Targeting CRAC channels and leukotriene receptors to suppress mast cell activation
Mast cells are tightly linked to the development of allergies and nasal polyposis, the latter affecting up to 2% of the population. In this issue of the Journal, Di Capite et al (p 1014) report the presence of a novel positive feedback cycle in mast cells that might sustain activation in diseased states. This positive feedback cycle involves interplay between Ca2+ release–activated Ca2+ (CRAC) channels and cysteinyl leukotriene type I receptors. In both rodent and human mast cells, Ca2+ entry through open CRAC channels drives the synthesis and secretion of leukotriene C4, which then acts in a paracrine manner to generate Ca2+ signals that drive further cysteinyl leukotriene production. This feed-forward loop results in an intercellular Ca2+ wave that spreads through the mast cell population. The authors report how a combination therapy that targets both proteins is effective at suppressing mast cell activation (see Figure). Importantly, the combination of a moderate concentration of a CRAC channel blocker with a modest dose of the cysteinyl leukotriene receptor type I antagonist was as effective at blocking paracrine activation of mast cells as higher concentrations of either drug. This is important clinically because it means that a lower concentration of drugs could be prescribed, reducing the side effects and drug dependence.
Combining montelukast with a CRAC inhibitor suppresses mast cell activation.
Prenatal and maternal influences on newborn immune responses of US urban children
Immunologic responses at birth likely relate to subsequent risks for allergic diseases and wheezing in infancy, but maternal and prenatal influences on neonatal responses are not well understood. At birth, cord blood mononuclear cells can respond to both innate and adaptive stimuli, although innate responses are more developed. The innate immune system defends the host from infection in a nonspecific manner. The adaptive immune system confers more long-lasting protective immunity against infection but also can be involved in allergic responses. Gold et al (p 1078) evaluated the influences of maternal and prenatal factors on cord blood mononuclear cell cytokine production in response to innate and adaptive stimuli in 560 and 49 children from families with and without an allergy/asthma history participating in URECA, a prospective multicenter urban birth cohort study. Responses to stimuli were generally lower to adaptive than innate stimuli and were lower in infants with a parental history of allergy/asthma. Season of birth (see Figure), birth weight, gestational age, and ethnicity influenced the magnitude of the responses. Maternal asthma was associated with reduced cytokine responses to respiratory syncytial virus. Pregnancy, birth, and family characteristics influence immune responses in children at birth. Follow-up of these urban children will help us understand the clinical implications of our findings on allergy and asthma development.
Season of birth influences cord blood mononuclear cell production of the cytokine IFN-γ in response to stimulation by tetanus toxoid, cockroach allergen, and dust mite allergen.
Peanut consumption during pregnancy and lactation protected offspring against peanut allergy
Until recently, the American Academy of Pediatricians and the United Kingdom Government's Chief Medical Officer's Committee on Toxicity of Chemicals in Food, Consumer Products, and the Environment suggested that maternal dietary avoidance during pregnancy and lactation might reduce the incidence of peanut allergy. However, there are no conclusive data that maternal avoidance is protective, and the American Academy of Pediatricians guidelines have been revised. It has recently been suggested that introduction of small amounts of peanut early in life might prevent sensitization. In this issue of the Journal, López-Expósito et al (p 1039) report the first murine model of the effect of maternal peanut consumption on the development of peanut allergy. They showed that offspring of mothers with peanut allergy exhibited anaphylactic symptoms on first peanut exposure. Feeding a small amount of peanut, together with an adjuvant, in a concentration that did not elicit clinical reactions in mothers with peanut allergy during pregnancy and lactation prevented first exposure reactions. Offspring of peanut-fed mothers exhibited lower peanut-specific IgE levels than offspring of non–peanut-fed mothers in response to subsequent experimental peanut sensitization. Peanut-specific IgG2a levels, in contrast, were significantly higher. Strict avoidance of peanut and other food allergens during pregnancy and lactation might be counterproductive.
Nitrosative stress is a prominent feature of persistent asthma in children
Airway nitric oxide (NO) is a highly reactive species that has been implicated in the pathogenesis of allergic asthma. Although NO has beneficial effects, an overabundance of NO can lead to NO oxidation and “nitrosative stress.” As reported in this issue, Fitzpatrick et al (p 990) quantified NO oxidation products in the proximal and distal epithelial lining fluid (ELF) of 30 children with severe asthma, 15 children with mild-to-moderate asthma, 5 age-matched control subjects, and 20 healthy adults. In comparison with control subjects, children with mild-to-moderate and severe asthma had increased concentrations of nitrite, nitrate, and nitrotyrosine in the airway ELF despite treatment with inhaled corticosteroids. Concentrations of these NO oxidation products were consistently higher in the proximal airways than in the distal airways (see Figure). Interestingly, no direct associations between these NO oxidation products and clinical features, such as exhaled NO (Feno), were detected. These data highlight the complexity of NO biochemistry in children with persistent asthma and suggest that the relationship between Feno and NO oxidation is not directly proportional. Thus in children with persistent asthma, lower Feno concentrations might not necessarily indicate the absence of airway inflammation but instead might reflect decreased NO bioavailability from increased NO oxidation.
NO oxidation products in the proximal (dark bars) and distal (light bars) ELF. ∗P ≤ .05; #P ≤ .05 versus control subjects.
Antibiotic use in infancy and symptoms of asthma, rhinoconjunctivitis, and eczema in 6- to 7-year-olds in the International Study of Asthma and Allergies in Childhood Phase III
Foliaki et al (p 982) have conducted the largest study to date of antibiotic use in the first year of life and the subsequent risk of symptoms of asthma, rhinoconjunctivitis, and eczema in children 6 to 7 years old. Phase III of the International Study of Asthma and Allergies in Childhood involved 193,412 children from 71 centers in 29 countries and showed a nearly 2-fold association between antibiotic use in the first year of life and subsequent asthma symptoms. The findings were stronger than those for paracetamol use previously reported from the same study. However, the authors concluded that further research is required to determine whether the observed associations are causal or are due to confounding by indication or reverse causation. The main concern is that antibiotics might have been prescribed because of respiratory symptoms early in life or were prescribed for chest infections that were risk factors for subsequent respiratory disease. The difficulty for clinicians is to decide on the appropriate use of antibiotics early in life while these issues remain unresolved. The well-intending clinician, however, often does give antibiotic prescriptions to infants and young children for vague respiratory symptoms without evidence of bacterial cause. A consensus on antibiotic use would be of immense benefit to the health of young children, given the difficult task of distinguishing asthma from chest infections in infants and in children in the early years.
Mutation of SLP-76 protects mice from anaphylaxis and serum-induced arthritis
The aberrant activation of mast cells (MCs) and neutrophils (PMNs) contributes to hypersensitivity disorders, asthma, endotoxic shock, and inflammatory arthritis. It is important to define the signaling mechanisms that control MC and PMN activation to better understand and manipulate their roles in disease. The Src homology domain 2–containing leukocyte protein of 76 kd (SLP-76) is required in MCs and PMNs to support immunoreceptor- and integrin-dependent signaling and cell activation. As reported in this issue, Lenox et al (p 1088) explored the importance of tyrosine (Y) residues 112, 128, and 145 of SLP-76 during MC and PMN function. Using primary cells isolated from genomic knock-in mice harboring phenylalanine (F) substitutions at residues Y112/128 or Y145, they show that both mutants impaired SLP-76 activity; however, Y145 appeared more important for many in vitro MC and PMN functions. Functional defects were recapitulated in vivo, where mice expressing Slp-76Y145F exhibited significantly reduced passive systemic anaphylaxis and dampened dermal inflammation. Most dramatically, mice expressing the Y145F mutation were completely protected from clinical and histologic signs of joint inflammation in a model of antibody-mediated arthritis (see Figure). Continued efforts to dissect how Y145 mediates MC and PMN activation will provide important insights into the pathogenesis and treatment of inflammatory conditions.
Mutation of Y145 of SLP-76 protects mice from serum-induced arthritis.
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