Apoptosis in the Nervous System in Experimental Allergic Encephalomyelitis

We report here for the first time the occurrence of apoptosis of cells in the spinal cord in experimental allergic encephalomyelitis (EAE), an autoimmune, T-cell-mediated demyelinating disease. Four different forms of EAE were studied in the Lewis rat: (i) acute EAE induced by inoculation with whole spinal cord and adjuvants; (ii) acute EAE induced by inoculation with myelin basic protein (MBP) and adjuvants; (iii) acute EAE induced by the passive transfer of MBP-sensitized spleen cells; (iv) chronic relapsing EAE induced by inoculation with whole spinal cord and adjuvants followed by treatment with low-dose cyclosporin A. Cells undergoing apoptosis were recognized at light and electron microscopy by the presence of either crescentic masses of condensed chromatin lying against the nuclear envelope or rounded masses of uniformly dense chromatin. They were found in both the white and grey matter of the spinal cord in all 4 forms of this disease. Although it was not possible to identify definitively the types of cells undergoing apoptosis, the size and location of some of the affected cells suggested that they were oligodendrocytes. As there is now a large body of evidence that T-cell-induced target cell death takes the form of apoptosis, it is attractive to hypothesize that oligodendrocyte apoptosis is occurring in EAE as a result of oligodendrocyte-directed T-cell cytotoxicity. However, other apoptotic cells were located within the myelin sheath, meninges and perivascular spaces and were clearly not oligodendrocytes but were most likely blood-derived mononuclear cells. The sparsity of their cytoplasm and the absence of phagocytosed material suggested that they were mainly lymphocytes rather than macrophages. Apoptosis has been shown to be involved in deleting autoreactive T-cells during the normal development of tolerance. Thus apoptotic deletion of myelin/oligodendrocyte-specific lymphocytes in the central nervous system in EAE might explain both the subsidence of inflammation and the acquisition of tolerance in this autoimmune disease

An electron microscopic study of giant cytosegresomes in acute liver injury due to heliotrine

Large, PAS-positive globules that develop in the cytoplasm of the liver parenchymal cells of rats poisoned with the pyrrolizidine alkaloid heliotrine were shown to have a heterogeneous structure when examined with the electron microscope. Some represent segregated areas of cytoplasmic degradation. Others do not contain remnants of organelles and are probably derived from endocytosis vacuoles. Large, composite bodies consisting of various combinations of homogeneous vacuoles and fragments of partially degraded cytoplasm were commonly seen. Many had clearly arisen by accretion of their diverse components in sequential, discrete steps. The findings are in accord with histochemical studies indicating that the globules are lysosomal in nature. Occasionally, small dense bodies were observed in the process of fusing with large vacuoles. This suggests that the globules acquire at least some of their digestive enzymes from pre-existing lysosomes

An electron microscopic study of liver cell necrosis due to albitocin

Liver cell necrosis produced in rats by injection of the triterpenoid glycoside albitocin was studied with the electron microscope. Coagulative necrosis was of two distinct types. The first was characterized by the presence of clumps of calcium-associated, electron-opaque granules in the matrix of mitochondria, the changes closely resembling those described in necrosis due to various other toxins. However, in the second, clumps of matrix granules were absent and the appearances were like those seen in ischaemic necrosis and in in vitro autolysis. It is probable that this second type of necrosis resulted from sinusoidal obstruction, which followed the development of the first type of necrosis in the peripheral parts of the lobules. Mitochondria1 abnormalities provided the best indication of the development of coagulative necrosis, but the findings cast doubt on the importance of calcium accumulation within mitochondria as a causative factor in the initiation of necrosis. Shrinkage necrosis involved cellular condensation followed by fission into multiple, membrane-bounded cytoplasmic fragments. Some of these were ingested by parenchymal cells and histiocytes. Others probably underwent a process akin to coagulative necrosis

Recurring digital fibrous tumour of childhood: An electron microscopic and virological study

A digital fibrous tumour of the type described by Reye was examined with the electron microscope. The large cytoplasmic inclusions that constitute the distinctive histological feature of this lesion were found to comprise compact masses of granules and filaments without a limiting membrane. They closely resembled structures that have been shown to develop in the cytoplasm of cells infected with various species of viruses and that have been interpreted as virus assembly sites. However, no viral particles could be identified in the tumour and attempts to isolate viruses were unsuccessful. Crystals were frequently found in the vicinity of the granular inclusions: their significance was not clear. Bodies that bore a superficial histological resemblance to the inclusions were seen in a tissue culture of the tumour, but contamination of the culture with a yeast prevented studies that might have elucidated their nature

Apoptosis: Its significance in cancer and cancer therapy

Apoptosis is a distinct mode of cell death that is responsible for deletion of cells in normal tissues; it also occurs in specific pathologic contexts. Morphologically, it involves rapid condensation and budding of the cell, with the formation of membrane‐enclosed apoptotic bodies containing well‐preserved organelles, which are phagocytosed and digested by nearby resident cells. There is no associated inflammation. A characteristic biochemical feature of the process is double‐strand cleavage of nuclear DNA at the linker regions between nucleosomes leading to the production of oligonucleosomal fragments. In many, although not all of the circumstances in which apoptosis occurs, it is suppressed by inhibitors of messenger RNA and protein synthesis. Apoptosis occurs spontaneously in malignant tumors, often markedly retarding their growth, and it is increased in tumors responding to irradiation, cytotoxic chemotherapy, heating and hormone ablation. However, much of the current interest in the process stems from the discovery that it can be regulated by certain proto‐oncogenes and the p53 tumor suppressor gene. Thus, c‐myc expression has been shown to be involved in the initiation of apoptosis in some situations, and bcl‐2 has emerged as a new type of proto‐oncogene that inhibits apoptosis, rather than stimulating mitosis. In p53‐negative tumor‐derived cell lines transfected with wild‐type p53, induction of the gene has, in rare cases, been found to cause extensive apoptosis, instead of growth arrest. Finally, the demonstration that antibodies against a cell‐surface protein designated APO‐1 or Fas can enhance apoptosis in some human lymphoid cell lines may have therapeutic implications

Apoptosis induced by mild hyperthermia in human and murine tumour cell lines: A study using electron microscopy and DNA gel electrophoresis

Mild hyperthermia is known to enhance apoptosis in a range of normal and neoplastic cell populations. Studies of tumours previously shown to respond to heating in this manner might be expected to provide insights not only into the mechanism of hyperthermic cell killing, but also into the apoptotic process in general. In the present study, cell death induced by 43°C heating for 30 min in two human Burkitt's lymphoma lines, BM 13674 and WW1, and in murine mastocytoma P‐815 × 2·1 was found to be exclusively apoptotic in type, identification being based on light and electron microscopic appearances and on the presence of internucleosomal cleavage of DNA into fragments that are multiples of 180–200 base pairs, which was demonstrated by agarose gel electrophoresis. The heat‐induced apoptosis was prevented by the presence of zinc sulphate, an inhibitor of the endonuclease considered to be responsible for the DNA cleavage, but was not suppressed by the protein synthesis inhibitor cycloheximide. The findings question the validity of the widely held view that active protein synthesis is an invariable prerequisite for the execution of apoptosis. It is suggested that an inositol triphosphate‐mediated increase in cytosolic Ca, resulting from limited membrane damage, might be the critical event responsible for activation of apoptosis by mild hyperthermia. Copyrigh

The spontaneous occurrence of apoptosis in squamous carcinomas of the uterine cervix

A distinctive type of individual cell necrosis occurring in squamous carcinomas of the uterine cervix has been studied by light and electron microscopy. The first stage of the process involves condensation and fragmentation of scattered tumour cells with the production of compact, membrane-bounded bodies in which organelles appear well preserved. These are then phagocytosed by either neoplastic epithelial cells or histiocytes, and are degraded by lysosomal hydrolases. The phenomenon is identical with shrinkage necrosis or apoptosis, which has been described in non-neoplastic tissues under both physiological and pathological conditions, and in several other neoplasms. The findings indicate that cell loss by this means is often considerable in cervical carcinomas, and are consistent with the hypothesis that the spontaneous occurrence of apoptosis might largely account for the discrepancy known to exist between the rate of cell multiplication in malignant tumours and their rate of growth