Morphologically distinctive forms of cutaneous mast cell degranulation induced by cold and mechanical stimuli: an ultrastructural study.

To determine whether morphological differences in the response of cutaneous mast cells characterize clinically distinct forms of urticaria, we used ultrastructural techniques to examine skin biopsy specimens from three patients with cold-induced urticaria and four patients with dermographism. Biopsy specimens were obtained before application of the stimulus and at the time of lesion formation. Patients with cold-induced urticaria exhibited morphological alterations only after stimulus application consisting of enlargement and uniform disorganization of some, but not all, granules, fusion of the membranes of adjacent granules, fusion of granule membranes with mast cell membranes, and discharge of electron-lucent and disorganized granule contents into the extracellular space. Mast cells from patients with immediate as well as delayed dermographism exhibited alterations before and after stimulus application consisting of enlargement of most granules, nonuniform (zonal) disorganization or solubilization of granule contents, fusion of granule membranes with mast cell membranes, and extracellular discharge of granule contents. Small cytoplasmic vesicles containing disorganized granular material were associated with the degranulation process. Endothelial cells lining nearby postcapillary venules exhibited prominent perinuclear condensation of contractile microfilaments during degranulation in both groups. Both before and after application of the stimulus, the walls of the superficial dermal vessels of the patients with dermographism were thinner and contained less extracellular matrix material than vessel walls of the patients with cold-induced urticaria. The morphologically distinctive types of mast cell degranulation that characterize these two clinically separable urticarial disorders may indicate different pathogenic mechanisms of lesion formation.

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.

Phenotypic transformation of macrophages to Langerhans cells in the skin.

Langerhans cells, important participants in the cutaneous cellular immune response, are markedly diminished in skin of patients undergoing allogeneic bone marrow transplantation during the first 4 weeks after this procedure. To determine the mechanism responsible for the subsequent repopulation of these cells, the authors studied the immunophenotypic and morphologic profiles of sequential skin biopsies during the posttransplantation period. Cells with surface antigens of monocytes/macrophages within the superficial dermis were gradually replaced by dermal and epidermal dendritic cells exhibiting coexpression of monocyte/macrophage and Langerhans cell surface antigens. Ultrastructural examination revealed that many of these cells contained both prominent phagolysosomes and Birbeck granules. Antigenically and structurally mature Langerhans cells were observed within the epidermis by the end of the second month after transplantation. Phenotypic transformation of phagocytic dermal macrophages to Langerhans cells appears to represent a mechanism for repopulation of Langerhans cells during the period of immunologic reconstitution in this patient population.

Association of basal-lamina defects with epidermal and dermal T6-positive cells: evidence of Langerhans-cell migration.

We observed the apparent migration of Langerhans cells across the basal lamina of normal human skin by immunoelectron microscopy using monoclonal anti-T6 antibody. This technique made it possible to visualize cytoplasmic processes of Langerhans cells not normally detectable by routine transmission electron microscopy, and therefore facilitated the documentation of the migratory process. Although events early in the migratory sequence were not observed, perhaps as the result of the evanescent nature of this phase, the association of Langerhans cells with focal disruptions in the epidermal basal lamina was documented. The basal lamina adjacent to these Langerhans cells was electron lucent, granular in character, and thinned, or intact, suggesting sequential reassembly after disruption. This study provides ultrastructural documentation supporting the hypothesis of ongoing migration of Langerhans cells across epidermal membranes, and suggests that this process is mediated by the disruption and reconstitution of the epidermal basal lamina.

Studies in cutaneous aging: I. The elastic fiber network.

We studied by light and electron microscopy the elastic fibers in he sun exposed and sun protected skin of normal and psoriatic individuals of different ages in order to separate the changes of actinic damage from those of chronological aging. The sun exposed skin showed 2 types of elastic fiber abnormalities-one related to actinic damage and the other to chronological aging. The sun protected buttock skin showed only the latter. From ages 30 to 70, a minority of the elastic fibers exhibited abnormalities that appeared to represent a process of fiber disintegration. After age 70, the majority of elastic fibers showed these abnormalities. These abnormalities were present without accompanying inflammatory cells. Also, there was morphological evidence of continuing synthesis of elastic fibers during the lifetime of these subjects, except that from ages 50-93, the fibers appeared to be loosely, rather than compactly, assembled. Incubation of dermal slices from buttock skin of young adults with porcine pancreatic elastase and bovine chymotrypsin produced elastic fiber degradation that closely simulated the changes that were observed in aged sun protected skin. We propose that one of the features of cutaneous aging is a slow, spontaneous, progressive degradative process inherent in the elastic fiber that can be enzymatically accelerated from decades to hours by elastase and chymotrypsin.

Studies in cutaneous aging: II. The microvasculature.

We studied by light and electron microscopy the microcirculatory vessels in the sun exposed and sun protected skin of normal and psoriatic individuals in order to separate the features of actinic damage from those of chronological aging. In actinically damaged skin, the vascular walls of postcapillary venules and of arterial and venous capillaries were thickened by the peripheral addition of a layer of basement membrane-like material. The veil cells which were intimately related to these layers often had dilated cisternae of rough endoplasmic reticulum containing electron dense material. In 3 of 8 individuals, 70, 70 and 72 yr old, the buttock skin showed mold vascular wall thickening. In 5 other patients, 59-88 yr old the vessels of the buttock skin were normal. In 4 individuals 80-93 yr old, the vessels were abnormally thin (0.5-1.0 micrometer). The veil cells were either absent or decreased in number in these specimens. We propose that (1) the veil cell is responsible for the synthesis and maintenance of the peripheral portion of the vascular wall of the dermal microcirculatory vessels; (2) the veil cell is stimulated to produce excessive basement membrane-like material in response to UV light, factors associated with diabetes mellitus, and possibly to factors associated with the early phase of chronological aging; and (3) with progressive aging there is a decrease in the number and synthetic activity of veil cells which correlates with the appearance of abnormally thin walled vessels.