentosa, staining was weaker in keratinocytes, but more prominent in Langerhans cells. In all sections, toluidine blue-positive mast cells and TA 99-positive basal epidermal melanocytes were the only cells to react with the c-kit antibody. Mastocytomas and urticaria pigmentosa lesions thus exhibit different patterns of stem cell factor expression. However, a possible pathogenetic role of this factor in mastocytosis remains to be determined.
Adolescent↗
Two novel mast cell phenotypic markers, monoclonal antibodies Ki-MC1 and Ki-M1P, identify distinct mast cell subtypes.
In order to identify more specific or selective mast cell markers, the reactivity of two monoclonal antibodies, Ki-MC1 and Ki-M1P, was studied by immunohistochemistry in two human cell lines (mast cell line HMC-1, basophilic cell line KU812), in mast cells cultured from blood precursors, in adherent mononuclear cells from peripheral blood, and in mast cells of tissue sections from 13 urticaria pigmentosa lesions, five mastocytomas and five normal skin specimens. Toluidine blue staining, fluorescence staining with FITC-conjugated avidin, and immunohistochemical staining (APAAP) with other mast cell reactive monoclonal antibodies, was performed for comparison. Double staining with the APAAP method, using the Ki-antibodies and toluidine blue, was also carried out. Both Ki-antibodies showed reactivity for skin mast cells, but with a different staining pattern. In addition, the Ki-MC1 antibody did not react with the cell lines, and reacted only with a few peripheral blood mononuclear cells and cultured mast cells. In contrast, the Ki-M1P antibody reacted with almost all cultured mast cells and blood mononuclear cells, but stained only about one-half of lesional and one-fifth of normal skin mast cells. Ki-M1P also reacted with many toluidine blue-negative dermal cells, particularly in urticaria pigmentosa. Ki-MC1 antibody can thus be considered as a useful additional marker for normal skin mast cells. In contrast, the Ki-M1P antibody primarily identifies immature mast cells and monocytes/macrophages, suggesting that these cell types probably originate from the same bone marrow precursor.
Adult↗
Expression of the c-kit receptor in hypomelanosis: a comparative study between piebaldism, naevus depigmentosus and vitiligo.
In order to investigate possible alterations in c-kit protein expression on epidermal melanocytes in different hypopigmentary disorders, we have examined skin specimens from one patient with piebaldism, one patient with naevus depigmentosus, and five patients with vitiligo. Cryosections were examined by immunohistochemistry using monoclonal antibodies against the c-kit protein (YB5.B8) and melanosomes (TA99). In piebaldism, hypomelanotic epidermis contained only a few TA99-positive epidermal melanocytes and no detectable c-kit protein, whereas in naevus depigmentosus the expression of c-kit protein was strong, and TA99 immunoreactivity was faint. In vitiligo lesions, no epidermal immunoreactivity for melanosomes or c-kit protein was found. Normally pigmented skin of all patients showed immunoreactivity of epidermal melanocytes for both c-kit protein and melanosomes. Different hypomelanotic lesions can thus be differentiated by absent melanocyte c-kit protein and low or no expression of melanosomal marker in piebaldism, normal c-kit but low melanosome expression in naevus depigmentosus, and the absence of all melanocyte markers in vitiligo.
Adult↗
P-glycoprotein expression in primary and metastatic malignant melanoma.
Metastatic malignant melanoma is notoriously resistant to chemotherapeutic agents, but the exact mechanisms involved in this drug resistance are unknown. One recently defined major mechanism of multidrug resistance involves the overexpression of P-glycoprotein on cell membranes. In order to evaluate the significance of this putative drug efflux pump for chemoresistance of malignant melanoma, five different antibodies were employed to examine P-glycoprotein expression on tissue from 33 primary malignant melanomas and 35 metastases, before and after chemotherapy, using immunohistological techniques. The expression of P-glycoprotein was low on primary cutaneous melanomas (three of 33), and on metastases (one of 35). Normal tissue in and around the melanoma showed reactivity of endothelial cells, stromal cells and eccrine sweat glands with several antibodies tested. Chemotherapy with drugs commonly used in metastatic melanoma, including agents known to induce P-glycoprotein expression in other tumours (vindesine, cisplatin) had no effect on P-glycoprotein expression in human melanoma metastases. The high chemoresistance of human melanoma cells in vitro and in vivo is probably not mediated via P-glycoprotein, and other possible mechanisms involved will have to be explored in future studies.
ATP Binding Cassette Transporter, Subfamily B, Mem↗