Importance of paraneoplastic papulosquamous disorders in patients with solid tumors.
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Humans↗
Biomedical subjects
N Silvestris
Publications and source records attributed to N Silvestris.
AIDS-related Kaposi's sarcoma: principal pathogenic mechanisms.
Kaposi's sarcoma (KS) is the most common malignancy that affects patients with HIV infection. Considerable progress has recently been achieved in understanding the pathogenesis of this vascular malignancy. A novel herpesvirus has been detected in KS lesions of all types, in skin-lesions of post-transplant immunosuppressed individuals and in various lymphoproliferative disorders. Apart from this, the increased severity of this neoplasm in patients infected with HIV may be due to HIV-derived tat protein synergising with cytokines and chemokines with angiogenetic activity. Finally, the lower incidence of the malignancy in females may be related to a protective effect of human chorionic gonadotrophin (HCG), presumably mediated by its effect on microvasculature. All these advances suggest new possibilities in the management of the disease.
Acquired Immunodeficiency Syndrome↗
Fas/Fas ligand (FasL)-deregulated apoptosis and IL-6 insensitivity in highly malignant myeloma cells.
IL-6 is a growth factor which interferes in the apoptosis of malignant plasma cells. Here we explore its role in the spontaneous and Fas/FasL-regulated apoptosis of seven myeloma cell clones (MCC). MCC-2 and -7 were constitutively defective in Fas antigen in the presence of large membrane exposure of FasL, and showed a high rate of cell proliferation irrespective of the presence of IL-6. Cytofluorimetric analysis following propidium iodide (PI) staining revealed a minimal extent of spontaneous apoptosis, as in other IL-6-insensitive, though Fas-positive MCC, namely MCC-3 and -5. By contrast, a regular amplitude of apoptosis occurred in the remaining IL-6-dependent clones. Their propensity to cell death, as well as their FasL membrane expression, were promptly down-modulated by the cytokine, whereas no substantial effect was detected in IL-6-independent MCC. Furthermore, we investigated the quantitative secretion of FasL. Both [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) cytotoxicity assay and PI staining of WC8 lymphoblasts from a Fas-transfected mouse lymphoma, incubated with supernatants from MCC, showed a variable cytocidal property, thus confirming the cellular release of FasL. However, a significant elevation of FasL secretion occurred in both Fas- MCC, whereas molecular cloning and sequencing of Fas revealed the presence of a splicing variant, namely Fas Exo4,6Del, in the cDNA from both MCC-3 and -5, which were previously demonstrated to be unresponsive to Fas stimulation. Taken together, these data provide evidence that concurrence of IL-6 insensitivity and deregulation of apoptosis in myeloma cells reflects a high malignancy grade. It is suggested that the secretion of Fas splicing variants in Fas+ plasma cells, as well as the over-production of FasL in Fas- myelomas, are differential mechanisms by which myeloma cells escape host immune surveillance.
ADP-ribosyl Cyclase↗
Mucocutaneous paraneoplastic syndromes (MCPS). A clinical-pathologic review.
Mucocutaneous paraneoplastic syndromes (MCPS) are a common group of dermatoses exhibiting a variable morphologic and pathologic picture which can occur in association with solid tumors or hematologic malignancies. In this review the Authors report the most important clinical characteristics and commonly associated malignancies of these dermatoses. Their identification is important because their superficial appearance and precocious arising are useful in the early diagnosis of an otherwise asymptomatic visceral malignancy and because differential diagnosis between skin metastases and malignancy-associated dermatoses is very important for a careful staging and management of the neoplasm. At the same time, MCPS may also be suggestive of the specific type of cancer present. Finally, the presence of a MCPS often carries grave oncologic implications. Once, therefore, the diagnosis of these dermatoses has been established, either an appropriate evaluation for an asymptomatic neoplasm in a cancer-free individual or an investigation for the recurrence of malignancy in an oncologic patient should be initiated.
Erythema↗
IgG M-components in active myeloma patients induce a down-regulation of natural killer cell activity.
Natural killer cell activity and related cell surface markers of peripheral blood lymphocytes were studied in 73 patients with multiple myeloma, 25 with monoclonal gammopathy of undetermined significance and 20 normal controls. Natural killer cell number was significantly higher in both multiple myeloma and monoclonal gammopathy patients than in controls, whereas the natural killer activity of multiple myeloma patients was inversely related to their disease status. Incubation of peripheral blood lymphocytes or natural killer cells with IgG myeloma proteins purified from several patients induced a down-modulation of basic natural killer activity. This inhibitory effect of monoclonal IgG was dose dependent and significantly stronger in patients with active (at diagnosis and at relapse) than stable multiple myeloma or in normal controls. Addition of exogenous recombinant interleukin-2 restored natural killer cell activity against K562 target cells, indicating that natural killer cells were able to recover their functions. However, recombinant interleukin-2-stimulated natural killer cells were responsive to down-modulation of monoclonal IgG. These data suggest that impaired natural killer cell function in active multiple myeloma is caused by the inhibitory effect of M-component.
Adult↗
Cross-linking of Fas by antibodies to a peculiar domain of gp120 V3 loop can enhance T cell apoptosis in HIV-1-infected patients.
Previous studies have demonstrated that T cell-reactive antibodies in HIV-1 infection contribute to lymphocyte depletion by cytotoxicity that involves differential membrane targets, such as the 43.5-kD receptor on CEM cells. Here, we show that these antibodies bind Fas as result of a molecular mimicry of the gp120. Both flow cytometry and immunoblotting using the human Fas-transfected mouse WC8 lymphoma revealed positive binding of immunoglobulin G from several patients to a 43.8-kD membrane receptor that also reacts with the CH11 anti-Fas monoclonal antibody. Specificity to Fas was further confirmed to chimeric recombinant human Fas-Fc by ELISA, whereas overlapping peptide mapping of a Fas domain (VEINCTR-N) shared by gp120 V3 loop demonstrated a predominant affinity to the full-length 10-mer peptide. Four anti-Fas affinity preparations greatly increased the subdiploid DNA peak of CEM cells similar to agonist ligands of Fas. In addition, anti-Fas immunoglobulin G strongly inhibited the [3H]thymidine uptake of CEM cells in proliferative assays, inducing a suppression as high as provoked by both CH11 mAb and recombinant human Fas ligand. Since anti-Fas were reactive to gp120, it is conceivable that antibodies binding that domain within the V3 region are effective cross-linkers of Fas and increase apoptosis in peripheral T cells. These results suggest that autologous stimulation of the Fas pathway, rather than of lymphocytotoxic antibodies, may aggravate lymphopenia in a number of HIV-1+ subjects.
Acquired Immunodeficiency Syndrome↗
[Common variable immunodeficiency. The authors' personal cases from the last 5 years].
Common variable immunodeficiency (CVI) is a heterogeneous syndrome characterized by defective antibody formation, resulting in abnormally low serum immunoglobulin levels. Clinical presentation usually includes recurrent infections of the respiratory tract, mostly induced by capsular bacteria. Patients are also highly prone to Giardia lamblia infections and related gastrointestinal disorders, as well as to a variety of autoimmune diseases which appear in approximately 20% of them. In addition, CVI can be frequently associated with a non-Hodgkin lymphoma or gastric carcinoma. In spite of its relatively frequent occurrence, the pathogenesis of CVI still remains poorly defined. An overview of the syndrome is published in this issue (pages 616-622). The authors experience (18 cases during last five years) is here reported.
Adolescent↗
[Common variable immunodeficiency].
Common variable immunodeficiency (CVI) is a heterogeneous syndrome characterized by defective antibody formation, resulting in abnormally low serum immunoglobulin levels. Clinical presentation usually includes recurrent infections of the respiratory tract, mostly induced by capsular bacteria. Patients are also highly prone to Giardia lamblia infections and related gastrointestinal disorders, as well as to a variety of autoimmune diseases which appear in approximately 20% of them. In addition, CVI can be frequently associated with a non-Hodgkin lymphoma or gastric carcinoma. In spite of its relatively frequent occurrence, the pathogenesis of CVI still remains poorly defined. In this review the authors describe clinical features, immunological abnormalities and replacement treatment with intravenous immunoglobulins of this antibody deficiency syndrome.
Autoimmune Diseases↗
[Indices of disease activity in systemic lupus erythematosus. Review of the literature].
Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the production of autoantibodies reacting with many different self antigens. The analysis of clinical expression and evolution of this disease is a milestone in the definition of therapeutic strategies. A parameter universally accepted as gold standard is lacking so far. About 60 indices for defining and measuring the activity of this disease have been proposed in the last 20 years. The most important of these are discussed in this review, focusing both on their role in the evaluation and outcome of patients and on the main studies assessing their validity and reliability.
Humans↗
[Apoptosis or programmed cell death: regulatory and pathophysiological mechanisms].
Apoptosis is an active death process genetically encoded to eliminate abnormal or unwanted cells. The phenomenon is induced by a cascade of molecular events leading to nucleolysis by endonucleases and involves a number of membrane receptors and cytoplasmic proteins. These structures (including Fas, müllerian inhibiting substance, p53 and the c-myc oncogene) contribute, by interactive regulatory mechanisms, to the promotion or inhibition of apoptosis, on the basis of both external stimulus and cell activation state. Since apoptosis is a selective process to suppress defective cells, deregulation of genes encoding for such apoptosis-related proteins could be relevant in the growth of several tumors. Remarkably, overexpression of the bcl-2 gene in a few experimental lymphomas has been associated with neoplastic proliferation because of its inhibitory effect on apoptosis. Conversely, early activation of Fas, an apoptosis-inducing gene on HIV-infected CD4+ lymphocytes, is thought to aggravate T cell lymphopenia in HIV infection by increasing the level of normal apoptosis. Genetic deregulation of apoptosis has also been postulated in the pathogenesis of several diseases. Indeed, while preliminary studies suggest that apoptosis plays a role in autoimmune disorders including systemic lupus erythematosus, the pathogenesis of a few degenerative neuropathies, such as Alzheimer's disease, could depend on a similar altered mechanism in apoptosis of neuronal cells. However, no studies are presently available to suggest that exploitation of molecular events of apoptosis would imply therapeutic progress.
Acquired Immunodeficiency Syndrome↗