Faculty Bibliography

Seven individuals with exercise-induced anaphylaxis under natural circumstances, characterized by the appearance of pruritic cutaneous erythema and urticaria and associated vascular collapse and/or upper respiratory tract symptoms and signs of angioedema, were subjected to a controlled period of exercise in a laboratory. Experimental challenge consisted of running in an occlusive suit on a treadmill of moving grade with maintenance or acceleration of speed for 5 to 17 min. Cutaneous pruritus and erythema without urticaria developed in four of the subjects and progressed to angioedema in two of them; the other three subjects were unaffected. Repeat challenge of three of the abnormal responders elicited a clinical response similar to that of the previous exercise challenge. In those subjects with a clinical response to exercise challenge, mean change from baseline levels of histamine to peak levels was 7.0 +/- 3.0 ng/ml (mean +/- SEM), whereas in the group without clinical symptoms the mean change from baseline was an increase of 0.6 +/- 1.6 ng/ml (mean +/- SEM). The abnormal elevations in serum histamine during the seven exercise-induced symptomatic episodes returned to normal in about 20 min while clinical signs were also subsiding. There were no changes in pulmonary function. Exercise-induced anaphylaxis is clinically separable from cholinergic urticaria and represents a distinct form of physical allergy

The local effects of intracutaneous injections into humans of 1-3 nmol of five products of arachidonic acid metabolism, leukotrienes (LT) C4, D4, E4, and B4 from the 5-lipoxygenase pathways and prostaglandin (PG) D2 from the cyclooxygenase pathway, were assessed clinically and histologically. In equimolar concentrations, LTC4, LTD4, and LTE4, elicited erythema and wheal formation, in which a wheal with central pallor was present up to 2 hr, and the erythema persisted as long as 6 hr. PGD2 elicited a wheal that lasted up to 1 hr and erythema that lasted up to 2 hr. The dermal vascular sites affected by LTD4 and PGD2 included capillaries, superficial and deep venules, and arterioles. LTB4 elicited a transient wheal and flare, followed in 3-4 hr by induration that was characterized by a dermal infiltrate comprised predominantly of neutrophils. The combination of LTB4 and PGD2 elicited tenderness and increased induration associated with a more intense neutrophil infiltration. Thus, the products of the 5-lipoxygenase pathway of arachidonic acid metabolism in nanomole amounts can induce cutaneous vasodilation with edema formation and a neutrophil infiltrate, and these responses are enhanced by a cyclooxygenase pathway product, PGD2

Malignant atrophic papulosis is a disease characterized by multiple distinctive cutaneous and often lethal visceral infarctions. In some individuals, the diagnosis is not made until the skin manifestations are noted in a seriously ill patient with gastrointestinal and/or central nervous system disease. In other individuals, the disorder may pursue a benign course with only skin manifestations for many years. Using refined light microscopy to examine the skin lesions, the extensive nature of the necrotic microvascular alterations, a predominant lymphocytic infiltrate, and neural changes are documented. These findings suggest that the cutaneous lesions of malignant atrophic papulosis may result from a lymphocyte-mediated necrotizing vasculitis that affects the entire cutaneous microvasculature

Anti-IgE-dependent activation of rat and human mast cells resulted in the preferential generation of the cyclooxygenase products prostaglandin D2 (PGD2) and prostaglandin I2 (PGI2) in the rat and PGD2 in the human. The average net generation of PGD2, determined by gas chromatography-mass spectrometry, was 13.1 ng/10(6) purified rat mast cells and 39.5 ng/10(6) dispersed, enriched human mast cells. After IgE-dependent activation, there was a linear relationship between the net quantities of PGD2 generated and of histamine secreted from dispersed human pulmonary cells when the number of mast cells was varied but the total number of cells was held constant, indicating that it is the number of mast cells participating in IgE-dependent activation, rather than total mast cell number, that determines PGD2 generation. A linear relationship was also shown between PGD2 generation, determined by radioimmunoassay, and the release of the granule marker beta-hexosaminidase from purified rat mast cells on the dose-response portion of the plot of their response to anti-IgE challenge. With higher concentrations of anti-IgE, PGD2 generation from rat mast cells plateaued, whereas net percent beta-hexosaminidase release increased further. In kinetic studies of rat mast cells activated with anti-IgE, the onset (1 to 2 min) and time of maximum generation (5 to 10 min) for PGD2 were delayed relative to the onset (15 to 30 sec) and completion (1 to 2 min) of beta-hexosaminidase release. Thus, the extracellular appearance of PGD2 during IgE-dependent mast cell activation represents a response additional to the secretion of granule-associated mediators

The effect of aging on epidermal Langerhans cells (LC) and on their response to a single ultraviolet (UV) exposure was studied in skin biopsy specimens of healthy adults, 4 aged 22-26 yr and 7 aged 62-86 yr. In unirradiated skin, old adults had fewer LC than young adults, 5.8 +/- 1.1 versus 10.0 +/- 0.8 (mean +/- SEM) per 3 mm wide cross-section (p = .015). Following irradiation with 3 times the minimal erythema dose, recognizable LC were absent in all but 2 subjects within 24 hr. However, LC number fell less rapidly in old adults and was almost unchanged at 4 hours (5.8 +/- 1.1 versus 5.0 +/- 1.2), while in young adults LC number decreased from 10.0 +/- 0.8 to 3.3 +/- 1.3 during the same period (p less than .05). Other changes noted in both young and old subjects following irradiation included cytoplasmic vacuolization, frequent apposition of LC to severely damaged keratinocytes, and the finding of LC in the basal layer of the epidermis rather than exclusively suprabasilarly as in control sections. These data demonstrate an age-associated loss of epidermal LC and slowing of LC response to UV irradiation. UV-induced LC changes appear qualitatively similar in young and old adults and include histological evidence of cellular damage, transient association of LC with damaged keratinocytes, and possible migration of LC from the irradiated epidermis within 24 hr

In order to determine the effect of age on the capacity of human skin to mount an inflammatory response, the sunburn reaction was studied quantitatively in 4 subjects aged 22-26 yr and 7 subjects aged 62-86 yr. Buttock skin of each subject was exposed to 3 time his minimal erythema dose, using the Hanovia mercury vapor lamp; 1 micrometer histologic sections and determinations of histamine and prostaglandin E2 (PGE2) from suction blister aspirates were used to monitor the reaction. Clinically, erythema and edema were less (p less than .05) in irradiated skin of the old subjects during the first 24 hr. Nonirradiated skin contained less histamine and PGE2 in old adults (p less than .05), approximately 50% of young adult levels. Histamine levels rose early in the reaction and returned to baseline by 24 hr; 4 hr peak values averaged 9.2 ng/ml in old vs. 18.3 ng/ml in young adults. PGE2 rose more slowly in blister aspirates from old adults (P less than .05), but reached comparable peaks, 6-9 pg/T.V., in both groups at 24 hr. Biopsies of control skin from old adult specimens contained fewer mast cells and venules (P less than .01). At 4 and 24 hr, old specimens revealed fewer sunburn cells and less striking alterations of perivenular mast cells and endothelial cells, but at 72 hr these changes were more prominent than in young adult specimens. The data suggest that with advancing age the sunburn reaction is quantitatively reduced and evolves more slowly following a standardize ultraviolet exposure

The eosinophilic activity appearing in the venous effluent of the cold-induced angioedematous extremity of patients with cold urticaria has been resolved into three fractions by gel filtration and Dowex-1 chromatography. The low molecular weight activity, 300-700 mw, is highly acidic while the activity of 1000-3000 mw is composed of highly acidic and less acidic moieties. Each of the three activities has a different retention time on high pressure liquid chromatography, indicating that they represent distinct fractions which differ in size, charge, and hydrophobicity. Each fraction requires a gradient to attract eosinophils in a dose-response fashion and each deactivates eosinophils at subchemotactic concentrations. The more acidic 1000-3000 mw fractions also attract human monocytes in a chemotactic gradient at concentrations identical to those which attract human eosinophils. These three classes of eosinophil chemotactic activities and the activity for monocytes appear and disappear from the venous effluent with essentially the same time course as a distinct neutrophil chemotactic factor and histamine with cold induction of angioedema in patients with cold urticaria. The elaboration of these diverse chemoattractants in experimentally induced physical allergy provides potential pathways for mast cell-mediated infiltrative reactions

To detect a potential defect in immunoregulatory function in atopic subjects, we studied histamine-induced suppressor-T-cell activity and histamine Type 1 and Type 2 receptors on T cells. Peripheral-blood mononuclear cells from 16 atopic subjects generated less histamine-induced suppressor activity than did those from 20 nonatopic normal controls (P less than 0.005). The percentage of T lymphocytes bearing histamine Type 2 receptors was lower in the atopic group than in the control group (P less than 0.001), but the percentage of cells with Type 1 receptors was the same in both groups. In the atopic subjects, the functional suppressor-cell abnormality positively correlated with the decreased phenotypic expression of histamine Type 2 receptors. No abnormality in concanavalin A-induced suppressor activity was detected in these subjects. Nonatopic control subjects with systemic mastocytosis had normal functional and phenotypic data, suggesting that chronic activation of atopic T cells in vivo by circulating histamine does not explain the abnormal histamine-induced suppressor response