Pathogenesis of IgE‐mediated food allergy

Food allergy is a prevalent disease for which there is no current treatment beyond careful food avoidance. Accidental exposure to foods causes reactions in allergic individuals that can range in severity from mild skin reactions to severe and life‐threatening anaphylaxis, and there are no validated tools to predict severity of reactions. A greater understanding of the pathogenesis of food allergy is needed to develop prevention and treatment strategies for food allergy. In the last few years, there have been significant developments in the field of food allergy that have led to new ideas about food allergy prevention, diagnosis, and treatment. This review will discuss these recent advances in the food allergy field as well as identify gaps in our knowledge about the immune mechanisms of allergy and tolerance to foods.     

Regulated production of the T helper 2-type T-cell chemoattractant TARC by human bronchial epithelial cells in vitro and in human lung xenografts

The chemokine TARC is a ligand for the chemokine receptor CCR4 expressed on T helper (Th)2-type CD4 T cells. Allergic airway inflammation is characterized by a local increase in cells secreting Th2-type cytokines. We hypothesized that bronchial epithelial cells may be a source of chemokines known to chemoattract Th2 cells. Regulated TARC expression was studied using normal human bronchial epithelial cells and a human lung xenograft model. TARC expression was increased in normal human bronchial epithelial cells in response to tumor necrosis factor-alpha stimulation, and further upregulation of TARC was observed with interferon (IFN)-gamma but not interleukin (IL)-4 costimulation. TARC functions as a nuclear factor (NF)-kappa B target gene, as shown by the abrogation of TARC expression in response to proinflammatory stimuli when NF-kappa B activation is inhibited. In an in vivo model, minimal constitutive TARC expression was observed in human lung xenografts. Consistent with our findings in vitro, TARC messenger RNA (mRNA) expression was upregulated in the xenografts in response to IL-1, and costimulation with IFN-gamma but not IL-4 further increased TARC mRNA and protein expression. In addition, bronchoalveolar lavage fluid from asthmatic subjects after allergen challenge contained significantly increased levels of TARC, suggesting that TARC production by bronchial epithelial cells may play a role in the pathogenesis of allergic asthma.     

Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector TH2 subsets

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Phorbol myristate acetateex vivo model of enhanced colonic epithelial permeability

The initiating mechanisms involved in colonic injury are currently unknown. The goal of the current study was to examine the role of the inflammatory mediators reactive oxygen metabolites and proteases in anex vivo model of selective epithelial permeability. Rats were prepared with exteriorized colonic chambers to which the protein kinase C (PKC) activator phorbol myristate acetate (PMA) was added in doses ranging from 5 to 800 g. PMA caused a dose-dependent transient increase in epithelial permeability, but had no significant effect on microvascular permeability. There was no accumulation of neutrophils and no apparent histological changes. PMA acts via a PKC-dependent mechanism, as assessed using the PKC-inactive phorbol analog 4-phorbol didecanoate, and the response is tachyphylactic. The mechanism is independent of reactive oxygen metabolites and proteases, as shown by the lack of effect of the free radical scavengers superoxide dismutase and catalase and the general serine protease inhibitor soybean trypsin inhibitor. The classic inflammatory process does not appear to be involved in the PMA-induced epithelial permeability changes. This finding suggests that noninflammatory mechanisms may regulate the increased epithelial permeability induced by PMA. Further study to elucidate these mechanisms is of importance for understanding both normal gastrointestinal physiology and initiation of pathology.     

Intravenous dexmedetomidine, but not midazolam, prolongs bupivacaine spinal anesthesia

Purpose

Midazolam has only sedative properties. However, dexmedetomidine has both analgesic and sedative properties that may prolong the duration of sensory and motor block obtained with spinal anesthesia. This study was designed to compare intravenous dexmedetomidine with midazolam and placebo on spinal block duration, analgesia, and sedation in patients undergoing transurethral resection of the prostate.

Methods

In this double-blind randomized placebo-controlled trial, 75 American Society of Anesthesiologists’ I and II patients received dexmedetomidine 0.5 μg · kg^?1, midazolam 0.05 mg · kg^?1, or saline intravenously before spinal anesthesia with bupivacaine 0.5% 15 mg (n = 25 per group). The maximum upper level of sensory block and sensory and motor regression times were recorded. Postoperative analgesic requirements and sedation were also recorded.

Results

Sensory block was higher with dexmedetomidine (T 4.6 ± 0.6) than with midazolam (T 6.4 ± 0.9; P < 0.001) or saline (T 6.4 ± 0.8; P < 0.001). Time for sensory regression of two dermatomes was 145 ± 26 min in the dexmedetomidine group, longer (P < 0.001) than in the midazolam (106 ± 39 min) or the saline (97 ± 27 min) groups. Duration of motor block was similar in all groups. Dexmedetomidine also increased the time to first request for postoperative analgesia (P < 0.01 compared with midazolam and saline) and decreased analgesic requirements (P < 0.05). The maximum Ramsay sedation score was greater in the dexmedetomidine and midazolam groups than in the saline group (P < 0.001).

Conclusion

Intravenous dexmedetomidine, but not midazolam, prolonged spinal bupivacaine sensory blockade. It also provided sedation and additional analgesia.     

Neutrophil-independence of the initiation of colonic injury

Although the role of neutrophils in the pathogenesis of several forms of gastrointestinal injury has been well demonstrated, their role in the development of experimental colonic injury is less clear. To examine whether neutrophils play a role in the development of experimental colitides, the effects of a sustained neutropenia on multiple indices of colonic injury in rats was examined 24 hr following the initiation of colitis with the intrarectal application of acetic acid, trinitrobenzene sulfonic acid (TNBS)-ethanol, or the potent proinflammatory agent, phorbol-12-myristate-13-acetate (PMA). In comparison to animals with normal neutrophil counts and colitis induced by any of the three agents, no attenuation in macroscopic damage or histopathologic injury was observed in neutropenic animals exhibiting a greater than 95% reduction in circulating neutrophils and 85% reduction in tissue-associated myeloperoxidase activity. Although the tissue edema associated with acetic acid or PMA-induced colitis was not reduced by neutropenia, the colonic edema associated with TNBS colitis was attenuated by prior neutrophil depletion with anti-neutrophil antiserum. Despite our initial hypothesis that neutrophils played a key role in the genesis of experimental colitis (especially that induced by PMA), the results demonstrated that these cells are not essential for the development of the major pathological features of colitis induced by this agent, acetic acid, or TNBS. Although these results support the proposal that in these models of colitis, inflammation develops secondary to injury (rather than the converse), further studies will be necessary to elucidate the role of inflammatory cells other than neutrophils in the genesis of experimental colitides.