The persistent production of allergen-specific IgE is a hallmark of type 1 allergies in human subjects. Analysis of the involvement of long-lived plasma cells as a source of persistent IgE production is the focus of the study reported in this issue of the Journal by Luger et al (p 819). The authors analyzed the lifetimes of allergen-specific IgE, IgG1, and IgA plasma cells using the well-established model of murine allergic asthma under immunosuppressive conditions. They found that long-lived plasma cells were generated in bone marrow and the spleen on systemic sensitization with ovalbumin (OVA). Furthermore, inhalation of OVA aerosol induced not only the development of local airway inflammation but also the generation of OVA-specific IgE-, IgG1-, and IgA-secreting plasma cells in the lung and secondary lymphoid organs (see Figure). These cells joined the pool of long-lived plasma cells in bone marrow and the spleen. After termination of OVA aerosol provocation, only systemic plasma cells in bone marrow and the spleen survived and sustained allergen-specific antibody titers over time. The study indicates that local aerosol allergen provocation induces the establishment of an allergen-specific humoral memory response in allergic patients. Thus, long-lived allergen-specific IgE plasma cells not effected by conventional treatment represent a new therapeutic target for IgE-mediated allergies.
Mucosal allergen challenge triggers the allergen-specific immune response and boosts IgE plasma cells in spleen.
Blockade of TH2 cytokines has been suggested as therapy for allergic diseases, including atopic dermatitis (AD). Previous work has shown that epicutaneous sensitization of mice elicits a systemic TH17 response that promotes airway hyperreactivity (AHR) in response to inhalation of allergens initially introduced through the skin. IL-17 is expressed in AD skin and in asthmatic airways. He et al (p 761) show that the systemic TH17 response to epicutaneous sensitization with ovalbumin is exaggerated in mice that are deficient in IL-4 or both IL-4 and IL-13 (DKO mice). In response to ovalbumin inhalation challenge, these mice experienced airway inflammation characterized by high IL-17 expression and abundant neutrophils and AHR, both of which were blocked by anti–IL-17 neutralizing antibody (see Figure). These results suggest that airway inflammation can occur in the absence of IL-4 and IL-13. More importantly, they suggest that blockade of IL-4 and IL-13 in patients with AD could result in a heightened IL-17 response and IL-17–driven airway inflammation and AHR. These results might also explain the failure of therapies targeting IL-4 receptor α in several clinical trials for asthma.
Effect of anti–IL-17 neutralizing mAb on airway inflammation in IL-4/IL-13 DKO mice EC sensitized and challenged with OVA. ctrl, Control.
How to interpret fraction of exhaled nitric oxide measurements?
There is uncertainty about how exhaled nitric oxide measurements should be interpreted in individual patients with asthma. In general, high levels (implying uncontrolled airway inflammation) and low levels (implying well-controlled inflammation) are helpful in assessing disease activity and its relationship to symptoms. Intermediate levels are indeterminate. Yet what is high and what is low? Cutpoints of greater than 50 ppb and less than 25 ppb in adults are recommended, but are these always appropriate? In the study by Smith et al (p 714), fraction of exhaled nitric oxide (FeNO) levels were measured (1) when asthma was poorly controlled, (2) after a course of oral prednisone when asthma was well controlled (personal best), and (3) during optimum treatment with inhaled steroids. All of the results were compared against predicted values for healthy subjects derived from recently published reference equations. It was found that targeting asthma treatment to achieve either predicted values or personal best values is not necessary. Adequate asthma control can be achieved with inhaled steroids at somewhat higher than personal best FeNO levels. The authors conclude that measuring FeNO during periods of good asthma control establishes the best “baseline” in individual patients and that subsequent changes should be used to guide clinical assessment.
Plasmacytoid dendritic cells during infancy linked to respiratory tract infections and childhood wheezing
Dendritic cells (DCs) have been implicated in the pathogenesis of allergic diseases, including asthma. However, it is not known whether alterations in DC subsets during early life might be linked to the subsequent incidence of asthma and related clinical phenotypes. As reported in this issue of the Journal, Upham et al (p 707) have now shown that relative deficiency of the plasmacytoid subset of DCs (pDCs) during the first year of life is linked to more frequent and more severe respiratory tract infections and to a greater likelihood of an asthma diagnosis up to age 5 years (see Figure). In contrast, levels of the myeloid subset of DCs (mDCs) during infancy were not associated with risk for respiratory tract infections or asthma but were associated with subsequently increased total IgE levels. The authors followed a cohort of children with a family history of atopy from birth to age 5 years, monitoring the children for respiratory tract infections, wheezing, and a physician's diagnosis of asthma and measuring DC subsets in blood by means of flow cytometry. Their findings suggest that DCs, particularly pDCs, play an important role during early life in protecting against respiratory tract infections and asthma.
DC subsets during infancy relative to the presence (red bars) or absence (blue bars) of asthma.
Pathogenesis of Omenn syndrome
Omenn syndrome (OS) is an autoimmunelike inflammatory disorder associated with combined immunodeficiency. The inflammation is believed to stem from leaky thymus caused by hypomorphic mutations in RAG1/RAG2, RMRP, ADA, γc, Zap-70, and other genes. Clonaly expanded T cells appear to cause lymphadenopathy and hepatosplenomegaly, as well as severe erythroderma typical of this disorder. Levels of the autoimmune regulator (AIRE), a thymic key regulator of central tolerance, were already shown to be profoundly reduced in thymi of some patients with OS. Somech et al (p 793) have expanded this observation by demonstrating that in patients with OS, PBMCs also express low AIRE transcripts (see Figure). In addition, these self-reactive cells express a restricted pattern of DNA recombination, further highlighting the pivotal role of AIRE in thymic function. In contrast, levels of forkhead box protein 3, a key regulator of peripheral tolerance, were normal in patients with OS, suggesting that regulatory T cells might not play a major role in the pathogenesis of OS. By using the TaqMan Low-Density Array, the authors also characterized the gene expression profile of a broad set of genes of the human immune system associated with the Omenn phenotype. The transcriptional profile associated with OS features revealed significant changes in 25.5% of the tested genes, some of which are well known to be closely involved in maintaining self-tolerance and autoimmunity.
Transcript expression (relative to control) of AIRE is reduced in an OS patient. In contrast, transcript expression of Foxp3 as well as protein expression of CD25 and FOXP3 in live CD4+ T cells gate are normal in an OS patient (4.6%, middle panel) and a control (4.9%, right panel).
Novel biologic activity of aspirin might explain therapeutic benefit of aspirin desensitization
Aspirin-exacerbated respiratory disease is characterized by asthma, nasal polyps, and intolerance to aspirin, along with overexpression of cysteinyl leukotrienes and their receptors. Through an unknown mechanism, aspirin desensitization is often a very effective treatment. As they report in this issue, Steinke et al (p 724) investigated the hypothesis that aspirin desensitization would block IL-4–induced leukotriene activity and other IL-4 functions through inhibition of signal transducer and activator of transcription 6 (STAT6)–mediated nuclear transcription. The authors used electrophoretic mobility shift assays to identify nuclear transcription factors binding STAT6 sites in leukotriene receptors. As displayed in the accompanying figure, nuclear extracts were obtained from enriched peripheral blood–derived mononuclear phagocytes under unstimulated, IL-4–stimulated (10 ng/mL), and IL-4 and aspirin (10 mmol/L)–costimulated conditions. The authors demonstrated that aspirin decreased IL-4–induced expression of nuclear STAT6. Inhibition of STAT6 activation might provide a mechanism by which aspirin desensitization followed by daily treatment results in downregulation of production and responsiveness to cysteinyl leukotrienes.
The presence of nuclear STAT6 is readily apparent with IL-4 activation but not when IL-4 stimulation occurred in the additional presence of aspirin.
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