Chronic urticaria/angioedema and Graves' disease: Coexistence of 2 antireceptor antibody-mediated diseases.
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Angioedema↗
Biomedical subjects
B Zweiman
Publications and source records attributed to B Zweiman.
Quantitative comparison of cytokine mRNA and inflammatory responses in cutaneous late phase allergic reactions.
UNLABELLED: The aim of this study was to quantitatively compare expression of mRNA for IL-5 and IFN-gamma with the frequency of mRNA-positive cells, total and activated eosinophils, neutrophils, lymphocytes, and vessels expressing adhesion molecules. Replicate biopsies of skin LPR to pollen antigens (Ag) and control injection sites (B) at 6 and 24 h were assessed for: (1) mRNA for IL-5 and IFN-gamma by quantitative RT-PCR (QC-RT/PCR); (2) frequency of cells expressing mRNA for IL-5 and IFN-gamma by in situ hybridization (ISH); (3) inflammatory cells and adhesion molecule expression. More mRNA for IL-5 was found in Ag- than in B-injected sites at 6 and 24 h by both QC-RT/PCR and ISH. Small amounts of mRNA for IFN-gamma were detected in Ag sites by QC-RT/PCR at 6 and 24 h, but were not significantly different than at B sites. The frequency of IFN-gamma mRNA(+)cells was higher in Ag than in B sites at 6 h. There was no correlation between the amount if IL-5 detected by QC-RT/PCR and frequency of IL-5 mRNA(+)cells by ISH. These findings also did not correlate with the degree of inflammatory responses. IN CONCLUSION: (1) greater IL-5 than IFN-gamma deposition in Ag sites suggests Th(2)predominance in LPR; (2) lack of correlation between QC-RT/PCR and ISH findings may reflect varying mRNA content of inflammatory cells.
Adult↗
Temporal patterns of mediator release during developing cutaneous late-phase reactions.
BACKGROUND: Several inflammatory mediators have been found released in sites of cutaneous late phase reactions (LPR). However, the temporal pattern of their release during LPR development has not been characterized. OBJECTIVE: Determine hourly accumulation of mediator release in comparison with gross and inflammatory cell responses during developing LPR. METHODS: Skin chamber appended to sites of allergen and diluent control challenge with hourly collections. Then, study of exuding leucocytes in chamber bases. RESULTS: In the allergen-challenged sites, histamine release peaked in the first hour, then low level release over the next 5 h. Lactoferrin release from neutrophils started by the second hour, likely associated with released IL-8. Eosinophil cationic protein levels started increasing slightly later. The percentage of exuding leucocytes which were activated was significantly higher in the allergen challenge sites than in the control challenge sites CONCLUSIONS: Both gross LPR and local inflammatory cell responses in the skin start soon after the immediate mast cell activation in IgE-mediated responses. Such inflammatory responses include leucocyte activation and mediator release.
Blood Proteins↗
Sequential patterns of inflammatory events during developing and expressed skin late-phase reactions.
BACKGROUND: Although there has been much study of the histologic features of the late-phase reactions (LPR) seen 6 to 24 hours after intradermal injection of allergens, much less is known about the events occurring during development of such LPR. OBJECTIVE: Our purpose was to compare sequential gross and histologic inflammatory responses during developing skin LPR within 6 hours after challenge. METHODS: Gross reactions were measured and biopsy specimens obtained at 20 minutes and 1, 2, and 6 hours after intradermal allergen (Ag) and buffer diluent control (B) injections in 7 atopic subjects with known immediate and LPR. Inflammatory cell responses were compared, as detected by immunohistochemistry in Ag and B sites. These findings were then compared with those at 24 hours. RESULTS: Gross LPR evolved without a hiatus from the immediate wheal responses over the next 6 hours (P =.04 vs that in B sites) and then decreased by 24 hours. Prominent PMN accumulation started by 20 minutes, peaking at 1 hour (P <.01). Eosinophil accumulation was significant, starting at 1 hour (P <.001) and peaking at 6 hours (P < .001). Many eosinophils were activated (EG(2)(+)). T-cell accumulation started at 2 hours (P =.01) and was most prominent at 24 hours. The frequency of vessels expressing E-selectin increased at 1 hour (P <.005), correlating with the degree of local PMN accumulation. The frequency of vessels expressing vascular cell adhesion molecules started increasing at 6 hours (P = .02), well after eosinophil accumulation was prominent. CONCLUSIONS: Skin LPR is characterized by evolution of a gross indurated reaction from the immediate whealing response over the first 6 hours after intradermal Ag challenge, with an early accumulation of PMN and eosinophils, not directly attributable to lymphocyte entry or vascular cell adhesion molecule expression. Likely, multiple other factors may also play roles in the complex pathogenesis of LPR.
Adult↗
Quantitative analysis of T-cell receptor beta variable-gene usage in cutaneous late-phase reactions: implications for T-lymphocyte recruitment in cutaneous inflammation.
To determine if functionally distinct T-lymphocyte (T cell) subsets accumulate in late-phase immunoglobulin E-mediated reactions (LPR), we quantitatively analyzed the immunophenotype and the T-cell receptor beta variable-gene (Vbeta) repertoire of T cells in cutaneous LPR. Peripheral blood and skin biopsies were obtained 6 or 24 h after sensitive subjects were challenged with intradermal injections of grass pollen allergen (Ag) and control (C) solution. The frequency of cells expressing CD3, CD4, CD8, CD45RO, and CD25/mm2 was determined by immunohistochemistry in nine subjects. Vbeta usage was assessed by reverse transcription-PCR in five of nine subjects. A significantly greater frequency of CD3(+) and CD45RO+ (memory) T cells was detected in Ag sites than in C sites at 24 h after challenge but not at 6 h. The frequency of activated (CD25(+)) and helper (CD4(+)) T cells appeared to be increased in Ag sites as well, though not significantly. Vbeta6 was the most commonly expressed Vbeta detected in Ag sites, but it was also detected in accompanying C sites. Vbeta2 was the most commonly expressed Vbeta detected in C sites. Sequence analysis in one case revealed Vbeta expression in a 6-h Ag site to be essentially polyclonal. Our findings suggest that memory T cells with Vbeta expression similar to that in normal skin accumulate in developing cutaneous LPR. The limited usage of Vbeta suggests a preferential recruitment or retention of reactive T cells from an endogenous subset of skin-homing T cells with its own skewed Vbeta repertoire.
Adult↗
Comparative effects of antilactoferrin antibodies and tumor necrosis factor on neutrophil adherence to matrix proteins.
Neutrophil adherence to matrix proteins likely plays an important role in inflammatory responses. Antineutrophil cytoplasm antibodies may activate neutrophils in certain diseases. Using an in vitro method that allows simultaneous quantitation of neutrophil adherence and superoxide secretion, we compared the effects of antibodies against neutrophil granule proteins and tumor necrosis factor alpha (TNF-alpha), a known neutrophil agonist. Antilactoferrin antibodies but not antielastase or antimyeloperoxidase antibodies stimulated increased adherence to fibronectin and laminin similar in degree to that induced by TNF-alpha. This, but not the simultaneous superoxide secretion, was inhibited in the presence of anti-CD18 antibodies. Humoral immune responses to lactoferrin, likely expressed on the neutrophil surface, can activate neutrophils in proinflammatory responses that may be pathogenic.
Antibodies↗
Patterns of inflammatory responses following rechallenge of skin late-phase allergic reaction sites.
BACKGROUND: Previous studies have suggested altered responses to repeat skin tests in the sites of IgE-mediated late-phase reactions (LPRs) induced within the previous 48 hours. To explore the possible modulation of LPRs in such rechallenge sites, we compared inflammatory responses in skin chambers induced over previous LPR and control sites. METHODS: Skin blisters were induced and unroofed in 12 human subjects over two sites of previous LPRs induced by intradermal injection of pollen antigens 24 hours or 48 hours earlier and two sites previously injected with buffer diluent (B). Skin chambers containing the same antigens were appended to one intradermal antigen site (called Ag/Ag) and one intradermal B site (B/Ag), and B-containing chambers were placed over antigen (Ag/B) and B (B/B) intradermal sites. Fluids were collected after the first and the second through fifth hours of challenge. RESULTS: In skin chamber challenges 24 hours after the intradermal injection, there was no significant difference after the first hours between the Ag/Ag or B/Ag sites in either histamine or tryptase levels; both were significantly higher than at Ag/B or B/B sites (p < 0.01). The same pattern of events was seen in fluids obtained from the second through fifth hours. The same pattern of findings was seen in examination of levels of the total leukocyte accumulation, total eosinophil accumulation, and frequency of activated (EG2+) eosinophils. Levels of lactoferrin, released from activated neutrophils, and eosinophil cationic protein, released from activated eosinophils, were also similar at Ag/Ag and B/Ag sites; both were significantly higher than at B/B sites, whereas levels at Ag/B sites were intermediate between those found at B/Ag and B/B sites. The pattern of events in skin chamber challenges 48 hours after intradermal injection was similar to that seen at 24 hours, except that levels of inflammatory mediators/cells in Ag/B sites were more intermediate between the B/Ag and B/B sites. CONCLUSION: There is no significant alteration of mediator or inflammatory cell responses after antigen rechallenge of previous LPR sites when compared with those found in antigen challenge of non-LPR sites.
Chymases↗
Comparison of inflammatory events in skin sites with and without cutaneous late-phase reactions after prominent immediate IgE-mediated responses.
BACKGROUND: A number of inflammatory events have been detected in skin chambers overlying sites of developing late-phase reactions (LPR) to pollen antigens in sensitive subjects. However, the pathogenic significance of such events is still unclear. OBJECTIVE: We sought to compare inflammatory responses and cytokine levels in skin chambers that overlie sites of antigen challenge in individuals with and individuals without LPRs after immediate wheal responses of similar intensity. RESULTS: Early histamine releases at antigen sites were similar in eight subjects with LPR (+/+ group) and eight subjects without LPR (+/- group). However, histamine releases during hours 2 through 5 of antigen challenge were significantly greater in the +/+ subjects than in the +/- subjects. Total exuding leukocytes; percent eosinophils; and levels of eosinophil cationic protein, lactoferrin, and IL-8 were significantly greater at antigen versus buffer control challenge sites in both the +/+ and +/- groups, with no significant differences between the groups. IL-1 and IL-6 levels were not greater at antigen sites than at buffer sites. CONCLUSIONS: The only significantly greater antigen-induced response detected in +/+ subjects than in +/- subjects was in later histamine release, which is possibly a marker of other inflammatory responses because histamine itself does not induce LPRs. Other inflammatory events assessed may be somewhat greater in +/+ subjects, but not significantly so.
Antigens↗
Immunohistochemical detection of human basophils in late-phase skin reactions.
BACKGROUND: Human basophils are difficult to detect with classic histochemical stains at sites of allergic inflammation. The 2D7 anti-basophil monoclonal antibody was used to identify basophils in skin during the late-phase response to a cutaneous allergen challenge. METHODS: The 2D7 monoclonal antibody was used on protease-digested sections of skin biopsy specimens obtained 6 and 24 hours after an allergen or buffer challenge. The skin chamber technique was used to compare buffer- and allergen-challenged sites at 6 hours, and intradermal injection of allergen was used to compare allergen-challenged sites at 6 and 24 hours. RESULTS: Dramatic increases in the numbers of 2D7+ cells and in tissue staining by 2D7 were observed 6 hours after allergen challenge compared with buffer challenge. Histamine levels in skin chamber fluid varied with 2D7+ cell concentrations. By 24 hours, 2D7+ cells and tissue staining appeared to diminish but were still detectable in the allergen-challenged sites. Basophils localized primarily in and around blood vessels, whereas mast cells remained mostly in the superficial dermis. Mast cells were 2D7- in both the allergen- and buffer-challenged skin. Metachromatic staining of 2D7+ basophils with toluidine blue was absent in these tissue sections. CONCLUSIONS: The 2D7 monoclonal antibody provides a more sensitive and precise marker than histochemical staining for human basophil involvement during the late-phase response to an allergen challenge. Basophil infiltration was observed at 6 hours only after allergen challenge and persisted at similar levels by 24 hours.
Allergens↗
Modulation of serum histamine releasing activity in chronic idiopathic urticaria.
BACKGROUND: Sera of about 30% of patients with chronic idiopathic urticaria (CIU) have increased histamine releasing activity (HRA+) on normal basophils. It is not known whether other CIU sera would be HRA+ if a more sensitive histamine release assay was used. Although most HRA+ CIU sera appear to have anti Fc(epsilon)R1 activity, it is not known whether post-binding basophil intracellular events are similar to those after anti-IgE stimulation. RESULTS: In the presence of D2O, the HR stimulated by 28 previously documented HRA- sera increased from 4+/-0.4 to 21+/-4% with 13 of the 28 sera now considered HRA+. No previous HRA sera was HRA+ with IL-3 treated cells. Histamine release induced by both HRA+ sera and anti-IgE were inhibited by genistein, and Ca2+/Mg2+ depletion but not by bisindoylmaleimide. HRA+ sera induced prominent HR from normal basophils with little surface IgE, but induced no increased HR from basophils unresponsive to anti-IgE. CONCLUSIONS: Up to 61% of CIU sera will induce increased HR from normal basophils in a sufficiently sensitive assay system. HR induced by most HRA+ sera is more prominent in basophils with very little surface IgE. However, there may be similar post-binding intracellular activation pathways following stimulation by HRA+ sera and anti-IgE.
Basophils↗
Comparison of inflammatory events during developing immunoglobulin E-mediated late-phase reactions and delayed-hypersensitivity reactions.
To compare cellular and mediator responses in early developing late-phase skin reactions (LPR) and delayed-hypersensitivity (DH) reactions in the same subjects, responses in skin chambers overlying sites of challenge with pollen antigen and Candida albicans antigens were compared in six humans with demonstrated prominent LPR and DH responses. Histamine levels in overlying chamber fluids at 1 h were much higher at LPR than at DH sites (P = 0.002). After the next 4 h, leukocyte exudation was higher at LPR than at DH sites (P = 0.005). Most leukocytes were activated neutrophils with greater frequency of superoxide-secreting cells and released lactoferrin at LPR than at DH sites (P = 0.01 and P = 0.02, respectively). The frequency of exuding eosinophils was higher, but not significantly so (P = 0.5), at LPR sites. Although significantly more eosinophils at LPR sites were activated (P = 0.02), the levels of released eosinophilic cationic protein were not significantly higher at LPR sites (P = 0.09). The levels of interleukin-8 (IL-8), but not IL-6, were greater at LPR than at DH sites. During the first 5 h of challenge there was greater mast cell activation and subsequent exudation of activated neutrophils at sites of developing LPR than at DH sites, possibly related to greater local IL-8 levels. The frequency of activated eosinophils was also greater at LPR sites. These different initial inflammatory responses could play a role in determining expression of LPR or DH reactions.
Allergens↗
Levels of tryptase, chymase, and Fc epsilon RI alpha messenger RNA in human skin are unchanged after IgE-dependent stimulation of cutaneous mast cells in vivo.
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Allergens↗
Nasal airway changes assessed by acoustic rhinometry and mediator release during immediate and late reactions to allergen challenge.
BACKGROUND: We have found that acoustic rhinometry is a reliable means of assessing nasal airway caliber changes during the immediate reaction to nasal allergen challenge of sensitive subjects. Comparison of such changes with symptoms and patterns of mediator release could help in the understanding of mechanisms of immediate and late-phase reactions after allergen challenge and their clinical relevance. METHODS: Nasal minimal cross-sectional area (MCA) was assessed sequentially for 6 hours after two blinded challenges in random order with pollen antigens and buffer diluent in five sensitive human subjects. Comparisons were made with: (1) symptom scores; (2) olfaction changes; and (3) nasal secretion levels of histamine, tryptase, leukotriene C4, serum albumin (a marker of vascular permeability), lactoferrin (a marker of local glandular secretion), and inflammatory cells in nasal scrapings. RESULTS: In four of five subjects there was a significantly greater decrease in MCA after antigen challenge than after diluent challenge, correlating with the degree of subjective nasal congestion. In two of these four subjects there was a prominent second late-phase decrease in MCA at 3 to 5 hours, whereas the MCA was persistently decreased in an additional subject with accompanying subjective congestion. No significant decrease in olfactory acuity occurred. Levels were significantly higher in nasal secretions obtained after antigen challenge than in those obtained after buffer challenge with histamine (9 +/- 2.7 ng/ml vs 1.2 +/- 0.5 ng/ml; p = 0.04); tryptase (95 +/- 83 ng/ml vs 3 +/- 0.9 ng/ml; p = 0.02), leukotriene C4 (5293 +/- 1385 ng/ml vs 578 +/- 183 ng/ml; p = 0.02), and albumin (123 +/- 9 ng/ml vs 19 +/- 1.6 ng/ml; p = 0.005) but not with lactoferrin (4.6 +/- 1.2 ng/ml vs 4.1 +/- 28 ng/ml; p = not significant). Granulocyte exudation was seen after antigen challenge but not after buffer diluent challenge. However, there was not a precise correlation between decreases in MCA with changes in levels of these mediators in individual subjects. CONCLUSIONS: Acoustic rhinometry can quantitatively assess congestion during immediate and late-phase reactions after nasal challenge without significant correlation to the degree of individual inflammatory events assessed.
Acoustics↗
Cytokine levels and inflammatory responses in developing late-phase allergic reactions in the skin.
BACKGROUND: Cytokines could play roles in the attraction of leukocytes into sites of IgE-mediated late-phase reactions (LPR) or in the activation of such cells at the sites. Previous studies found increased release of IL-6, IL-1, and granulocyte-macrophage colony-stimulating factor into skin chambers overlying allergen-challenged sites, mainly after 6 hours when LPR are already well-developed. OBJECTIVE: To compare levels of several cytokines with inflammatory responses in skin chambers overlying developing LPRs. METHODS: Skin chambers were appended to denuded blister bases in 15 sensitive subjects, then challenged over a 5-hour period with pollen allergens (Ag) or buffer control (B). Levels of several chemotactic cytokines, eosinophil cationic product (released from eosinophils), and lactoferrin (released from neutrophils) were measured and leukocyte accumulation was assessed. RESULTS: Levels of the chemokines IL-8, RANTES, and monocyte chemotactic protein-1 (but not IL-1, IL-6, or granulocyte-macrophage colony-stimulating factor) were significantly higher at Ag-challenge sites than at B-challenge sites. IL-5 was not detected. In individual chamber fluids at Ag-challenge sites, (1) IL-8 levels correlated strongly with levels of lactoferrin but not with eosinophil cationic protein levels; (2) RANTES levels correlated with numbers of eosinophils but not with eosinophil cationic protein levels; and (3) levels of monocyte chemotactic protein-1 correlated weakly with histamine released after the first hour. CONCLUSIONS: During LPRs developing during the first 5 hours of Ag challenge, there is increased local release of several chemokines, which could play roles in the observed attraction and subsequent activation of leukocytes and continued histamine release observed at such sites.
Blister↗
Cellular inflammatory responses during immediate, developing, and established late-phase allergic cutaneous reactions: effects of cetirizine.
BACKGROUND: In some previous studies, the antihistamine cetirizine has inhibited both developing (at 6 hours) and established (at 24 hours) gross late-phase skin reactions (LPR) to pollen antigens, possibly relevant to clinical drug effects. However, the effects of cetirizine at the histologic level require further definition. OBJECTIVE: To characterize cetirizine effects on gross and histologic inflammatory events from 20 minutes to 24 hours after intradermal antigen challenge in sensitive patients. METHODS: Gross and histologic responses to intradermal pollen antigen, codeine, histamine, and buffer diluent were assessed during randomized 7-day treatments with cetirizine and placebo. Accumulated neutrophils, eosinophils, activated (EG2+) eosinophils, and T lymphocytes were quantitated. The degrees of extracellular deposition of lactoferrin from neutrophils and eosinophilic cationic protein (ECP) from eosinophils were also assessed. RESULTS: During placebo treatment, wheal-and-flare responses were significantly greater to antigen at 20 minutes (p < 0.01) and induration at 6 hours (p < 0.01) at antigen challenge sites than at buffer diluent sites. During cetirizine treatment, these wheal-and-flare responses to antigen were inhibited significantly (p < 0.01) but gross LPRs were not affected. During placebo treatment, significantly more cells per high-power field were found in antigen sites than in buffer sites of neutrophils at 20 minutes (p < 0.01) and 24 hours; than in eosinophils at 20 minutes, 6 hours, and 24 hours (p < 0.01 for each); than in EG2+ cells at 20 minutes (p = 0.004), 6 hours (p = 0.001), and 24 hours (p = 0.02); and at T lymphocyte sites at 24 hours (p = 0.001). Extracellular deposition of lactoferrin and ECP was significantly greater at antigen sites than at buffer sites at 6 and 24 hours. Cetirizine treatment had no significant effect on these responses. CONCLUSION: Neutrophils, eosinophils, and T lymphocytes were persistently more common at antigen sites than at buffer sites through 24 hours. Many of these neutrophils and eosinophils were activated, releasing more lactoferrin and ECP into the extracellular dermis for at least 24 hours after antigen challenge. Cetirizine inhibited gross immediate responses to antigen, but not the gross LPR nor the cellular inflammatory responses seen in such LPR sites.
Administration, Cutaneous↗
Cellular inflammatory responses and mediator release during early developing late-phase allergic cutaneous inflammatory responses: effects of cetirizine.
BACKGROUND: Events in developing cutaneous late-phase allergic reactions can be characterized by a combination of skin chamber and biopsy approaches. In some previous studies, cetirizine reportedly inhibited mediator release and/or inflammatory cell responses in late-phase reactions. OBJECTIVE: This study was carried out to determine the effects of cetirizine on early late-phase reactions by using skin chamber and skin biopsy specimens. METHODS: Skin chamber responses during a 6-hour challenge with pollen antigens were assessed in 15 sensitive subjects during randomized, crossover treatment with cetirizine (20 mg/day) or placebo for 7-day periods with measurements of humoral and cellular components. Biopsy specimens of the underlying dermis were obtained. RESULTS: During cetirizine treatment, there was significant (p < 0.01) inhibition of immediate wheal and flare reactions to pollen antigens (34, 46%), codeine (41, 65%), and histamine (38, 68%). However, gross late-phase reactions at 6 hours were unaffected. During both cetirizine and placebo treatment, there was significantly greater accumulation at antigen sites in: (1) skin chamber levels of histamine, total cells, lactoferrin, and eosinophil cationic protein; (2) eosinophils (total and activated) on appended cover glasses; (3) deposition of lactoferrin and eosinophil cationic protein in the underlying dermis. However, these responses were not significantly different during cetirizine treatment compared with placebo treatment periods. CONCLUSION: A persistent pattern of inflammatory cell accumulation with release of granule proteins during early late-phase reactions was unaffected by cetirizine treatment.
Antigens↗
Inflammatory myopathy, bronchiolitis obliterans/organizing pneumonia, and anti-Jo-1 antibodies--an interesting association.
We report an interesting association of inflammatory myopathy, characterized pathologically as dermatomyositis, with bronchiolitis obliterans/organizing pneumonia and anti-histidyl-tRNA synthetase (Jo-1) antibody. The relations of different types of pulmonary involvement to inflammatory myopathy and antisynthetase antibodies are discussed.
Autoantibodies↗
Characteristics of histamine-releasing activity in the sera of patients with chronic idiopathic urticaria.
BACKGROUND: The serum histamine-releasing activity (HRA) found in a sizable percentage of patients with chronic idiopathic urticaria (CIU) has been partially characterized. However, the variable effect of individual HRA+ sera in basophils of different donors and the relationship of HRA to the clinical course require further investigation. OBJECTIVE: The study was performed to characterize the HRA found in sera of some members of a sizable group of carefully evaluated patients with CIU. METHODS: Sera of 70 patients with CIU, evaluated with a standard protocol, were screened for increased HRA. HRA+ sera were fractionated, heated, and tested on unaltered and altered basophils obtained from a panel of normal donors. HRA levels were compared with concomitant clinical manifestations. RESULTS: HRA+ sera were found in 30% of our patients with CIU, HRA was predominantly in the IgG fraction, sensitive to 56 degrees C heating for 4 hours, and generally reacted more with IgE-stripped basophils. Considerable variation in the degree of response to HRA+ sera in the basophils of different normal subjects did not correlate with the degree of response of these cells to heterologous anti-IgE antiserum. Serum HRA levels were generally much lower when symptoms decreased in these patients with CIU. CONCLUSION: Serum HRA from patients with CIU appears to bind most commonly to the IgE receptor and may be a marker of clinical disease activity. HRA appears in an IgG-containing fraction of the serum and may contain IgE in some cases.
Basophils↗