Biomedical subjects
Publications and source records attributed to B Zweiman.
We found increased serum histamine-releasing activity (HRA) in 27% of patients with chronic idiopathic urticaria. Patterns of clinical manifestations were similar in those with and without serum HRA, including responses to a standard treatment regimen. In HRA+ patients the degree of serum HRA generally correlated with clinical disease activity.
A 44-year-old woman presented with a long history of nausea and vomiting and was found to have hypokalemic metabolic acidosis with elevation of the urine bicarbonate level consistent with the new onset of renal tubular acidosis, type I. Her laboratory findings and histologic picture of a buccal biopsy sample of two minor salivary glands were consistent with Sjögren's syndrome. Treatment with steroids markedly improved her symptoms.
Acoustic rhinometry is a recently developed method for the objective assessment of nasal patency. In this study, acoustic rhinometry was used to measure changes in nasal cavity dimensions in the immediate response to nasal allergen challenge in eight pollen-sensitive subjects. Acoustic rhinometric changes were compared with subjective symptoms, as well as histamine in nasal secretions, cytology of nasal mucosal scrapings, and changes in olfactory function. A significantly greater decrease in nasal airway caliber occurred following allergen challenge as compared to buffer diluent challenge in the same individuals (70% +/- 7% versus 22% +/- 5%). During an allergic response, a strong correlation was found between the minimum cross-sectional area and the volume of the nasal cavity measured by acoustic rhinometry (r = .9). However, no correlation was observed between nasal airway caliber and concomitant subjective congestion reported by the subjects. A modest decrease in olfactory function was seen following allergen challenge (3.1 +/- 1.4 fewer odors identified correctly out of 20; p = .08). However, the alterations of olfactory function did not correlate with changes in nasal patency. The results presented in this study demonstrate that acoustic rhinometry has great potential as a reproducible method for the objective assessment of nasal obstruction occurring in nasal allergen challenge studies.
The stimuli for the accumulation and activation of eosinophils, which are prominent components of IgE-mediated allergic late-phase reactions (LPRs), are not defined. Messenger RNA for interleukin-5 has been found in lymphocytes present in biopsy specimens of skin obtained during LPR 24 hours after antigen challenge. However, it is not known whether interleukin-5 is present to attract or activate the eosinophils that accumulate during the first 6 hours after antigen challenge when cutaneous LPRs are developing. Using reverse transcription-polymerase chain reaction, we have found mRNA for interleukin-5 in biopsy specimens obtained from control challenge sites nor in specimens from sites of antigen challenge of nonreactive subjects. We also found mRNA for interleukin-4 in these sites developing LPR. This pattern suggests that these cytokines may be important in eosinophil accumulation and activation during developing LPR. These findings are of considerable clinical relevance because the eosinophils in LPR are postulated to play major pathogenic roles in chronic allergic diseases.
BACKGROUND: There have been conflicting reports about the effects of inhibition of arachidonic acid metabolism on early- and late-phase cutaneous reactions. We re-examined this question with a unique nonsteroidal antiinflammatory drug, tenidap sodium. Tenidap sodium has been demonstrated in in vitro studies to inhibit cyclooxygenase, lipoxygenase, and cytokine production (interleukin-1, interleukin-6, tumor necrosis factor-alpha). METHODS: In a double-blind, randomized, crossover study, seven pollen-sensitive subjects ingested tenidap (120 mg, by mouth, daily) and placebo for 9 days with a 3-week washout period between treatments. On the eighth day they underwent allergen skin testing, measurable for up to 12 hours, and on the ninth day they underwent 5-hour skin chamber exposures to allergen and buffer. Chamber fluids were analyzed for cellular content, neutrophil granule protein release, cyclooxygenase and lipoxygenase arachidonic acid metabolites, histamine, and tryptase. RESULTS: Tenidap did significantly inhibit cyclooxygenase metabolites at both antigen and buffer sites but had no effect on histamine, tryptase, lipoxygenase metabolites, or granulocyte infiltration. Neutrophil granule release of lactoferrin was lower at the antigen site during tenidap administration, but there was no reduction of elastase release. Prostaglandin E2 and leukotriene E4 increased significantly at antigen sites compared with buffer sites during placebo administration and were the most prominent arachidonic acid metabolites detected. CONCLUSION: Tenidap, despite inhibiting cyclooxygenase release at antigen sites, had no effect on skin test responses to antigen or on antigen-induced mediator release or granulocyte infiltration. We conclude that cyclooxygenase metabolites are not important in the development of an allergic cutaneous inflammatory response.
Previous studies have identified two ultrastructurally distinct forms of mast cell (MC) degranulation following activation. Immunoglobulin E (IgE)-mediated reactions are characterized by a very rapid swelling and fusion of MC granules and abrupt mediator release. In certain chronic disease states (e.g., bullous pemphigoid), there is "piecemeal" degranulation with a more-gradual mediator release effected by microvesicular transport of "pieces" of granules to the cell surface. It is unclear whether these two degranulation patterns are determined by the different natures of the stimuli, heterogeneity among responding MC granules, or temporal factors. To investigate these issues, we have carried out electron microscopic studies with skin biopsies obtained from ragweed-sensitive subjects 15 and 30 s and 1, 3, 5, and 10 min after intradermal ragweed injection. "Anaphylactic"-type granule changes began by 15 s after ragweed injection and were complete by 5 min; unaffected granules were juxtaposed with granules that were swollen and fused. The remaining granules subsequently underwent changes in appearance similar to those seen in piecemeal degranulation. However, microvesicular transport of granule components to the surface was not observed. These findings indicate that skin MC changes in sites of IgE-mediated reactions include not only the typical very rapid anaphylactic degranulation but also a slower onset of gradual alteration of other granules, frequently within the same MC. These different patterns could reflect MC granule heterogeneity with attendant different responses to IgE-mediated stimuli.
Tryptase, a protease produced by all mast cells, was evaluated as a clinical marker of systemic mastocytosis. Two sandwich immunoassays were evaluated, one which used the mAb G5 for capture, the other which used B12 for capture. The B12 capture assay measured both recombinant alpha- and beta-tryptase, whereas the G5 capture assay measured primarily recombinant beta-tryptase. G5 binds with low affinity to both recombinant alpha-tryptase and tryptase in blood from normal and nonacute mastocytosis subjects, and binds with high affinity to recombinant beta-tryptase, tryptase in serum during anaphylaxis, and tryptase stored in mast cell secretory granules. B12 recognizes all of these forms of tryptase with high affinity. As reported previously, during systemic anaphylaxis in patients without known mastocytosis, the ratio of B12- to G5-measured tryptase was always < 5 and approached unity (Schwartz L.B., T.R. Bradford, C. Rouse, A.-M. Irani, G. Rasp, J.K. Van der Zwan and P.-W.G. Van der Linden, J. Clin. Immunol. 14:190-204). In this report, most mastocytosis patients with systemic disease have B12-measured tryptase levels that are elevated (> 20 ng/ml) and are at least 10-fold greater than the corresponding G5-measured tryptase level. Most of those subjects with B12-measured tryptase levels of < 20 ng/ml had only cutaneous manifestations. The B12 assay for alpha-tryptase and beta-tryptase, particularly when performed in conjunction with the G5 assay for beta-tryptase, provides a more precise measure of mast cell involvement than currently available assessments, a promising potential screening test for systemic mastocytosis and may provide an improved means to follow disease progression and response to therapy.
The effect of weight loss on immuno function was evaluated in 14 middle-aged obese women. Cutaneous delayed-type hypersensitivity to five recall antigens was measured before a weight loss of 21 kg and again after weight had been stabilized. Weight loss was associated with a decrease in both number and magnitude of delayed-type hypersensitivity responses. The number of positive skin tests decreased from 3.1 +/- 0.2 to 2.4 +/- 0.3 per subject, and the mean cutaneous induration size decreased by 38%. The decrease in induration size was positively correlated with the decrease in body mass index (r = 0.63), weight (r = 0.59), and fat mass (r = 0.52). These preliminary findings suggest that large weight losses may result in decreased expression of immune function.
We previously found that platelet-activating factor (PAF) stimulated greater lactoferrin secretion by neutrophils of atopics than nonatopics. To help understand underlying mechanisms, we compared agonist-stimulated lactoferrin secretion with another response, superoxide generation, to determine whether there is a global alteration in the reactivity of atopic neutrophils to these stimuli. We also determined Ca2+ mobilization in such neutrophils because such mobilization is a signaling pathway for both superoxide generation and granule content exocytosis. Although PAF again stimulated greater lactoferrin secretion in atopic than in nonatopic neutrophils, the peak superoxide secretion and cytosolic Ca2+ mobilization were not significantly different in atopics and nonatopics. Leukotriene B4-induced superoxide secretion and cytosolic Ca2+ shifts were also similar in atopics and nonatopics. These findings suggest that (1) the enhanced PAF-induced lactoferrin secretion in atopic neutrophils is not a reflection of greater PAF binding or broad-based cell hyperreactivity and (2) a selective signaling pathway in atopic neutrophils may be responsible for the enhanced lactoferrin secretion. These findings may be relevant to in vivo events because we have found increased PAF and lactoferrin release in skin chambers overlying immunoglobulin E-mediated human skin reactions.
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BACKGROUND: Marked variability in the amount of histamine released in the first hour of ongoing cutaneous reactions has been noted. This variability occurs even among subjects with similar degrees of skin test reactivity to antigen. METHODS: To determine gender effects on mediator release, we retrospectively compared: (1) skin chamber histamine release after a 0 to 1-hour and 1 to 5-hour exposure to antigen; (2) neutrophil accumulation after 5 hours of antigen exposure and skin test reactivity to antigen, histamine, and codeine in 91 male and 60 female subjects. RESULTS: There was no difference in skin test reactivity to antigen, histamine, or codeine between male and female subjects. However, in the group as a whole, male subjects released higher amounts of histamine in the first hour (74 +/- 4 ng/ml) than female subjects (55 +/- 4 ng/ml), (p < 0.01). When subjects were matched for equivalent skin reactivity to antigen, male subjects who were sensitive to 10 PNU/ml and 1 PNU/ml released more histamine (67 +/- 9 ng/ml and 82 +/- 9 ng/ml) than female subjects (51 +/- 7 ng/ml and 55 +/- 7 ng/ml) (p < 0.05 and < 0.01). In the most sensitive subjects, those with skin sensitivity to 0.01 PNU/ml of antigen, there was not a significant difference between the histamine release in the first hour in male (79 +/- 12 ng/ml) or female (69 +/- 9 ng/ml) subjects. No difference was observed between male and female subjects in either neutrophil or histamine accumulation in the 1- to 5-hour period. CONCLUSIONS: Since the first hour release of histamine is secondary to mast cell activation and the 1- to 5-hour histamine release is secondary to basophil activation, we conclude that the gender of the subject influences the degree of in vivo antigen-induced histamine release from mast cells.
BACKGROUND: Fibrin formation, assessed by fibrinopeptide A levels, was evaluated over a 5-hour period at skin chamber sites challenged continuously with pollen antigen or codeine in 10 reactive individuals. METHODS: The levels of fibrinopeptide A at antigen sites were compared with those at sites challenged with buffer diluent alone or with codeine for the first 3 hours, followed by antigen challenge during the subsequent 2 hours. RESULTS: Findings showed: (1) fibrinopeptide A levels were higher at antigen challenge sites than at codeine challenge sites by the third hour, with these levels at both sites greater than those at buffer sites; (2) antigen challenge of the previous codeine sites during the third to fifth hours led to a further increase in fibrinopeptide A levels; (3) fibrinopeptide A levels correlated with chamber fluid immunoglobulin G levels but not with chamber fluid histamine levels. CONCLUSIONS: Because antigen and codeine both activate mast cells prominently, these findings suggest that other factors play a role in the persistent fibrin formation at allergic skin reaction sites. Because antigen activates both basophils and mast cells and codeine only activates mast cells, we conclude that both basophils and mast cells contribute to the persistent fibrin formation at sites of allergic reactions.
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To help understand effector mechanisms in experimental allergic encephalomyelitis (EAE) we examined the effects of adding 'irrelevant' lymphocytes from non-EAE donors to major basic protein (MBP)-reactive lymphocytes in the adoptive transfer of EAE (Tr-EAE). The intravenous injection of tetanus toxoid-reactive lymphocytes (TT-cells) and phytohemagglutinin-stimulated lymphocytes on the same day or 2 days after intra-arterial injection of MBP-reactive lymphocytes enhanced the clinical and pathological expression of Tr-EAE. In lymphocyte trafficking studies there was significant accumulation of these injected TT-cells in the central nervous system during enhanced transfer of EAE. W3/25-positive cells were much more predominant in lesion of central nervous system when reinjected with TT cells along with MBP cells compared with lesions of rats injected with MBP cells alone. These findings suggest possible participation of lymphocytes other than MBP-reactive cells in the expression of EAE and provide a useful model to further explore effector mechanisms in the future.
Late phase IgE-mediated reactions (LPR) likely play a major role in the pathogenesis of chronic allergic diseases. Although a number of cellular and humoral alterations in LPR sites have been described recently, the pathogenesis of the LPR is still unclear. LPR follow IgE-mediated but not opiate-induced mast-cell activation suggesting different patterns of mast cell mediator release and/or additional effects of the antigen-IgE interaction. Granulocyte accumulation in developing LPR is accompanied by altered expression of adhesion molecules on local vascular endothelium. Lymphocytes and the cytokines they produce play an important role in developing and perpetuating LPR. These findings point to the likely complex pathogenesis of LPR with implications for the therapy of allergic diseases.
Common variable immunodeficiency (CVI) is a heterogenous disorder with hypogammaglobulinaemia and multiple bacterial infections primarily involving the sinopulmonary tract. CVI patients have been known to have an increased tendency to develop autoimmune manifestations. Commonly associated autoimmune diseases include immune thrombocytopenic purpura, autoimmune haemolytic anaemia, and rheumatoid arthritis. In this paper we report a case of CVI presenting with multiple unusual autoimmune diseases including parotitis, vitiligo, atrophic gastritis, pernicious anaemia, and primary biliary cirrhosis. To our knowledge, this is the first case of CVI with polyautoimmunity and antimitochondria antibody. Recognition of this association is important because early diagnosis and treatment can greatly influence the prognosis.
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The levels of histamine, fibrinopeptide A (FPA), and IgG were determined in chamber fluids overlying sites of antigen versus buffer incubation for up to 7 hours in seven atopic and four antigen-nonreactive subjects. Significant increases in histamine were observed at antigen versus buffer sites in the atopic subjects throughout the 7-hour period. FPA and IgG levels were higher in antigen than in buffer sites from 0 to 5 hours in the atopic subjects. Furthermore, FPA levels correlated with the magnitude of induration at 6 hours after antigen injection in atopic subjects. There were no differences in the levels of histamine, FPA, or IgG at antigen versus buffer sites in the skin test-negative subjects. We suggest that the combination of vascular leakage of proteins, induced by vasoactive mediator release, and activation of these proteins during ongoing cutaneous reactions is responsible for fibrin formation that contributes to the pathophysiology of late-phase allergic responses in the skin.