Papillomaviruses, p53, and cervical cancer.
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Genes, p53↗
Biomedical subjects
D M MacDonald
Publications and source records attributed to D M MacDonald.
Epidermal dendritic cells in psoriasis possess a phenotype associated with antigen presentation: in situ expression of beta 2-integrins.
BACKGROUND: Epidermal dendritic cells (DCs) isolated from psoriasis possess greatly enhanced T lymphocyte-activating properties compared with DCs from normal skin, suggesting that DCs in psoriasis express surface antigens crucial for antigen presentation. These include beta 2-integrins and intercellular adhesion molecule (ICAM)-1. OBJECTIVE: Our purpose was to determine DC phenotype in psoriatic compared with normal epidermis with respect to these molecules. METHODS: Tissue sections were single labeled with a peroxidase antiperoxidase (PAP) immunohistochemical technique and double labeled where necessary with a combination of a PAP and an alkaline phosphatase-anti-alkaline phosphatase technique. RESULTS: In psoriatic compared with normal skin, decreased numbers of DCs expressed CD1a (p less than 0.05), whereas increased numbers of DCs expressed class II major histocompatibility antigens (p less than 0.05). In normal skin positive staining for CD18 was not observed, whereas in psoriasis both CD1a+ and CD1a- DCs expressed beta 2-integrins, LFA-1 (CD11a/CD18), and gp 150/95 (CD11c/CD18). DCs in atopic dermatitis and lichen planus were also found to express beta 2-integrins. Neither MAC 1 (CD11b/CD18) nor ICAM-1 was observed on DCs. CONCLUSION: These data are consistent with either migration of dendritic antigen-presenting cells into the epidermis or in situ cytokine modulation of Langerhans cell phenotype in inflamed skin. Furthermore, they indicate that epidermal DCs in psoriasis and other cutaneous inflammatory diseases express molecules that are known to be crucial for Langerhans cell-driven T-cell activation in vitro.
Cell Adhesion Molecules↗
Effect of in vivo interleukin-1 on adhesion molecule expression in normal human skin.
We have examined the expression of three endothelial adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], endothelial leukocyte adhesion molecule-1 [ELAM-1], and vascular cell adhesion molecule-1 [VCAM-1]) in normal human skin following intradermal injection of stratum corneum-derived interleukin-1 alpha (SCIL-1 alpha). In control skin, constitutive expression of ICAM-1 was found on endothelial cells and at low levels on dermal dendritic cells but not on keratinocytes. ELAM-1 and VCAM-1 were present in low levels on endothelium and perivascular dendritic cells, respectively. SCIL-1 alpha injection produced marked endothelial ELAM-1 upregulation. Double staining with neutrophil elastase demonstrated that many ELAM-1-positive vessels contained marginating neutrophils and that interstitial neutrophils were clustered around ELAM-1-positive vessels. An increase in dermal dendritic cell ICAM-1 expression occurred and in two of three biopsies there was keratinocyte expression of ICAM-1 in the SCIL-1 alpha-injected tissue. Also, there was upregulation of VCAM-1 on vascular endothelium and an increase in the dermal dendritic cell expression of this molecule. These results give in vivo confirmation that SCIL-1 alpha modulated endothelial and dermal dendritic cell adhesion molecule expression, and show that endothelial VCAM-1 is regulated in vivo by SCIL-1 alpha, thus providing a regulatable ICAM-1-independent means of mononuclear cell recruitment.
Adult↗
Adhesion molecule expression in polymorphic light eruption.
Endothelial leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) are cytokine-regulated cell-surface leukocyte adhesion molecules. We have investigated the in vivo kinetics and pattern of expression of these adhesion molecules in relation to tissue accumulation of leukocytes in the photodermatosis, polymorphic light eruption (PMLE), which is characterized by dense perivascular leukocytic infiltration. Immunohistology was performed on biopsies taken at varying time points from PMLE lesions induced in 11 subjects by suberythemal solar simulated irradiation. Vascular endothelial ELAM-1 expression was first observed at 5 h, maximal at 24 to 72 h, and remained elevated at 6 d. VCAM-1, minimally expressed in control skin, was induced above background levels on endothelium and some perivascular cells after 24 h and maintained at 6 d. Endothelial cell ICAM-1 expression was increased above control levels at 72 h and 6 d. Keratinocyte ICAM-1 expression, most marked overlying areas of dermal leukocytic infiltration, began at 5 h and was strong at 72 h and 6 d. In addition to lymphocytes, significant numbers of neutrophils but not eosinophils were detected in the dermal leukocytic infiltrate that appeared at 5 h and persisted at 6 d. The pattern of adhesion molecule expression that we have observed is similar to that seen in normal skin during a delayed hypersensitivity reaction. These observations support an immunologic basis for PMLE.
Biopsy↗
Preferential adherence of T lymphocytes and neutrophils to psoriatic epidermis.
T lymphocytes and neutrophils accumulate in psoriatic epidermis. To determine whether the epidermis plays an active role in this process through the production of cellular adhesion factors, leucocyte adherence to lesional psoriasis was compared with normal skin in a modified frozen-section adhesion assay. Lymphocyte and neutrophil suspensions were prepared by standard Ficoll-Hypaque techniques from peripheral blood of normal volunteers and overlaid on to glutaraldehyde-fixed 8-microns cryostat sections of skin. Adhesion of phorbol ester-activated T lymphocytes to the epidermis was significantly greater in psoriasis compared with normal skin (P < 0.01). Adhesion was absent (a) at 7 degrees C, (b) in the presence of EDTA and (c) in the absence of lymphocyte activation. Immunostaining demonstrated that all adherent lymphocytes were CD3+ve (i.e. T cells). Likewise, neutrophils adhered more prominently to psoriatic epidermis. Adhesion was most prominent at the tips of dermal papillae, corresponding to areas of maximal intercellular adhesion molecule-1 (ICAM-1) expression. Both neutrophils and lymphocytes adhered to dermal papillary vascular endothelium. These studies provide functional data that psoriatic epidermal cells are actively involved in leucocyte adherence. The distribution of adhesion suggests that both ICAM-1-dependent and independent mechanisms are involved.
Adult↗
Cutaneous lymphocyte trafficking in the inflammatory dermatoses.
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Cell Adhesion↗
Aberrant expression of p53 tumour-suppressor protein in non-melanoma skin cancer.
Expression of the cellular p53 tumour-suppressor protein was examined in 78 epidermal tumours, including basal and squamous cell carcinomas, keratoacanthomas, solar keratoses, Bowen's disease and viral warts. An immunohistochemical study was employed using the antibody CM-1, raised against recombinant human p53 protein. Positive staining for p53, not detectable in normal cells because wild-type p53 is rapidly degraded, reflects abnormal stabilization of p53 protein, and in many cases suggests p53 gene mutation. p53 immunoreactivity was not observed in normal skin or in viral warts. In contrast, positive staining for CM-1 was seen throughout the tumour in the majority of basal and squamous cell carcinomas and in Bowen's disease. Immunoreactivity to p53 was also observed in the majority of keratoacanthomas and solar keratoses, but was confirmed to areas of dysplastic basal epithelium. This study demonstrates that accumulation of p53 protein, suggestive in many cases of p53 gene mutation and hence loss of tumour-suppressor function, may occur as an important early step in the development of diverse epidermal cancers.
Bowen's Disease↗
Abnormal expression of epidermal growth factor receptor in cutaneous epithelial tumours.
Epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) are important keratinocyte mitogens. Their effects are mediated by a cell membrane receptor (EGFR), quantitative and qualitative abnormalities of which may be responsible for deranged keratinocyte proliferation and differentiation. We have therefore examined EGFR expression immunohistochemically in a variety of benign and malignant epithelial neoplasms using monoclonal antibodies to the extracellular and intracellular receptor domains. In benign tumours (virus wart, seborrhoeic keratosis, keratoacanthoma), there was an ordered pattern of EGFR expression. In malignant tumours (basal and squamous cell carcinoma), there was loss of membrane labelling and cytoplasmic accumulation of the receptor. In premalignant proliferations, there was loss of membrane receptor with either absent cytoplasmic EGFR (actinic keratosis) or cytoplasmic receptor accumulation (Bowen's disease). Evidence of truncated receptors was not found. We suggest that dysregulation of the EGFR may be important in the development of cutaneous epithelial malignancies but that grossly abnormal forms of the receptor do not occur.
Antibodies, Monoclonal↗
Renal disease, epidermal necrosis, and epithelial cell antibodies.
OBJECTIVE: To describe the association between epithelial cell IgM, which has previously been associated with an increased incidence of loss of renal graft in children, with a novel cutaneous eruption and unexplained native renal disease. DESIGN: Observational study on children with epithelial cell antibody presenting with unexplained renal or skin disease. SETTING: General paediatric department and regional paediatric nephrology unit. PATIENTS: Six children (five girls, one boy), who presented to the unit in 1989-90. RESULTS: Three children, two of whom had a history of a hyperpigmented rash, presented with hypertension, proteinuria, and impaired renal function. Renal biopsy specimens from two of these children showed severe arteriolar endothelial cell swelling with arteriolar occlusion. These children fully recovered after treatment with antihypertensive drugs. The third child developed end stage renal failure and required dialysis. Three other children presented with an unusual cutaneous eruption but no evidence of renal disease. Histology of the skin lesions showed acute epidermal necrosis and features consistent with a viral infection. CONCLUSIONS: The aetiology and pathogenesis of the epithelial cell antibody are unknown. These cases indicate that it may have a role in native kidney disease and focal epidermal necrosis. Clinical and histological features suggest that the antibody may be associated with a viral infection.
Acute Kidney Injury↗
Human orf and milkers' nodule: a clinicopathologic study.
We report the clinical and histopathologic features of 17 patients with orf or milkers' nodule infection. The majority were male, 12 to 65 years of age, and gave a history of contact with farm animals. Most lesions affected the hands or arms, ranged in size from 1 to 3 cm, and occurred on average 3 weeks after presumed exposure. On low-power examination the epidermis showed endophytic strandlike proliferations and the dermal papillae were distended by intense edema. There was massive capillary proliferation and dilation and a dense inflammatory infiltrate. High-power examination revealed epidermal viral cytopathic changes with inclusion bodies, clumping of keratohyalin, and cytoplasmic vacuolation that had a distinctive "spongiform" appearance within follicular structures. We conclude that orf and milkers' nodule infection have distinctive histopathologic features, and, in contrast to some previous reports, viral changes may frequently be found.
Adolescent↗
The development of a reproducible immunocytochemical technique for demonstrating colocalized cutaneous antigens.
A number of double immunocytochemical labeling techniques are available that allow simultaneous identification of two antigens in one tissue section. Those most commonly used are (a) the acid elution method, which uses acid buffer to remove one set of antibodies, thus allowing a second set to be applied; (b) the use of noncross-reacting combinations of immunoglobulin subclass and subclass-specific antibodies; and (c) application of the diaminobenzidine (DAB) reaction product as an antibody-blocking reagent, preventing cross-reaction of one set of antibodies with those of a second labeling method. We assessed each technique, using a variety of immunoenzyme methods, for the ability to label antigens that are anatomically separate in one tissue section and those that are colocalized on the same cell surface. Acid elution methods increased antibody cross-reaction. The use of immunoglobulin subclass antibodies resulted in inferior staining. The DAB blocking method, using peroxidase antiperoxidase (DAB substrate) and alkaline phosphatase antialkaline phosphatase (APAAP) (fast red substrate) optimally labeled non colocalized antigens. The substitution of fast blue as the APAAP substrate proved optimal for colocalized antigens, producing brown and blue single-labeled and black double-labeled cells.
Antibodies, Monoclonal↗
Expression of simple epithelial keratins 8 and 18 in epidermal neoplasia.
A systematic study of keratin expression in epidermal lesions (six actinic keratoses, 10 Bowen's disease, seven squamous cell carcinomas) has been undertaken by using a large panel of monospecific monoclonal antibodies to individual keratins. Expression of differentiation-specific keratins was frequently delayed or lost from dysplastic regions. Novel expression of the embryonic, or simple epithelial, keratins 8 and 18 was widely observed in intradermal areas of poorly differentiated squamous cell carcinomas. In addition, the most proliferative of in situ malignancies (Bowen's disease) also contained small numbers of cells expressing simple epithelial keratins. These observations suggest that the expression of simple epithelial keratins may be of functional importance in malignancy of keratinocytes and could be related to tumor invasion and/or to changes in epithelial-mesenchymal interactions.
Antibodies, Monoclonal↗
Endothelial leucocyte adhesion molecule-1 (ELAM-1) expression in cutaneous inflammation.
Endothelial leucocyte adhesion molecule-1 (ELAM-1) is a recently described endothelial surface glycoprotein which is inducible by interleukin 1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) or bacterial lipopolysaccharide (LPS). Using an immunohistochemical technique and a monoclonal antibody (1.2B6) specific for ELAM-1 we have found marked vascular endothelial expression of ELAM-1 in many cutaneous inflammatory disorders, including allergic contact dermatitis, atopic dermatitis and psoriasis, and in dermal infiltrates associated with benign, premalignant and malignant keratinocyte proliferation. In normal skin, minimal levels of ELAM-1 expression were detected. In psoriasis, double-immunoenzyme staining studies revealed a close spatial relationship between ELAM-1 expression and neutrophil margination, suggesting a functional link. Recombinant human interferon-gamma (30 micrograms) injected intradermally in normal adult human volunteers did not substantially upregulate ELAM-1 in contrast to its marked effect on intercellular adhesion molecule-1 (ICAM-1) expression, indicating that this cytokine is probably not involved in ELAM-1 induction in vivo. These results indicate that ELAM-1 is widely induced in cutaneous inflammation with a time course of expression that is longer than that observed in vitro. As ELAM-1 acts as an adhesion ligand for neutrophils, and perhaps monocytes, the expression of this molecule in cutaneous lesions is likely to be an indication of the ability of vascular endothelium to recruit these cells from the circulation. Furthermore, the cytokine inducibility of ELAM-1 is indirect evidence for functional interactions between perivascular mononuclear cells, other resident cells and the blood vessel wall.
Antigens, CD↗
Gamma glutamyl transpeptidase expression in foetal skin, inflammatory dermatoses and cutaneous neoplasia.
Gamma glutamyl transpeptidase (GGT) is an enzyme expressed by some epithelial neoplasms but not normal interfollicular epidermis. In order to examine the relationship between malignant change and de-differentiation we studied histochemically the expression of GGT in human foetal skin, various inflammatory dermatoses and epidermal neoplasms. In foetal skin GGT was detectable after 7 weeks' gestation, reached a maximum at 11 weeks and was undetectable by 24 weeks. It was expressed strongly by squamous cell carcinoma and focally in Bowen's disease and actinic keratoses. There was no GGT expression in basal cell carcinoma or most benign skin tumours, but keratoacanthomas were weakly positive. Keratinocytes in the vicinity of malignant melanocytes also expressed GGT. This study suggests that GGT expression, while not a simple marker of malignancy, may represent reversion to a less differentiated or 'foetal' phenotype.
Adolescent↗
The epidermal basement membrane in basal cell carcinoma: an immunohistochemical study.
An immunohistochemical study of basal cell carcinomas of varying histological type, using a panel of antibodies to constituents of the epidermal basement membrane, showed marked deficiencies in the expression of the antigens identified by the antibodies LH7.2, GB3 and G71. There was no correlation between loss of immunoreactivity to these antibodies and the histological features of the tumour.
Antibodies, Monoclonal↗
Antigenic profile of human acrosyringium.
The demonstration of HLA-DR on human acrosyringium has led to the suggestion that eccrine epithelium, through its interaction with certain molecules, might play an active role in epidermal immune responses. An immunohistochemical study was undertaken to identify the antigenic profile of acrosyringium in normal skin and following the intradermal administration of a T-lymphocyte-derived cytokine, interferon gamma (IFN-gamma). Acrosyringium in normal skin, in contrast to interappendageal epidermis, was found to lack CD1a+ Langerhans cells. However, antigens CD36 (OKM5) and L1 (MAC387) were uniquely expressed by keratinocytes immediately adjacent to the distal portion of acrosyringium. Constitutive expression of each class II MHC antigen, namely HLA-DR, DP and DQ was observed on luminal acrosyringial cells. EMB11 antigen (CD68), a mononuclear cell determinant, was similarly expressed on acrosyringial epithelium in normal skin. Following intradermal administration of IFN-gamma, intercellular adhesion molecule-1 (ICAM-1) (CD54) was induced on acrosyringial epithelium and the expression of HLA-DR was intensified. A range of other markers including CD3, CD4, CD8, CD11a, CD11b and CD15 were not expressed by acrosyringium either in normal skin or after administration of IFN-gamma. Expression of antigens associated with cell-mediated immune mechanisms on acrosyringium is consistent with the hypothesis that it may have an immunological role in epidermal immune responses.
Adult↗
Pulmonary capillary leak syndrome complicating generalized pustular psoriasis: possible role of cytokines.
Two cases are reported of generalized pustular psoriasis complicated by profound alterations in pulmonary capillary permeability. Several features suggest the involvement of cytokines in the pathogenesis of this condition.
Adult↗
The development of excess numbers of melanocytic naevi in an immunosuppressed identical twin.
The development of cutaneous proliferative lesions following renal transplantation has been well documented in the literature. Those lesions most commonly seen include viral warts, actinic keratoses and basal-cell and squamous-cell carcinomata. More recently it has been suggested that melanocyte proliferation, both benign and malignant, may follow renal transplantation, probably as a result of immunosuppression. We report the case of an identical twin who developed numerous benign melanocytic naevi following renal transplantation; no such proliferation of naevi occurred in his identical sibling.
Child↗