Faculty Bibliography

The release of histaminase, a diamine oxidase of the human neutrophil, is initiated by soluble secretagogues. Histaminase is simultaneously inactivated by the reactive oxygen intermediates generated by the respiratory burst. Thus, quantitative assessment of histaminase release relative to other granule markers is best achieved in the presence of superoxide dismutase and catalase. Human neutrophils activated with secretagogues preferential for the specific granule, such as calcium ionophore A23187 in a limited concentration, phorbol myristate acetate (PMA), formyl-methionyl-leucylphenylalanine (fMLP), and concanavalin A, release vitamin B12-binding protein, lysozyme, and histaminase but not beta glucuronidase. PMA activation in the presence of cytochalasin B augments the release of lysozyme and initiates the release of beta glucuronidase through recruitment of the azurophilic granule but has no incremental effect on the release of vitamin B12-binding protein and histaminase observed with PMA alone. Subcellular fractionation of resting neutrophils by sucrose density gradient centrifugation to separate specific granules from two classes of azurophilic granules selectively distributes vitamin B12-binding protein and histaminase to the specific granule fractions

A peroxidase-antiperoxidase study using monoclonal antibodies directed against T and B lymphocytes and Langerhans cells/indeterminate cells (LC/IC) was undertaken in order to understand more clearly the changes observed in erythema multiforme. At the various stages of development, from normal skin to target lesions, the quantity of inflammatory cells differed, but in each case the number of T8+ (cytotoxic/suppressor) cells was greater than the number of T4+ (helper/inducer) cells in the epidermis, whereas the latter exceeded the former in the dermis. Concomitant with the initial epidermis changes, there was an increase in the number of T6+ (LC/IC) cells in the upper and lower epidermis. With slight to moderate basal unit destruction, the number of LC/IC in the upper epidermis exceeded those in the lower epidermis. With severe basal unit destruction, there was a loss of LC/IC in the lower epidermis as detected by T6 reactivity. In fully formed blisters, the LC/IC in the upper half of the epidermis were decreased in parallel with the degree of epidermal necrosis. The character of the lymphocytic inflammatory infiltrate and redistribution in LC/IC are similar to those findings described in allergic contact dermatitis. The clinical, histologic, and immunopathologic changes in erythema multiforme appear to be due in part to cellular immune mechanisms with the lymphocyte as the predominant effector cell, and our data suggest a possible role for LC/IC in this disorder

Dapsone (diaminodiphenylsulfone) has been used therapeutically for a variety of disorders in which mast cell participation has been demonstrated, including bullous pemphigoid and some form of necrotizing vasculitis. The mechanism of action of dapsone in these disorders is unknown but potentially relates to inhibition of mast cell activation and prevention of generation and/or release of mast cell mediators. Evidence for this possibility has been obtained in rat mast cells in which dapsone in a concentration-dependent manner prevented generation of prostaglandin D2 PGD2 from exogenous or endogenous arachidonic acid with 50% inhibition achieved at 1 and 0.2 to 0.4 mM, respectively. Dapsone inhibited cyclooxygenase conversion of arachidonic acid to PGD2 but not the GSH-dependent conversion of 14C-PGH2 to PGD2 by PGH-D isomerase in broken cell preparations. Dapsone prevented the immunologic generation of PGD2 from antigen-challenged rat mast cells but did not affect the release of histamine. Thus dapsone may exert some of its therapeutic effects by prevention of mast cell PGD2 generation

We have examined the effects of a standardized, moderately erythemogenic dose of long-wave ultraviolet (UVA) radiation on normal human skin, with the use of an appropriately filtered solar simulator and sequential biopsy specimens processed as 1-micron Epon-embedded sections. Histologic changes were present immediately after irradiation and evolved slowly during the 48-hour study. The epidermis manifested slight intracellular and intercellular edema and progressive loss of Langerhans cells to approximately one-fifth control values. A dermal infiltrate of neutrophilic polymorphonuclear leukocytes was present in all postirradiation specimens and peaked at 3 hours. A perivascular lymphocytic infiltrate, moderate endothelial cell enlargement, mast cell hypogranulation, occasional massive venular dilation, and sparse red blood cell extravasation were also noted. Overall, our findings expand and quantify earlier impressions that, compared to UVB, UVA has a relatively greater histologic effect on the dermis than on the epidermis, depletes epidermal Langerhans cells, and recruits neutrophils into irradiated human skin

Mycosis fungoides is a T cell lymphoma with a predilection for cutaneous involvement. This paper describes the clinical manifestations and histopathologic features of a case of mycosis fungoides with necrotizing vasculitis localized to the lesions of cutaneous lymphoma. Elevated levels of circulating immune complexes were found in this patient. The large numbers of perivascular malignant helper T lymphocytes may have induced immunoglobulin synthesis, resulting in the formation of these complexes followed by deposition in vessel walls and subsequent necrotizing vasculitis. Possible alternative mechanisms include the presence of anti-T cell antibodies, or cytotoxic effector cells

Mast cells in skin are distributed around dermal and subcutaneous blood vessels. Activation of tissue mast cells produces secretion and/or generation and secretion of a variety of biologically active molecules. Mast-cell-dependent mediators may be classified as smooth-muscle-contracting and vasoactive activities, chemotactic factors, enzymes, and proteoglycans. These mediators alter the microenvironment to produce a biphasic response. The initial or humoral phase of the response is mediated by materials that alter vascular permeability; peripheral blood leukocytes attracted by chemotactic factors establish the cellular phase. Failure to limit the humoral phase creates a pharmacologic state that may be recognized in skin as urticaria/angioedema. The inability to control the cellular phase permits progression to a local inflammatory state with subacute and chronic tissue injury recognized in skin, for example, as necrotizing vasculitis. As an example of the former, certain forms of physical urticaria have provided experimental models in humans to allow observation of the clinical manifestations, study of tissue alterations by histologic analysis, measurement of mediators released into the circulation, and assessment of motility of peripheral blood leukocytes. An example of the role of the mast cell in the production of subacute and chronic inflammatory cutaneous disease is suggested by studies in a patient in whom exposure to the physical stimuli of cold and trauma was followed by initial mast cell degranulation, subsequent tissue deposition of circulating immune complexes, and the development of a necrotizing vasculitis

The buttock skin of clinically normal human subjects was subjected to approximately 2.5 minimal erythema doses of ultraviolet A irradiation. Deep red erythema developed during irradiation, faded slightly within the next few hours, increased to maximum intensity between 9-15 h, and decreased gradually thereafter although still persisting strongly at 48 h. Suction blister exudates were obtained at 0, 5, 9, 15, 24, and 48 h after irradiation as well as suction blister exudates from a contralateral control site and assayed for arachidonic acid, prostaglandins D2 and E2, and the prostacyclin breakdown product 6-oxo-prostaglandin F1 alpha by gas chromatography-mass spectrometry, and for histamine by radioenzyme assay. Increased concentrations of arachidonic acid and prostaglandins D2, E2, and 6-oxo-prostaglandin F1 alpha were found maximally between 5-9 h after irradiation, preceding the phase of maximal erythema. Elevations of histamine concentration occurred 9-15 h after irradiation, preceding and coinciding with the phase of maximal erythema. At 24 h, still at the height of the erythemal response, all values had returned to near control levels. Hence increased concentrations of arachidonic acid and its products from the cyclooxygenase pathway, and of histamine, accompany the early stages up to 24 h. A causal role in production of the erythema seems likely for these substances although other mediators are almost certainly involved

The role of histamine in the hemodynamic and plasma catecholamine responses to intravenous morphine in subjects without cardiovascular disease and not receiving prior medication has not been reported. Systemic hemodynamics and serum histamine and plasma catecholamine concentrations were measured in 10 subjects before and 2, 5, 10, and 20 min after, 0.3 mg kg-1 IV morphine. Serum histamine concentration increased 2, 5, and 10 min after the morphine. Systolic and mean arterial pressures and systemic vascular resistance decreased and cardiac output increased because of increases in heart rate and stroke volume. The most important changes in hemodynamic function occurred after 2 min in association with a 400% increase in serum histamine concentration; these variables, together with serum histamine concentration, returned toward baseline values after 20 min. There was a negative correlation between peak increase in serum histamine concentration and maximum decrease in systemic vascular resistance. Plasma epinephrine concentrations were elevated 5, 10, and 20 min after morphine injection, suggesting activation of the adrenal medulla by histamine. Our data suggest that histamine plays an important role in the acute hemodynamic and plasma epinephrine response to morphine

The sequence of alterations occurring in recurrent erythema multiforme was studied with clinical observations, 1-micrometer tissue sections, and immunofluorescence techniques. Lesions evolved through 3 stages: an initial red papule, a vesicle surmounting a red papule, and a target (iris) lesion. Focal endothelial cell swelling was present in clinically normal skin. In the red papule, endothelial cytoplasmic swelling, vacuolization, and nuclear hypertrophy with luminal obliteration of superficial venules developed. These venular alterations were more marked with endothelial cell necrosis, and involved deeper venules as well in vesicular and target lesions. Lymphocytes surrounded the venules and infiltrated the lower epidermis in the red papule and the vesicular lesions. Venular damage was correlated with the degree of infiltration by lymphocytes, apparently the primary effector cell, suggesting the venule as a primary target of injury. Hypogranulated basophils were noted around venules in vesicular and target lesions. Fibrin deposits were identified within and interstitially beneath the vesicles. The presence of lymphocytes, basophils, and interstitial fibrin deposition is similar to the changes of cutaneous delayed-type hypersensitivity and suggests a role for cell-mediated immunity in the pathogenesis of erythema multiforme