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• Respiratory syncytial virus and subsequent recurrent wheezing
• Impaired T-cell receptor activation in IL-1 receptor–associated kinase 4–deficient patients
• Lifetime pet exposure is not associated with allergen sensitization in teenagers
• CD69: A brake for allergy and inflammation
• Inducible costimulator–positive regulatory T cells control the development of skin inflammatory reactions to haptens
• Fas ligand and matrix metalloproteinase 7: A dysfunctional relationship in asthma
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Respiratory syncytial virus and subsequent recurrent wheezing 

As reported in this issue of the Journal, Simões et al (p 256) used protection by passively administered mAbs against respiratory syncytial virus (RSV) to separate the effects of RSV-induced lower respiratory tract infections and an atopic diathesis on subsequent recurrent wheezing. Although it has been known that RSV-induced lower respiratory tract infections in early life are associated with later airway hyperreactivity, it has been unclear whether there is a causal relationship. In a prospective, multicenter, matched study conducted in 27 centers in Europe and Canada, the authors compared the rates of physician-diagnosed recurrent wheezing in premature infants of less than 36 weeks' gestation who had not received palivizumab in the first year of life (see Figure). They found that in 146 palivizumab-treated infants compared with 171 untreated infants, the relative protective effect of palivizumab on physician-diagnosed recurrent wheezing through 2 to 5 years of age was 68% in those with no family history of asthma and 80% in those with no family history of atopy or food allergies (n = 101 palivizumab-treated subjects and 100 untreated subjects). In contrast, no effect was seen in the 90 children with a family history of atopy or food allergies in comparison with 130 untreated infants with atopic families. This suggests that RSV predisposes to recurrent wheezing in an atopy-independent mechanism.

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• Effect of palivizumab prophylaxis on subsequent physician-diagnosed recurrent wheezing.

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Impaired T-cell receptor activation in IL-1 receptor–associated kinase 4–deficient patients 

IL-1 receptor–associated kinase 4 (IRAK-4), a protein kinase that is an effector of all Toll-like receptors (except Toll-like receptor 3), is critical for the detection of pathogens. Patients deficient in IRAK-4 are susceptible to fatal infections with pyogenic bacteria, particularly in infancy and early childhood, but outgrow this susceptibility by mid adolescence. Maturation and compensation by the adaptive immune system is hypothesized to contribute to improved outcomes. As reported in this issue of the Journal, McDonald et al (p 332) evaluated T-cell function in a cohort of 4 IRAK-4–deficient children. T cells were activated by cross-linking T-cell receptors (TCRs) with anti-CD3 and anti-CD28 antibodies. The investigators found that TCR-induced T-cell activation in the IRAK-4–deficient patients, as measured by upregulation of expression of CD25 and CD63 and production of IL-6 and IFN-γ (but not IL-2), was significantly impaired in T cells from IRAK-4–deficient patients, perhaps contributing to their susceptibility to invasive bacterial infections. The authors suggest that longitudinal analysis of T-cell functions in IRAK-4–deficient patients will be needed to determine whether their T-cell function improves with age, perhaps contributing to improved outcomes in these patients.

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Lifetime pet exposure is not associated with allergen sensitization in teenagers 

Wegienka et al (p 274) report that there was no overall association between various patterns of indoor pet keeping over childhood and having allergic sensitivity (IgE antibody) to common allergens in early adulthood. The results are from the Childhood Allergy Study, a longitudinal study from suburban Detroit in which participants were followed since birth (approximately 20 years before). The participants were interviewed about living with indoor cats and dogs throughout their lives, and this information was combined with questionnaires on indoor pet keeping collected from the parents when the participants were young. Blood samples for allergen-specific IgE antibodies for grass, dust mite, ragweed, peanut, dog, cat, and Alternaria alternata were measured in the subjects' blood after their 18th birthdays. Living with indoor cats or dogs in the first year of life, total years living with indoor pets, and the specific ages at which they lived with indoor cats or dogs were considered in the analyses. No pattern of exposure was associated with being allergic to the panel of common allergens. However, those living with cats or dogs in the first year of life had lower total IgE antibody levels than those who had not had pets at this age.

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CD69: A brake for allergy and inflammation 

Affecting the lungs and skin, respectively, asthma and contact dermatitis, which are 2 of the most common allergic diseases, have been shown to be related or at least to share some molecular mechanisms. In both diseases IL-17 is a potent inducer of the migration and activation of inflammatory cells that perpetuate chronic inflammation. However, the molecular mechanisms underlying the inflammatory response that triggers allergic reactions have not yet been fully elucidated. In this issue Martín et al (p 355) describe the role of the leukocyte activation antigen CD69 in the control of inflammation in murine models of asthma (OVA-induced allergic airway inflammation) and contact dermatitis (contact hypersensitivity). CD69 deficiency and treatment with anti-CD69 mAbs increased inflammation in both experimental systems. The study of T-lymphocyte effector function showed that T_H2 and T_H17 responses in the asthma model and T_C1 and T_C17 responses in the contact dermatitis model are enhanced in CD69-deficient mice (see Figure). Moreover, in both experimental systems adoptive transfer of lymphocytes from CD69-deficient mice increased the inflammatory and allergic response in recipient mice. This study identifies CD69 as an important regulatory molecule in allergic diseases, enabling the development of new targeted therapies.

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• CD69 deficiency enhanced skin inflammation in a murine model of contact dermatitis.

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Inducible costimulator–positive regulatory T cells control the development of skin inflammatory reactions to haptens 

The phenotype, specificity, origin, and functional activity of regulatory T (Treg) cells in the control of skin allergic reactions are not well known. In a study reported in this issue, Vocanson et al (p 280) showed, in a murine model of allergic contact dermatitis to the hapten 2,4-dinitrofluorobenzene, that epicutaneous sensitization prompts activation of highly suppressive CD4⁺CD25⁺ forkhead box protein 3–positive Treg cells. These cells were observed to control, both in vitro and in vivo, induced CD8⁺ effector T cells in a hapten-specific manner. A subpopulation of CD4⁺CD25⁺ T cells defined by high inducible costimulator (ICOS) expression showed very high suppressive activity (see Figure). It is derived from the pool of natural Treg cells independently of the priming of specific CD8⁺ effector T cells. Very interestingly, CD4⁺CD25⁺ICOS⁺ T cells produce IL-10, IL-17, and IFN-γ in contrast to their ICOS⁻ counterparts. The definition of hapten-specific ICOS⁺ Treg cells endowed with high suppressive activity and T_H17/T_H1 features suggests an intrinsic association between the induction of such potent Treg cells and the conditions of active inflammation responsible for the strong effector response induced by the hapten. In addition, the plasticity of the Treg cells appears crucial to adapting their behavior according to the context in which the hapten is perceived by the innate immune cells.

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• Highly suppressive ICOS⁺ Treg cells primed on 2,4-dinitrofluorobenzene sensitization.

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Fas ligand and matrix metalloproteinase 7: A dysfunctional relationship in asthma 

Airway inflammation and epithelial damage are hallmarks of chronic asthma. The molecule Fas ligand (FasL) is potentially involved in both processes; expression of membrane FasL on lung epithelial cells confers a protective “immune barrier” defense against damage caused by infiltrating immune cells, but FasL can be cleaved into a proinflammatory soluble attractant for neutrophils, an important effector cell in asthma. Wadsworth et al (p 366) demonstrate that the protease matrix metalloproteinase 7 (MMP-7) is potentially important in airway epithelial health and inflammation in patients with asthma through direct cleavage of membrane FasL off epithelial cells. The authors show that MMP-7 expression is altered in the airway epithelium of patients with severe asthma in vivo. As shown in the Figure, they demonstrate that treatment of airway epithelial cells in vitro with an “asthma-like” T_H2 cytokine mix causes MMP-7 (green) and FasL (red) to colocalize (yellow) at the cell membrane. This interaction leads to cleavage of the protective FasL from the epithelial cell membrane and release of the soluble proinflammatory form. The T_H2 cytokine environment in the airways of asthmatic patients might therefore trigger a persistent increase of epithelial cell MMP-7 activity with associated FasL cleavage. The authors show airway epithelial MMP-7 as a potential target in patients with severe asthma to reduce airway inflammation and epithelial remodeling events.

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• T_H2 cytokines trigger colocalization of airway epithelial FasL and MMP-7.