Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves.

An ultrastructural examination of intradermal nerve fibers in Fabry disease revealed signs of lipid accumulation and small unmyelinated nerve fiber degeneration. Many axons were swollen, and their internal organelles were lost. In several damaged axons, dense inclusions, probably lipid, were observed. No lipid inclusions were found in Schwann cells, which may indicate that they utilize different metabolic processes or are impervious to ceramide trihexoside. It is hypothesized that Schwann cells and myelin sheaths act as a metabolic barrier protecting the larger myelinated fibers. Lacking this barrier, the smaller unmyelinated fibers are more susceptible to lipid infiltration. This view may explain the small fiber neuropathy in Fabry disease.

Bullous pemphigoid, an ultrastructural study of the inflammatory response: eosinophil, basophil and mast cell granule changes in multiple biopsies from one patient.

We have studied by electron and light microscopy the inflammatory reaction in lesions at various stages of clinical development from a patient with bullous pemphigoid. The evolution of clinical lesions was associated with a sequence of histopathologic events which began with alterations of mast cells and proceeded to infiltration, first with lymphocytes and later with eosinophils and basophils. Mast cells in the papillary and reticular dermis demonstrated a unique, focal, irregular loss of granule contents. Intact eosinophils demonstrated intracytoplasmic losses of granule contents and karyorrhectic and karyolytic eosinophils had released membranebound granules. Partially and completely degranulated basophils were present within a fibrin gel which formed in the dermis. Thus, the sequence of histopathologic events in the pathogenesis of bullous pemphigoid includes mast cell granule alterations and release of granule contents from eosinophils which are undergoing nuclear and cytoplasmic damage.

Surface membrane alterations in guinea pig basophils undergoing anaphylactic degranulation. A scanning electron microscopic study.

Purified guinea pig blood basophils in short-term tissue culture were studied by scanning and transmission electron microscopy and by 1-micrometer. light microscopic Epon sections after exposure to specific antigen (sheep serum), to guinea pig serum, or to serum-free medium at intervals from 1 minute to 48 hours. Basophils fixed before culture, or after culture in serum-free medium, were spherical cells with uniformly distributed microvilli, ridges, and folds. In cultures with guinea pig serum, basophils frequently assumed a hand mirror configuration, characteristic of motile cells, with a single posterior, microvilli-bearing uropod and anterior ruffles. Specific antigen induced basophils to become rounded, regardless of the culture medium, and resulted in basophil degranulation and histamine release within 5 to 20 minutes. Exposure of cytoplasmic granules to the external medium was initiated by the development, early in degranulation, of a single, 1 to 2 micrometer. in diameter, opening (degranulation pore) in the plasma membrane. The degranulation pore enlarged progressively over 24 to 36 hours, ultimately permitting the egress of membrane-free cytoplasmic granules. The cell pole opposite the degranulation orifice bore numerous prominent folds and ruffles, changes that persisted for at least 24 hours. By 48 hours after exposure to specific antigen (sheep serum), the surface features of basophils had reverted to those exhibited by unstimulated control cells.

Melanoma. An ultrastructural study of the host inflammatory and vascular responses.

Electron microscopic studies of 4 surgically excised human primary superficial spreading melanomas of the skin were done with special emphasis on the host inflammatory and vascular responses to tumor. Host cells participating in the inflammatory response included numerous small lymphocytes, activated macrophages, and mast cells. Some mast cells had lost local portions of granule content, but complete degranulation of mast cells was not seen. Activated macrophages had avidly ingested melanin granules and cellular debris and often were close to dying tumor cells. Lymphocytes, many displaying motile forms, were actively invading the epidermis; formed perivascular cuffs around damaged vessels; and were in intimate contact with living, damaged, and dead melanoma cells. Basophils, eosinophils, and neutrophils were absent from inflammatory infiltrates. Changes of the microvasculature included focal endothelial necrosis and hypertrophy as well as basal lamina changes indicative of repeated episodes of endothelial injury, necrosis and regeneration. These findings are discussed in relationship to a number of recent studies of the immunologically-mediated inflammatory responses to contact allergy, graft rejection, and syngeneic tumor rejection, in man and animals.

Crohn's disease: transmission electron microscopic studies. II. Immunologic inflammatory response. Alterations of mast cells, basophils, eosinophils, and the microvasculature.

Transmission electron microscopy was done using surgically resected specimens from 12 patients with Crohn's disease and three control subjects. Nonulcerated involved areas of ileum as well as proximal, grossly uninvolved resection margins were chosen for study. Specimens for transmission electron microscopy were prepared for viewing by a variety of techniques. Six hundred five Epon embedded blocks were studied by light microscopy, and 112 of these were viewed in the transmission electron microscope. Study of the immunologic inflammatory response revealed a number of changes of interest. The number of mast cells was markedly increased, and they were found predominantly in edematous submucosa and between smooth muscle cells in the muscular coats of the involved gut. Evidence of focal and complete degranulation of mast cells was frequently seen. Basophilic leukocytes, some of which had degranulated, were also identified. Another frequently encountered cell, the eosinophil, showed changes in the granules, which might reflect the release of eosinophil granule materials. Eosinophils also contained an increased number of small dense granules of the arylsulfatase containing type. Eosinophils, basophils, and mast cells formed close associations. Evidence of acute and chronic damage to vascular endothelia was present. Small lymphocytes, plasma cells, macrophages, and epithelioid cells were present. Multinucleated giant cells were infrequently encountered. Lymphoblasts, however, were rarely seen.

Crohn's disease: transmission electron microscopic studies. III. Target tissues. Proliferation of and injury to smooth muscle and the autonomic nervous system.

Transmission electron microscopy was done on surgical specimens from 12 patients with Crohn's disease and three control subjects. Nonulcerated involved areas of ileum as well as proximal, grossly uninvolved resection margins were chosen for study. Specimens for transmission electron microscopy were prepared by a variety of techniques and 112 blocks were examined by electron microscopy. The study was concentrated on two target tissues of the gut: the autonomic nervous system and the smooth muscle. Proliferative and injurious changes were found in each. Proliferation, myofibroblastic transformation, hypercontraction, and necrosis characterized the smooth muscle changes seen in Crohn's disease of the ileum. Autonomic nervous system changes included proliferation of axons containing dense core granules (catecholamines) and axonal necrosis. The possible pathogenetic significance of these changes is discussed here and in the accompanying article beginning on page 606 of this issue.