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• Long-term clinical efficacy of grass allergy immunotherapy tablets
• Component-resolved diagnostics facilitate the diagnosis of peanut allergy
• Host-microbial interactions in childhood atopy
• The unexpected plasticity of TH17 cells
• A novel dendritic cell pathway potentiates the effects of thymic stromal lymphopoietin
• Omenn syndrome: When T cells lose control
• Copyright

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Long-term clinical efficacy of grass allergy immunotherapy tablets 

Seasonal allergic rhinitis affects 20% to 25% of the populations of Europe and the United States and has a considerable influence on quality of life in addition to being an independent risk factor for asthma. Specific immunotherapy is the only treatment modality with the potential to modify the course of this disease and provide sustained efficacy in post-treatment years. In a study by Durham et al (p 131), the sustained efficacy after a 3-year period with grass allergy immunotherapy tablet treatment was evaluated 1 year after completion of treatment. Statistically significant and clinically relevant differences in the primary end points in comparison with placebo were found at the 1-year follow-up (see Figure). Significant improvements in quality of life were also reported, both during treatment and during follow-up. No safety issues were identified, the most frequent adverse events being mild local reactions lasting some minutes after tablet intake. This is the first time that disease modification by means of sublingual immunotherapy has been shown in a large-scale, randomized, placebo-controlled trial. The results support allergy tablet immunotherapy as an option in those patients with hay fever whose symptoms remain uncontrolled with symptomatic medications. The observed long-term benefits raise the question of whether the treatment should be considered earlier in the course of the disease.

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• Primary end points: relative differences between treatment groups and corresponding P values.

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Component-resolved diagnostics facilitate the diagnosis of peanut allergy 

Not all peanut-sensitized children experience allergic reactions on exposure. Tests that could discriminate peanut allergy from tolerance without the need to perform oral food challenge would be extremely useful. Within the context of a population-based birth cohort, Nicolaou et al (p 191) determined, on the basis of peanut challenge, the proportion of children with peanut allergy among those considered peanut-sensitized using skin prick tests, sIgE measurements, or both (with whole peanut extract) and investigated whether blood tests with component-resolved diagnostics (microarray with major peanut and cross-reactive components) could differentiate peanut allergy from tolerance. Although approximately 1 in 10 children 8 years of age in the United Kingdom is peanut sensitized, on the basis of the oral food challenge, only 1 in 50 has peanut allergy. Component-resolved diagnostics revealed marked differences in the pattern recognition between subjects with peanut allergy and peanut-tolerant subjects (see Figure). Children with peanut allergy had higher responses to Ara h 1 to 3, whereas peanut-tolerant children had higher responses to grass components and cross-reactive carbohydrate determinants. Ara h 2 offered the best discrimination between the groups. These data confirm that the majority of children considered peanut sensitized on the basis of standard test responses do not have peanut allergy and suggest that measurement of IgE response to Ara h 2 might prove to be a clinically useful tool in predicting peanut allergy.

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• Pattern of component recognition between subjects with peanut allergy (yellow) and peanut-tolerant subjects (green). Ara h 2 offers best discrimination.

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Host-microbial interactions in childhood atopy 

Intestinal bacteria play an important role in shaping the developing immune system in early life. Perturbations in the composition of the gastrointestinal microbiota have been linked to atopic diseases, whereas atopy is also modified by genetic variations in the innate immune receptors that recognize these microbes. In this issue of the Journal, Penders et al (p 231) report on the interaction between the intestinal gram-negative bacterium Escherichia coli and genetic variations in the CD14 and Toll-like receptor 4 (TLR4) genes in relation to atopic manifestations in children from the KOALA Birth Cohort Study. They show that the effect of E coli colonization on subsequent atopic sensitization was modified by a polymorphism in TLR4. E coli colonization was associated with a decreased risk of sensitization only in children with the rs10759932 TT genotype and not in children with the minor C allele. The potential effect-modifying role of genetic variations on microbially driven immune regulation can have major implications for therapeutic strategies. Understanding host-microbial interactions in asthma and atopy might improve preventive strategies and targeted interventions, such as specific treatments to modulate the gut microbiota of infants at risk.

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The unexpected plasticity of T_H17 cells 

As reported in this issue, Cosmi et al (p 222) are the first to demonstrate the existence, both at the clonal level and in fresh peripheral blood, of CD4⁺ T cells showing the ability to coproduce IL-17A and IL-4; they have named these T_H17/T_H2 cells. The authors found that these cells probably originate when memory T_H17 cells stand in an IL-4–rich microenvironment. Thus having previously provided the first demonstration of the plasticity of T_H17 cells toward the T_H1 phenotype (see the authors' reference 11), which is now proved even for murine T_H17 cells, they now provide evidence for the plasticity of human T_H17 toward the T_H2 phenotype (see Figure). These studies, together with other findings from the same group (see the authors' reference 20) showing that, contrary to the persistent dogma, TGF-β is not essential for the differentiation of human T_H17 cells (as recently confirmed in mice), support the concept that human studies have depicted T_H17 cells better than studies in mice (Annunziato and Romagnani. Blood 2009;114:2213-9). In this article the authors found that T_H17/T_H2 cells can also produce other T_H2-related cytokines, such as IL-5, IL-9, and IL-13, in addition to IL-17A, and are able to directly induce the production of IgE by B lymphocytes. This finding, together with the demonstration that the number of T_H17/T_H2 cells is significantly higher in the circulation of atopic asthmatic patients compared with that seen in healthy subjects, suggests their possible role in inducing either IgE- and eosinophil-mediated inflammation (caused by IL-4, IL-5, and IL-13) or neutrophilic infiltration (caused by IL-17A). Thus these new findings appear to be clinically relevant for explaining the complexity and severity of some forms of bronchial asthma.

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• Plasticity of T_H17 cells. Human T_H17 cells, which express retinoic acid receptor–related orphan receptor C (RORC), T-box transcription factor (T-bet), IL-12Rβ2, IL-4Rα, CD161, and CCR6 in the presence of IL-12 produced by dendritic cells, exhibit upregulation of T-bet expression, acquire CXCR3 on their surface, and shift to the production of IFN-γ (T_H17/T_H1 and T_H1 cells), as has recently been shown even in mice. In the presence of IL-4, which can be produced by T_H2 cells, basophils, and mast cells, human T_H17 cells upregulate GATA-3 and shift to the production of IL-4 (T_H17/T_H2 cells).

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A novel dendritic cell pathway potentiates the effects of thymic stromal lymphopoietin 

Dendritic cell (DC)–based vaccines provide an approach to treat allergic disease. Previous work showed that the allergen variant H22–Fel d 1, which targets cat allergen to the high-affinity IgG receptor (FcγRI) on DCs, modulates T-cell responses in subjects with cat allergy. In theory this effect could be altered by mediators that act on DCs in vivo. Hulse et al (p 247) investigated whether T-cell responses induced by H22–Fel d 1 were influenced by the T_H2-promoting cytokine thymic stromal lymphopoietin (TSLP). This cytokine, which is expressed at sites of allergic inflammation, acts primarily through DCs. The authors report that monocyte-derived DCs (moDCs) from subjects with cat allergy that were coprimed with H22–Fel d 1 and TSLP induced a robust T_H2 response compared with that seen in moDCs primed with either stimulus alone. This suggested an interplay between FcγRI and the TSLP pathway. Further studies revealed that H22–Fel d 1 upregulated surface TSLP receptor (TSLPR) on moDCs through a process regulated by FcγRI-associated signaling components. Blocking TSLPR upregulation in coprimed moDCs abolished their T_H2-promoting effect. The discovery of a novel T_H2 regulatory pathway linking FcγRI signaling to TSLPR suggests that allergen vaccines that target specific Fc receptors might augment T_H2-driven inflammation by potentiating the effects of TSLP.

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• Copriming moDCs from a subject with cat allergy with H22–Fel d 1 and TSLP provides a potent T_H2 stimulus compared with priming with non–receptor-targeted Fel d 1 (Fel), H22–Fel d 1 (H-Fel), or TSLP alone.

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Omenn syndrome: When T cells lose control 

Omenn syndrome (OS) is an inherited disorder caused by hypomorphic mutations in recombination-activating genes (RAG) and characterized by the peculiar coexistence of severe combined immunodeficiency and autoimmunity. A lack of central tolerance contributes to the autoimmune pathology of the disease, leading to release of autoreactive T cells in the periphery. At this level, self-tolerance is enforced by CD4⁺CD25^high forkhead box protein 3 (FOXP3)–positive regulatory T cells. Cassani et al (p 209) analyze FOXP3 expression in the peripheral blood and lymphoid organs of 9 patients with OS. Although children with OS have a variable number of circulating FOXP3⁺ T lymphocytes, these cells coexpress activation markers, and when sorted on the basis of the CD4⁺CD25^hiCD127^low/− phenotype, they do not suppress proliferation of allogeneic activated CD4⁺CD25⁻ T cells. Furthermore, the authors report a severe reduction of FOXP3⁺ cells in lymph nodes and the thymus (see Figure) of patients with OS. These results indicate that expression of FOXP3 in peripheral blood of patients is not a reliable marker for regulatory T cells but rather is consistent with an in vivo T-cell activation process. Clinical applications of this research include the identification of previously unrecognized targets for therapeutic intervention while preparing for hematopoietic stem cell transplantation.

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• FOXP 3 expression in the thymus and lymph nodes of patients with OS.