A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease.
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The respiratory allergens that induce experimental Th cell type 2-dependent allergic lung inflammation may be grouped into two functional classes. One class of allergens, in this study termed type I, requires priming with adjuvants remote from the lung to overcome airway tolerogenic mechanisms that ordinarily preclude allergic responses to inhaled Ags. In contrast, the other, or type II, allergen class requires neither remote priming nor additional adjuvants to overcome airway tolerance and elicit robust allergic lung disease. In this study, we show in an experimental model that diverse type II allergens share in common proteolytic activity that is both necessary and sufficient for overcoming airway tolerance and induction of pulmonary allergic disease. Inactivated protease and protease-free Ag fragments showed no allergenic potency, demonstrating that only active protease acting on endogenous substrates was essential. Furthermore, induction of airway tolerance could be aborted and allergic lung disease established by simply adding purified protease to a type I allergen. Thus, exogenous proteases are common to type II allergens and may be generally required to overcome the innate resistance of the airway to Th cell type 2 activation and allergic inflammation, raising concern for their potential contribution to diseases such as asthma. (+info)
Canine model of nasal congestion and allergic rhinitis.
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The ragweed- and histamine-induced decreases in nasal patency in cohorts of ragweed-sensitized and nonsensitized dogs were assessed. The volume of nasal airways (V(NA)) was assessed by acoustic rhinometry and resistance to airflow (R(NA)) by anterior rhinomanometry. Histamine delivered to the nasal passages of five dogs caused a rapid and prolonged increase in R(NA) (0.75 +/- 0.26 to 3.56 +/- 0.50 cmH(2)O. l(-1). min), an effect that was reversed by intranasal delivery of aerosolized phenylephrine. Ragweed challenge in five ragweed-sensitized dogs increased R(NA) from 0.16 +/- 0.02 to 0.53 +/- 0.07 cmH(2)O. l(-1). min and decreased V(NA) from 12.5 +/- 1.9 to 3.9 +/- 0.3 cm(3), whereas administration of saline aerosol neither increased R(NA) nor decreased V(NA). Prior administration of d-pseudoephedrine (30 mg po) attenuated the ragweed-induced increase in R(NA) and decrease in V(NA). Ragweed challenge changed neither R(NA) nor V(NA) in four nonsensitized dogs. Mediator-induced nasal congestion and allergen-induced allergic rhinitis in ragweed-sensitized dogs, which exhibit symptoms similar to human disease, can be used in the evaluation of safety and efficacy of antiallergic activity of potential drugs. (+info)
Transient neutrophil infiltration after allergen challenge is dependent on specific antibodies and Fc gamma III receptors.
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Following allergen challenge of sensitized mice, neutrophils are the first inflammatory cells found in bronchoalveolar lavage (BAL) fluid. To determine the underlying mechanism for their accumulation, mice were sensitized to OVA on days 0 and 14, and received, on day 28, a single intranasal challenge (s.i.n.) with either OVA or ragweed. Eight hours after the s.i.n., BAL fluid was obtained. BALB/c mice sensitized and challenged with OVA showed significantly higher total cell counts and numbers of neutrophils in BAL fluid compared to the OVA-sensitized and ragweed-challenged or nonsensitized mice. Levels of neutrophil chemokines in BAL fluid supernatants were markedly elevated in the sensitized and OVA-challenged mice; Fc epsilon RI-deficient mice showed comparable numbers of neutrophils and neutrophil chemokines in BAL fluid after s.i.n. But in sensitized mice lacking the Fc common gamma-chain and B cell-deficient mice, the number of neutrophils and levels of neutrophil chemokines in BAL fluid were significantly lower. Further, mice lacking the FcgammaRIII did not develop this early neutrophil influx. Neutrophil infiltration could be induced in naive mice following intranasal instillation of allergen combined with allergen-specific IgG1. In addition, macrophages from sensitized mice were stimulated with allergen and activated to produce neutrophil chemokines. These results demonstrate that neutrophil influx after allergen challenge requires prior sensitization, is allergen-specific, is mediated through FcgammaRIII, and is dependent on the presence of Ab. (+info)
The antibody mechanisms of ragweed allergy; electrophoretic and chemical studies. I. The blocking antibody.
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Three human serums containing artificially produced blocking antibody against low ragweed allergen were studied for the possibility of relating blocking antibody to electrophoretically definable components. An adaptation of the qualitative passive transfer test to quantitative interpretation is described, methods and procedures are given and uncertainties and possible errors due to lack of precision and accuracy are presented and discussed. At least 65 per cent, but probably more, if not all of the blocking antibody is attributable to gamma globulin. However, no rise of gamma globulin, either its absolute amount or its relative percentage value, paralleled the appearance of blocking antibody. Blocking antibody is not contained in albumin or in alpha-1 globulin. Blocking effect could not be ascertained unequivocally as being connected with alpha-2 or with beta globulin and sizable participation of these two latter electrophoretic components appears improbable. Blocking antibody and sensitizing antibody appear to be chemically different entities. (+info)
Detection of non-precipitating antibodies in sera of individuals allergic to ragweed pollen by an in vitro method.
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A hemagglutination test capable of demonstrating antibodies in sera of ragweed-sensitive individuals has been described in detail. This test involves coupling of the antigen to rabbit erythrocytes via stable azo bonds. The antigen-coated cells are then suspended in the serum which is suspected to contain the homologous antibodies. The test has been shown to be specific and highly sensitive. Precipitating antibodies to ragweed pollen extract produced in experimental animals can be demonstrated in dilutions as high as 10(5) to 10(7), while antibodies to ragweed in allergic sera are detected only in dilutions of the order of 10(3). Positive results were obtained with all sera from treated or non-treated allergic individuals containing skin-sensitizing and/or blocking antibodies. Absorption of these sera with antigen-coated erythrocytes yielded a supernatant devoid of either skin-sensitizing, blocking, or hemagglutinating capacity. It is concluded that the hemagglutinating factor has the properties of a divalent antibody. (+info)
S epsilon S mu and S epsilon S gamma switch circles in human nasal mucosa following ex vivo allergen challenge: evidence for direct as well as sequential class switch recombination.
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B cells switch to IgE under the influence of IL-4, IL-13, and CD40 costimulation through a multistep process involving epsilon germline transcription and class switch recombination. Classically, switching has been considered an event restricted to lymphoid tissues; however, epsilon germline transcripts (I(initiator)epsilon RNA) have been observed within lung, sinus, and nasal tissue of individuals with asthma, sinusitis, and rhinitis. Furthermore, nasal mucosal tissue from allergic rhinitics produces epsilon germline transcripts following ex vivo allergen challenge. Collectively, these studies raised the possibility that switching to IgE may occur locally, at sites of allergic inflammation. Although epsilon germline transcripts are considered necessary to target the IgE locus, it is class switch recombination that ultimately leads to de novo IgE production. In this study, we demonstrate that S epsilon S mu DNA switch circles (products of class switch recombination) as well as I epsilon and C epsilon RNA are produced within nasal tissue from allergic individuals following ex vivo allergen challenge. epsilon germline transcription was inhibited when tissue was cultured with a combination of allergen and neutralizing Abs against IL-4 and IL-13, indicating that de novo cytokine production mediated the isotype switch. We also show allergen-induced appearance of S epsilon S gamma DNA switch circles and up-regulation of C gamma 4 mRNA, illustrating that sequential switching to IgE also occurred. This work strongly suggests that B cells residing within the nasal mucosa undergo switching to IgE in the context of a local immune response to allergen. (+info)
Parental allergic status influences the risk of developing allergic sensitization and an asthmatic-like phenotype in canine offspring.
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Increasing evidence suggests that parental allergic status, especially that of the mother, may play a unique and important role in influencing the development of fetal infant immune responses to inhaled allergens, independently of genetic predisposition. We have developed an experimental model in dogs where the offspring from allergic parents, when exposed to inhaled allergen, develop allergic sensitization and an asthmatic phenotype, whereas the offspring from non-allergic parents do not. Offspring from ragweed-sensitized (two litters, n = 10) or non-sensitized (two litters, n = 11) Beagle dogs were exposed repeatedly, by inhalation, to ragweed or filtered air (negative control) beginning within 1 week after birth. Serum levels of total immunoglobulin (Ig)E, and ragweed-specific IgE and IgG, were measured at specific time-points up to 40 weeks after birth. Cell differentials in the bronchoalveolar lavage were determined on days 1 and 4 following ragweed instillation into the offspring's lungs at 26 weeks of age. Changes in pulmonary resistance following challenge with histamine and ragweed (five breaths) were measured at 40 weeks after birth. Offspring from sensitized parents exposed to ragweed developed elevated serum total IgE and ragweed-specific IgE and IgG, and showed an increased pulmonary resistance to histamine and ragweed, and increased numbers of eosinophils in bronchoalveolar lavage. In contrast, offspring from non-sensitized parents did not exhibit this immune response. These results suggest that parental allergic sensitivity is important in the development of allergic sensitization and an asthmatic phenotype in the offspring. (+info)
Ragweed pollen in the air of Szczecin.
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The aim of the study was to analyse the ragweed (Ambrosia) pollination in Szczecin (western Poland) in the years 2000-2002. Measurements were performed by the volumetric and gravimetric method. Pollen seasons were defined as the periods of 90 % of the total catch. Ragweed pollen is known as a very potent aeroallergen. In recent years ragweed appeared in Europe in hitherto unknown localities, and the number of people allergic to the allergens of this plant has been gradually increasing. In the period of the study a strong tendency towards increasing ragweed pollen counts in the air of Szczecin was noted. Of the three years studied, the lowest concentration of ragweed pollen observed in 2000 equalled a few pollen grains in 1 m(3) per 24 h. In 2001, the highest airborne concentration of 30 grains in 1 m(3) per 24 h was noted at the end of August. The annual pollen count of ragweed in 2002 was 3 times higher than in 2001. The pollen season started in the second decade of August and lasted until the beginning of September. The highest airborne concentration of 98 grains in 1 m(3) per 24 h was noted at the beginning of September on a sunny day with strong wind. The pollen count of ragweed was found to depend on the weather conditions, especially on wind speed and relative humidity, diversity of local flora and long distance transportation. (+info)