Expression of activation antigens by T cells infiltrating basal cell carcinomas.

The association of T lymphocytes and dendritic cells with the stromal mononuclear cell response to basal cell carcinomas has led to speculation that cellular immunity may, in part, regulate the growth and development of this neoplasm. It has not been established, however, whether these T cells are functionally competent, or simply coincidental bystanders. We examined the immunologic phenotypes of mononuclear cells in 32 lesions of basal cell carcinoma obtained from 26 patients. The majority of infiltrating mononuclear cells were T cells that were equally distributed between the helper/inducer (Leu 3a+) and cytotoxic/suppressor (Leu 2a+) subtypes; a minority of cells were dendritic and expressed Leu 6 antigen. Virtually all T cells and dendritic cells were HLA-DR+, and many (greater than 30%) of the T cells expressed antigens consistent with stages of ongoing activation (T9, T10). TS2/7, a novel monoclonal antibody recently documented to identify activation-specific subcomponents of 210/165/130 kD glycoprotein complex present on the surface of mitogen- or alloantigen-stimulated human T cells, was also used. Greater than 50% of the T cells observed were TS2/7+. These observations provide in situ immunomorphologic evidence of stromal T cell activation in association with basal cell carcinomas, and suggest a role for active and ongoing cellular immune mechanisms as a determinant of local biological behavior of this neoplasm.

Cutaneous acute graft-versus-host disease to minor histocompatibility antigens in a murine model: histologic analysis and correlation to clinical disease.

Graft-versus-host disease (GVHD) can occur in bone marrow-transplant recipients even when donor and host are identically matched at the major histocompatibility complex. GVHD in this context presumably arises because of differences in minor histocompatibility antigens. Murine GVHD to minor histocompatibility antigens has been studied in an effort to determine whether skin is a target of the immune response in this model system. T cell-depleted marrow cells (10(7)) from B10.BR (H-2k) mice were supplemented with varying numbers of nylon wool-enriched splenic B10.BR T cells and transplanted intravenously into irradiated (1100 R) CBA (H-2k) mice. Sequential biopsies of ear skin were obtained at weekly intervals over a 7-week period. Histopathologic evaluation revealed basal cell layer vacuolization, exocytosis, and satellitosis of mononuclear cells in the epidermis. Dyskeratosis was observed only in animals receiving T cells, and proved to be the most reliable histologic parameter of disease with the number of dyskeratotic cells per linear millimeter of epidermis correlating both with severity of clinical disease and with the number of transplanted T cells. Ultrastructural examination revealed exocytosis of mononuclear cells into the epidermis where they were frequently apposed to degenerating and necrotic keratinocytes. These data indicate that the skin is an informative target organ for study of experimental GVHD to minor histocompatibility antigens.

Inhibition of rat skin allograft rejection by cyclosporine. In situ characterization of the impaired local immune response.

Cyclosporine (CsA) is known to induce long-term survival of skin allografts, although the cellular mechanisms responsible for this effect are not well understood. To further define the effects of CsA-induced immunosuppression, we performed a morphological and immunohistological study of acute skin allograft rejection in the rat, comparing untreated and CsA-treated animals. Three significant differences were found between grafts in CsA-treated and untreated rats. First, CsA-allografts contained fewer MRC OX-8+ cytotoxic T cells than untreated allografts. Second, although the presence and numbers of infiltrating macrophages (W3/25+, W3/13- cells) was not influenced by CsA treatment, CsA treatment blocked expression of a macrophage membrane activation antigen, defined by the monoclonal antibody A1-3, which has previously been linked with development of macrophage procoagulant activity (PCA). Third, diminution in MRC OX-8+ lymphocytes and A1-3+ macrophages in CsA allografts was associated with an absence of the widespread thrombotic and necrotizing microvascular injury typical of acute rejection in untreated rats. We conclude that prolongation of skin allograft survival by CsA is related to its ability to prevent cell mediated injury to the endothelium of graft vessels, and possibly also to inhibition of macrophage PCA with consequent reduced thrombus formation.

Evidence that large granular lymphocytes of donor origin mediate acute graft-versus-host disease.

We have studied the phenotype of mononuclear cells infiltrating target organs of mice with acute graft-versus-host disease after bone marrow transplantation from H-2-identical donors. Infiltrating mononuclear cells with characteristics of large granular lymphocytes (LGL) were frequently found in close association with dead or dying epithelial cells in the skin, liver, and colon. The phenotype of these putative effector cells was Thy-1+, ASGM1+, Mac-1+, Lyt-1-, Lyt-2-, Ia-, which is characteristic of LGL. Differences in the Thy-1 allele between donor and host were used to demonstrate that these cells were of donor origin. Analysis of cytolytic function in GVHD splenocytes indicated high natural killer activity and low cytolytic T lymphocyte (CTL) activity. These findings suggest that an important effector cell in systemic acute graft-versus-host disease is a large granular lymphocyte of donor origin.

Cytotoxic T lymphocytes and phenotypically abnormal epidermal dendritic cells in fixed cutaneous eruptions.

Fixed cutaneous eruptions are erythematous plaques or bullae that recur, often after drug ingestion, at precisely the same cutaneous sites. The study of this condition may provide insight into the mechanisms responsible for regionally localized, immunologically mediated dermatoses. Biopsy specimens from both advancing borders and established centers of fixed eruptions were studied by immunofluorescence microscopy, light microscopy (1-micron sections), and transmission electron microscopy, and with a panel of monoclonal antibodies to Langerhans cells and subsets of T lymphocytes. The dermal inflammatory infiltrates of the advancing edges of the lesions were composed predominantly of OKT4/Leu-3a-positive lymphoid cells in perivascular array. In more established regions (the centers of the lesions), the majority of mononuclear cells were OKT8-positive lymphocytes disposed along the dermal-epidermal junction and migrating into the epidermis through focal defects in the basement membrane. In these areas, keratinocyte reactivity for anti-HLA-DR antibody and the apposition of intraepidermal lymphocytes to degenerating keratinocytes were observed. T6-positive epidermal dendritic cells were observed in normal numbers in the epidermis, although extensive study failed to reveal characteristic Langerhans cell granules within these cells. It is concluded that fixed cutaneous eruptions are characterized by an early vascular phase involving lymphocytes with helper/inducer phenotypes, and a later epidermal phase involving cytotoxic/suppressor cells. Potential effector cells with the phenotypic characteristics of cytotoxic T cells appear to represent important mediators of the epidermal damage characteristic of fixed cutaneous eruptions. Morphologically abnormal epidermal dendritic cells may contribute to regionally altered antigen presentation and may thus be relevant to the recurrence of lesions at identical cutaneous sites.

Lymphocyte subsets and Langerhans' cells in toxic epidermal necrolysis. Report of a case.

Toxic epidermal necrolysis is a life-threatening disease, the pathogenesis of which remains largely unknown. Histologically, in addition to the characteristic epidermal alterations, there is a sparse mononuclear cell infiltrate in the dermis. The immunologic characteristics of this infiltrate are not well known. In a case of drug-induced toxic epidermal necrolysis with fatal outcome in a 48-year-old man, we demonstrated that the majority of the inflammatory cells were of helper/inducer T-lymphocyte subsets, having only a minority of cytotoxic/suppressor T-lymphocytes and rare cells with natural killer cell phenotype. The significance of these observations is discussed, with reference to the occurrence of lesions at epithelial sites bearing local networks of antigen-presenting cells (Langerhans' cells).

Pigmented melanocytic lesions of the conjunctiva--a new approach to their classification.

We report a series of 23 malignant melanomas and 24 cases of benign and premalignant lesions of the conjunctiva and propose a new classification of non-nevoid pigmented benign, premalignant and malignant melanocytic lesions. The question of prognostic features in conjunctival melanoma is briefly discussed.

Dose due to mushroom ingestion in Spain.

The dose due to ingestion of mushrooms depends on their radioactive content. However, not all the mass of the mushroom ingested is digested and assimilated completely by man. To analyse the degree of assimilation of the radioactive content of mushrooms, we have carried out culture under controlled laboratory conditions for Pleurotus eryngii mushrooms to which we added known activities of 134Cs, 85Sr and 239Pu. We then applied the Van Soest method to the fruiting bodies, which were obtained in order to determine the fraction of these radionuclides associated with the major components of the cell that are assimilable by man. Finally, on the basis of the results, we determined the dose due to 137Cs, 90Sr and (239+240)Pu for several mushroom species collected in different natural and semi-natural ecosystems in Spain.

Indoor radon levels in buildings in the Autonomous Community of Extremadura (Spain).

Indoor air samples taken in buildings throughout the provinces of Cáceres and Badajoz in the Autonomous Community of Extremadura, Spain, were analysed for airborne radon concentrations using charcoal canisters. Measurements were made during the years 1998-2000. The geometrical mean indoor concentration was 90 Bq m(-3). An estimated annual effective dose of 1.6 mSv y(-1) was calculated for residents, assuming an equilibrium factor of 0.4 and an occupancy factor of 0.8. The relative importance of the principal variables that condition radon concentrations inside buildings was also delimited experimentally. These were: soil type, construction materials used, the height of the room above ground level, and the degree of ventilation. The temporal evolution of the radon concentration was analysed, as this aspect could be particularly important in a Continental-Mediterranean climate such as that of the two provinces of the study.

Cyanamide-induced liver cell injury. Experimental study in the rat.

Hepatocyte inclusion bodies similar to those described in alcoholics treated with cyanamide were reproduced in the rat. The characteristic inclusions were developed in animals receiving 8 or 16 mg/kg of body weight, whether they were prepared previously with ethanol intake or not. Inclusion bodies consist of round, well-demarcated cytoplasmic areas, which contain a large amount of glycogen disposed in beta-granules, lipid droplets, and secondary lysosomes. They appear at the 13th week of cyanamide treatment onward. Initially, hepatocytes bearing inclusion bodies are located predominantly at the periportal areas, but the lesion later progresses toward the center of the lobule. Prior to the inclusion body development, cyanamide induces another morphologic change in liver cells, consisting of cytoplasmic homogeneous areas, made up of glycogen disposed in alpha-granules and smooth endoplasmic reticulum tubules. This change is described for the first time in relation to this drug.

A comparative ultrastructural study of chondrosarcoma, chordoid sarcoma, and chordoma.

A morphologic and electron microscopic study was made of two chordoid sarcomas. These lesions were compared with two classical chondrosarcomas and two chordomas. These chondrosarcoma cells showed many features common to chondrocytes, such as abundant RER, well-developed Golgi complexes, and microvillous cytoplasmatic membranes. The chordoid sarcomas bore a close morphologic resemblance to the chordomas but the ultrastructural features revealed a close relationship to the chondrosarcomas. The chordoid sarcoma and chondrosarcoma cells had scalloped cytoplasmatic membranes, variable amounts of glycogen, round or oval nuclei and microfibrils, collagen, and electron-dense granules in the ground substance. The chordoma was characterized by the presence of stellate and physalipherous cells, as well as many transitional cells, with varying nuclear morphology; dilated and irregular RER in contact with mitochondria and morphologically varied vacuoles are the main features in the cytoplasm. This study suggests that chordoid sarcoma represents a variety of the chondrosarcoma rather than a form of chordoma. These findings also support the suggestion of Weiss that chordoid sarcoma is an extraskeletal myxoid chondrosarcoma.

Cyanamide-induced liver injury. A predictable lesion.

Cyanamide, a drug frequently used for aversion therapy in chronic alcoholism, induces a liver-cell lesion consisting of cytoplasmic inclusion bodies, structurally similar to those of Lafora. In order to know how frequently the lesion is associated with the intake of this drug, a prospective study was carried out. A biopsy was performed in ten chronic alcoholic patients who had been treated with Cyanamide. Inclusion bodies were present in all patients (7 cases) whose biopsy was taken when they were on Cyanamide and in two other patients whose biopsies were taken 3 and 7 years after discontinuation of the treatment. Inclusion bodies were absent in one case who was treated for a short time and with a small dose and whose biopsy was performed 3 years after cessation of treatment. On the basis of these findings, the lesion may be considered to be predictable. The absence of inclusions in one patient may be explained by their disappearance after cessation of treatment.

Blood-borne spread of a benign giant cell tumor from the radius to the soft tissue of the hand.

A unique case of giant cell tumor of the distal epiphysis of the radius that spread to the soft tissue of the hand after an en bloc excision is reported. Three months after the excision, 27 cutaneous-subcutaneous tumoral nodules, ranging from 0.3 to 1.5 cm in diameter, were observed spreading from wrist to fingers on both hand aspects. Microscopically, the tumor tissue displayed the pattern of a benign giant cell tumor. Multiple tumor tissue emboli were lodged in venules of the soft tissue between nodules and in a small vein. The findings suggest that the tumor emboli arrived at the hand through a mechanism of retrograde embolism through the superficial veins.

Structural hepatic changes associated with cyanamide treatment: cholangiolar proliferation, fibrosis and cirrhosis.

The authors present the clinical and histological findings in a series of 42 liver biopsies from 39 chronic alcoholics treated with cyanamide as aversion therapy. All biopsies displayed characteristic cytoplasmic inclusions in the liver-cells. Fibrosis and disruption of the parenchymal-connective tissue interface were observed in all cases. According to the severity and extension of fibrosis, three stages could be depicted: Stage I. Periportal activity cholangiolar type (ACT), which is defined by cholangiolar proliferation, fibroblastic activation and inflammatory infiltrate, which together cause a blurred appearance of the parenchymal-connective tissue junction. It is the elementary lesion and was observed alone in 26 biopsies. Stage II. Portal-to-portal linkage. It was observed in 10 biopsies, all of which also showed periportal ACT. Three of these came from patients with two biopsies in which transition from stage I (first biopsy) to stage II (second biopsy) was observed. Stage III. Nodular parenchymal regeneration, associated with changes observed in stage I and II. It was found in six patients. The histological picture resembles the biliary type of cirrhosis. There is a clear-cut correlation between the length of treatment and the stage of the hepatic lesion.

Acute cutaneous graft-versus-host disease to minor histocompatibility antigens in a murine model. Evidence that large granular lymphocytes are effector cells in the immune response.

We studied the morphologic and immunophenotypic characteristics of inflammatory infiltrates in the skin of mice with acute graft-versus-host disease induced by bone marrow transplantation between strains differing only in minor histocompatibility antigens. The strain combinations employed (B10.Br - greater than CBA) have been shown to produce a lethal graft-versus-host disease with clinical severity proportional to the number of T lymphocytes added to the donor marrow inoculum. Transplant recipients developed pronounced clinical signs of graft-versus-host disease, including copious diarrhea and weight loss, and histologic alterations in skin strikingly similar to this disease in humans. Our findings indicate that the preponderant mononuclear cell in lesional skin from these animals has phenotypic characteristics of a natural killer cell. This cell was often found in apposition with necrotic epidermal cells. The origin, function, and potential relevance of natural killer cells in lesion formation in this experimental model are discussed.

Hepatitis induced by drugs used as alcohol aversion therapy.

We report here on the hepatic lesions produced in 17 alcoholic patients who had received Cyanamide or Disulfiram as aversion therapy. The characteristic lesion consists of cytoplasmic inclusions, similar to Lafora bodies. They are found predominantly in periportal hepatocytes, including those lining the cholangioles. They appear to be persistent but are lost after death of the inclusion-bearing liver-cell when both the inclusion body and the dead hepatocyte are removed by macrophages. As well as the inclusion bodies, portal or periportal inflammation and necrosis of isolated liver-cells are seen. The inflammatory infiltrate is usually denser in the periportal areas and is associated with liver-cell destruction. The inflammation is usually followed by portal fibrosis which can be severe if treatment is prolonged. In one case, in which two biopsies were performed, cirrhosis developed while that patient was on Cyanamide.

Artritis aguda gotosa y linfoma no Hodgkin / Acute gouty arthritis and non-Hodgkin´s lymphoma

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