The Journal of Allergy and Clinical Immunology - Articles in Press

Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System - Corrected Proof

Linda Cox, Desiree Larenas-Linnemann, Richard F. Lockey, Giovanni Passalacqua — 2010-02-08

Subcutaneous allergen immunotherapy (SCIT) is an effective treatment for allergic rhinitis, asthma and venom hypersensitivity and has the potential of producing serious life-threatening anaphylaxis. Adverse reactions are generally classified into 2 categories: local reactions, which can manifest as redness, pruritus, and swelling at the injection site, and systemic reactions (SRs). SRs can range in severity from mild rhinitis to fatal cardiopulmonary arrest. Early administration of epinephrine, which is the treatment of choice to treat anaphylaxis, may prevent the progression of an SR to a more serious life-threatening problem. Although there is little debate about using epinephrine to treat a SCIT SR, there is a lack of consensus about when it should be first used. A uniform classification system for grading SCIT SRs will be helpful in assessing more accurately when epinephrine should be administered. The primary purpose of this article is to discuss the proposed grading system for SCIT SRs.

Reply - Corrected Proof

Robert J. Hancox, Piush J. Mandhane, Malcolm R. Sears — 2010-02-08

To the Editor: We thank Dr Brenna for his comments on our article. We do not know what aspect of cat and dog ownership might reduce the risk of allergy. As we acknowledge in the article, the apparent protective effect could be a result of exposure to allergens, endotoxins, or perhaps some other exposure associated with pet ownership, as Dr Brenna suggests. However, we do not think that a “healthy worker” effect can account for our findings because neither a family history of allergies nor a personal history of atopy influenced pet ownership.

Reply - Corrected Proof

Päivi M. Salo, Darryl C. Zeldin — 2010-02-08

To the Editor: Dr Brenna raises several important issues in his commentary. In epidemiologic studies, selection bias and lack of generalizability are not uncommon concerns. Study findings can be influenced by self-selection (ie, the healthy worker effect), especially in cross-sectional occupational studies. Studies of farming populations, however, have provided a unique opportunity to study the role of environmental factors in the development of atopic disorders. In the study by Mandhane et al, the longitudinal data were derived from a large, unselected, population-based cohort, which is one of the major strengths of the work. Indeed, the authors found no signs of selection bias in their study.

Cats and dogs: An attractive remedy versus atopy? - Corrected Proof

Oreste V. Brenna — 2010-02-08

To the Editor: Because I am very keen on cats and dogs, I read with interest both the article by Mandhane et al and the related editorial. The first article provides evidence that living with cats and dogs is associated with a lower risk of atopy during childhood and young adulthood.

Adolescents with asthma or atopic eczema have more febrile days in early childhood: A possible explanation for the connection between paracetamol and asthma? - Corrected Proof

Terhi Tapiainen, Teija Dunder, Merja Möttönen, Tytti Pokka, Matti Uhari — 2010-02-08

To the Editor: It has been proposed in several observational studies that paracetamol might be a risk factor for asthma (see the recent review by Farquhar et al in the Journal of Allergy and Clinical Immunology). Confounding factors are difficult to control in observational studies because the allocation to treatment groups does not take place at random. A large sample size will increase the statistical precision, however, and allow adjustment for multiple confounders, but it does not eliminate the problems entailed in observational surveys.

Advances in environmental and occupational respiratory diseases in 2009 - Corrected Proof

David B. Peden, Robert K. Bush — 2010-02-08

The year 2009 led to a number of significant advances in environmental and occupational allergic diseases. The role of exposure to environmental pollutants, respiratory viruses, and allergen exposure showed significant advances. New allergens were identified. Occupational asthma and the relationship of complementary and alternative medicine to allergic diseases were extensively reviewed. New approaches to immunotherapy, novel vaccine techniques, and methods to reduce risks for severe allergic disease were addressed.

Decreases in human dendritic cell–dependent TH2-like responses after acute in vivo IgE neutralization - Corrected Proof

2010-02-05

Background: Dendritic cells (DCs) and other professional antigen-presenting cells express a variant of the high-affinity IgE receptor known as αγ2, which, on the basis of in vitro findings, has long been implicated to function in facilitating allergen uptake and presentation to TH cells.Objectives: To use omalizumab as an in vivo tool to neutralize IgE binding to circulating dendritic cells and to assess whether this results in altered DC-dependent T-cell responsiveness to allergen ex vivo.Methods: Subjects with cat allergy were enrolled in a 3.5-month, double blind, randomized (3.5:1), placebo-controlled trial of omalizumab using standard dosing for allergic asthma. Blood plasmacytoid and myeloid DCs were assessed at baseline and posttreatment for expression of surface IgE, FcεRIα, and induction of CD4+T-cell proliferation and cytokine responses to cat allergen.Results: IgE expression on plasmacytoid and myeloid DCs from omalizumab-treated subjects (n = 12) decreased by ≥95% posttreatment (P = .0005), whereas FcεRIα expression decreased by 66% and 48%, respectively (P = .0005). Cat allergen–induced proliferation in DC/T-cell cocultures observed at baseline was suppressed ∼20% to 40% postomalizumab treatment (P = .001). Multiplexing for cytokines in plasmacytoid DC/T-cell cocultures also showed decreases in IL-5, IL-13, and IL-10 (P < .05), whereas IL-2 and IFN-γ were unaltered or slightly increased. These changes were not evident in placebo-control subjects (n = 4).Conclusion: IgE likely facilitates allergen presentation by dendritic cells in vivo and is also important in regulating DC-dependent T-cell cytokines during effector phases of allergic disease.

CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis - Corrected Proof

2010-02-04

Background: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe, bullous cutaneous diseases with uncertain pathogenesis, although cytotoxic T cells seem to be involved. Natural killer (NK)–like activity has been found in blister infiltrates. Cytotoxic T lymphocytes (CTLs) with NK-like activity (NK-CTLs) have been shown to express T-cell receptors restricted by the HLA-Ib molecule HLA-E. Alternatively, the HLA-E–specific activating receptor CD94/NKG2C can trigger T-cell receptor–independent cytotoxicity in CTLs.Objective: Our aim was to test whether HLA-E expression sensitizes keratinocytes to killing by CTLs with NK-like activity and to explore the expression of activating receptors specific for HLA-E in blister cytotoxic lymphocytes.Methods: We used flow cytometry and immunohistochemistry to analyze HLA-E expression in keratinocytes from affected skin in patients with SJS, TEN, and other less severe drug-induced exanthemas. The expression of CD94/NKG2C was analyzed by means of flow cytometry in PBMCs and blister cells from patients. PBMCs and blister cells were analyzed for their ability to kill HLA-E–expressing cells. Involvement of CD94/NKG2C in triggering degranulation of cytolytic cells was explored by means of CD107a mobilization assays and standard cytotoxicity chromium release assays.Results: We found that keratinocytes from affected skin expressed HLA-E and that cell-surface HLA-E sensitizes keratinocytes to killing by CD94/NKG2C+ CTLs. Frequencies of CD94/NKG2C+ peripheral blood T and NK cells were increased in patients with SJS and TEN during the acute phase. Moreover, activated blister T and NK lymphocytes expressed CD94/NKG2C and were able to degranulate in response to HLA-E+ cells in an NKG2C-dependent manner.Conclusion: CD94/NKG2C might be involved in triggering cytotoxic lymphocytes in patients with SJS and TEN.

Differential effects of outdoor versus indoor fungal spores on asthma morbidity in inner-city children - Corrected Proof

2010-02-04

Background: Although sensitization to fungal allergens is prevalent in inner-city children with asthma, the relationship between fungal exposure and morbidity is poorly understood.Objective: We examined relationships between fungal sensitization, exposure, and asthma morbidity in inner-city children.Methods: Participants were 5 to 11 years old and enrolled in the Inner-City Asthma Study. This report includes the subset of children with at least 1 positive skin test (PST) response to a fungal allergen extract; for these children, indoor and outdoor airborne culturable fungi levels were measured at baseline and throughout the 2-year study. Asthma morbidity measures were collected prospectively. The primary outcome was symptom days per 2 weeks.Results: At baseline, children with a PST response to a fungal allergen extract had significantly more symptom days compared with those without a PST response to any fungal allergen extract (6.3 vs 5.7 days per 2 weeks, P = .04). During the study, increases in total fungal exposure and indoor Penicillium species exposure were associated with increases in symptom days and asthma-related unscheduled visits. Indoor exposures to total fungi and to Penicillium species were associated with significant increases in unscheduled visits, even after controlling for outdoor fungal levels. Adverse effects associated with exposure to a specific fungus were stronger among children with PST responses to that fungal allergen extract compared with those seen in children with negative skin test responses.Conclusion: Outdoor fungal exposure is primarily associated with increased asthma symptoms and increased risk of exacerbations in this population.

Naturally processed T-cell–activating peptides of the major birch pollen allergen - Corrected Proof

2010-02-04

Background: Although antigen processing and presentation of allergens to CD4+T lymphocytes are key events in the pathophysiology of allergic disorders, they still remain poorly understood.Objective: To investigate allergen processing and presentation by dendritic cells using the major birch pollen allergen Bet v 1 as a model.Methods: Endolysosomal extracts of dendritic cells derived from patients with birch pollen allergy were used to digest Bet v 1. Dendritic cells were pulsed with Bet v 1, and peptides were eluted from MHC class II molecules. Peptides obtained by either approach were sequenced by tandem mass spectrometry. Bet v 1–specific T-cell cultures were stimulated with HLA-DR–eluted Bet v 1–derived peptides. Bet v 1–specific T-cell lines were generated from each patient and analyzed for epitope recognition.Results: A high proportion of Bet v 1 remained intact for a long period of endolysosomal degradation. The peptides that appeared early in the degradation process contained frequently recognized T-cell epitopes. Bet v 1–derived peptides eluted from MHC class II molecules corresponded to those generated by endolysosomal degradation, matched known T-cell epitopes, and showed T-cell–activating capacity. The Bet v 1–specific T-cell line of each individual harbored T cells reactive with peptides located within the MHC class II–eluted Bet v 1–derived sequences demonstrating their occurrence in vivo.Conclusion: We report for the first time how epitopes of allergens are generated and selected for presentation to T lymphocytes. The limited susceptibility of Bet v 1 to endolysosomal processing might contribute to its high allergenic potential.

Inflammation and airway function in the lung periphery of patients with stable asthma - Corrected Proof

Sylvia Verbanck, Daniel Schuermans, Walter Vincken — 2010-02-04

Background: An important role for exhaled nitric oxide (NO) measurement could be in the distinction between proximal and peripheral lung contributions to inflammation, with a particular interest for the alveolar lung zone and its implication on airway function.Objective: We aimed to isolate the acinar lung zone contribution to both inflammation and airway function to seek a relationship between them.Methods: In 30 patients with asthma with an asthma control test score exceeding 20, indices of conductive and acinar ventilation heterogeneity (Scond, Sacin) were obtained from a multiple breath washout. NO production in the conductive airways (J'awNO), alveolar NO concentration (CANO), and the standard exhaled NO at 50 mL/s (FENO50) were obtained from exhaled NO.Results: Scond was consistently abnormal in all patients with stable asthma, but without any correlation to inflammation abnormality in that compartment (J'awNO). Sacin was particularly abnormal in the asthma subgroup receiving >500 μg budesonide equivalent, and a correlation was found between Sacin and CANO (r = 0.61; P = .015); in this subgroup, a weak association was found between Scond and J'awNO or FENO50 (r = 0.50; P = .059 for both).Conclusion: The persistent functional abnormality of small conductive airways in patients with stable asthma is largely independent of inflammation as measured by exhaled NO. In the alveolar compartment, a functional correlate of alveolar NO was found in a subgroup of patients with stable asthma on moderate-to-high maintenance doses of inhaled steroids. These patients in particular could benefit from novel therapies specifically aimed at improving airway functionality at the level of the acinar entrance and beyond.

Evidence for neuronal expression of functional Fc (ε and γ) receptors - Corrected Proof

2010-02-04

To the Editor: The Fc receptor family plays a key role in adaptive immunity through the binding of immunoglobulin antibodies that recognize an immune insult and elicit an inflammatory response leading to its clearance. Dysregulation of this receptor family may have untoward consequences that result in autoimmune and allergic diseases. Many of these diseases seem to involve the nervous system and are exacerbated by stress or other neurologic challenges. Recently, the presence of Fc receptors was uncovered on dorsal root ganglion neurons and suggested an IgG and possibly IgE-mediated activation of neurons. We set out to explore more extensively which Fc receptors might be expressed in neurons, and whether they were functional and able to transmit signals to interconnected neurites in vitro and in vivo.

Ethnic differences in asthma–panic disorder comorbidity - Corrected Proof

2010-02-04

To the Editor: Adults with asthma are at substantially higher risk for panic disorder (PD) than individuals without asthma. There is evidence that asthma and PD may interact with each other and produce greater morbidity for each disease. Respiratory-related symptoms, such as dyspnea, chest tightness, and sensations of smothering are common in both disorders. The overlap in symptoms may lead an individual to mistake a panic attack as an asthma attack. This confusion may trigger a maladaptive cycle of using short-acting β2-agonists to treat respiratory anxiety symptoms, mistaken as asthma, and thus further increasing feared bodily sensations and panic.

Serum ferritin and transferrin levels are not serologic markers of toluene diisocyanate–induced occupational asthma - Corrected Proof

2010-02-04

To the Editor: In a recent article, Hur et al reported that by using a proteomic approach, ferritin expression was downregulated whereas transferrin expression was upregulated in bronchoalveolar lavage fluid in subjects with methylene diphenyl diisocyanate–induced occupational asthma (MDI-OA) or eosinophilic bronchitis compared with exposed asymptomatic control workers (AECs) to methylene diphenyl diisocyanate (MDI). The authors also measured these compounds by ELISA using sera from the MDI-OA/eosinophilic bronchitis and AEC groups. The results showed that serum ferritin and transferrin can be serologic markers in diagnosing MDI-OA. To identify subjects with MDI-OA, the optimal serum cut-off levels were 69.84 ng/mL for ferritin and 2.48 mg/mL for transferrin. When these 2 parameters were combined, the sensitivity was 71.43%, and the specificity was 85.71%. These authors speculate that some susceptible subjects with defects in iron metabolism and lower serum ferritin levels may develop MDI-OA after MDI exposure, whereas some subjects with lower serum transferrin levels may be resistant to MDI exposure. The authors then argue that ferritin might act defensively against MDI, and some subjects with an impaired ferritin level may be more susceptible to MDI-OA than those who have a normal iron metabolism and are exposed to MDI.

Early-life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology - Corrected Proof

2010-02-01

Background: Asthma typically originates in early-life, and the impact of infection during immunologic maturation is a critical factor in disease pathogenesis. The progression of aberrant TH2 cell responses and disease development has been attributed to a lack of infections. However, exposure to specific pathogens such as Chlamydia may alter immunologic programming and predispose to asthma.Objective: To investigate the effects of chlamydial infection at different ages on allergic airways disease in later life.Methods: Neonatal, infant, or adult BALB/c mice were infected and 6 weeks later were sensitized and subsequently challenged with ovalbumin. Hallmark features of allergic airways disease were compared with uninfected allergic and nonallergic controls.Results: Early-life (neonatal and infant) but not adult chlamydial infection enhanced the development of hallmark features of asthma in ovalbumin-induced allergic airways disease. Notably early-life infection increased mucus-secreting cell numbers, IL-13 expression, and airway hyperresponsiveness. Neonatal infection attenuated eosinophil influx and ovalbumin-specific TH2 cytokine release and numbers of activated myeloid dendritic cells (DCs) in lymph nodes. By contrast, infant infection augmented features of allergic inflammation with increased airway eosinophils, TH2 cytokine, and DC responses. Both neonatal and infant infection increased systemic DC-induced IL-13 release from CD4+ T cells. The timing of infection had significant effects on lung structure because neonatal but not infant or adult infection induced increases in alveolar diameter.Conclusion: Early-life respiratory chlamydial infections modulate immune responses, alter lung function and structure, and enhance the severity of allergic airways disease in later life.

Abel, Takamine, and the isolation of epinephrine - Corrected Proof

John Parascandola — 2010-01-18

In the second half of the 19th century, medical researchers paid increasing attention to the so-called ductless (endocrine) glands. In 1848, German physiologist Arnold Berthold provided the first evidence that one of these glands could secrete a physiologically active substance directly into the bloodstream. A castrated rooster normally exhibited a shrinking of its comb, but Berthold showed that this shrinking did not occur if the excised testes were transplanted into the abdominal cavity. He suggested that the testes must be secreting some substance into the blood that affected the comb.

Lessons learned from variation in response to therapy in clinical trials - Corrected Proof

Stanley J. Szefler, Richard J. Martin — 2010-01-14

In the past, we viewed lack of response to asthma medications as a rare event. Based on recent studies, we now expect significant variation in treatment response for all asthma medications. However, little information is available about methods to predict favorable treatment response. Research conducted in the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network and Childhood Asthma Research and Education Network verified this variability in response to several long-term control medications, specifically inhaled corticosteroids and leukotriene receptor antagonists, in adults and children with mild-to-moderate persistent asthma. The networks also identified potential methods to use patients' characteristics, such as age and allergic status, and biomarkers, such as bronchodilator response, exhaled nitric oxide, and urinary leukotrienes, to help predict response to inhaled corticosteroids and leukotriene receptor antagonists and to determine which of the 2 treatments might be more effective in individual patients. This information now assists the clinician in personalizing asthma treatment at the time of initiating long-term control therapy.

3. Adaptive immunity - Corrected Proof

Francisco A. Bonilla, Hans C. Oettgen — 2010-01-11

The innate immune system provides critical mechanisms for the rapid sensing and elimination of pathogens. Adaptive immunity has evolved to provide a broader and more finely tuned repertoire of recognition for both self- and nonself-antigens. Adaptive immunity involves a tightly regulated interplay between antigen-presenting cells and T and B lymphocytes, which facilitate pathogen-specific immunologic effector pathways, generation of immunologic memory, and regulation of host immune homeostasis. Lymphocytes develop and are activated within a series of lymphoid organs comprising the lymphatic system. During development, sets of gene segments are rearranged and assembled to create genes encoding the specific antigen receptors of T and B lymphocytes. The rearrangement mechanism generates a tremendously diverse repertoire of receptor specificities capable of recognizing components of all potential pathogens. In addition to specificity, another principal feature of adaptive immunity is the generation of immunologic memory. During the first encounter with an antigen (pathogen), sets of long-lived memory T and B cells are established. In subsequent encounters with the same pathogen, the memory cells are quickly activated to yield a more rapid and robust protective response.

30. Embryonic and adult stem cell therapy - Corrected Proof

Anne C. Brignier, Alan M. Gewirtz — 2010-01-11

There are many types of stem cells. All share the characteristics of being able to self-renew and to give rise to differentiated progeny. Over the last decades, great excitement has been generated by the prospect of being able to exploit these properties for the repair, improvement, and/or replacement of damaged organs. However, many hurdles, both scientific and ethical, remain in the path of using human embryonic stem cells for tissue-engineering purposes. In this report we review current strategies for isolating, enriching, and, most recently, inducing the development of human pluripotent stem cells. In so doing, we discuss the scientific and ethical issues associated with this endeavor. Finally, progress in the use of stem cells as therapies for type 1 diabetes mellitus, congestive heart failure, and various neurologic and immunohematologic disorders, and as vehicles for the delivery of gene therapy, is briefly discussed.

20. Diagnostic testing and interpretation of tests for autoimmunity - Corrected Proof

Christine Castro, Mark Gourley — 2010-01-11

Laboratory testing is of great value when evaluating a patient with a suspected autoimmune disease. The results can confirm a diagnosis, estimate disease severity, aid in assessing prognosis and are useful for following disease activity. Components of the laboratory examination include a complete blood count with differential, a comprehensive metabolic panel, measurement of inflammatory markers and autoantibodies, and flow cytometry. This chapter discusses these components and includes a discussion about organ-specific immunologic diseases for which immunologic laboratory testing is used. Comprehensive laboratory evaluation of a suspected autoimmune illness in conjunction with a thorough clinical evaluation provides a better understanding of a patient's immunologic disease.

24. Immune responses to malignancies - Corrected Proof

Theresa L. Whiteside — 2010-01-11

Immune responses to tumor-associated antigens (TAs) are often detectable in tumor-bearing hosts, but they fail to eliminate malignant cells or prevent the development of metastases. Patients with cancer generate robust immune responses to infectious agents (bacteria and viruses) perceived as a “danger signal” but only ineffective weak responses to TAs, which are considered as “self.” This fundamental difference in responses to self versus nonself is further magnified by the ability of tumors to subvert the host immune system. Tumors induce dysfunction and apoptosis in CD8+ antitumor effector cells and promote expansion of regulatory T cells, myeloid-derived suppressor cells, or both, which downregulate antitumor immunity, allowing tumors to escape from the host immune system. The tumor escape is mediated by several distinct molecular mechanisms. Recent insights into these mechanisms encourage expectations that a more effective control of tumor-induced immune dysfunction will be developed in the near future. Novel strategies for immunotherapy of cancer are aimed at the protection and survival of antitumor effector cells and also of central memory T cells in the tumor microenvironment.

Remodeling and inflammation in Chinese versus white patients with chronic rhinosinusitis - Corrected Proof

2010-01-11

To the Editor: The authors of the article entitled “Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese” claim to confirm our data on the deficit of forkhead box protein 3 (or T-regulatory cells) and a decreased production of TGF-β1 in Chinese patients with chronic rhinosinusitis with nasal polyps versus controls; they also claim that, in contrast with our findings in white patients, mucosal samples of patients with chronic rhinosinusitis without nasal polyps (CRSsNP) in China would be characterized by a decrease in T-regulatory cells and TGF-β expression.

Reply - Corrected Proof

Ping-Ping Cao, Hua-Bin Li, De-Yun Wang, Martin Desrosiers, Zheng Liu — 2010-01-11

To the Editor: We appreciate the critical comments from Zhang et al on our study. The major criticism questions the sensitivity and accuracy of the measurements of TGF-β1 and forkhead box protein 3 (Foxp3) mRNA expression in our study, because these results are discordant with previous reports by their group. In response to this question, we have retested TGF-β1 and Foxp3 mRNA expression, using both the primers constructed for our previous study and new ones constructed from the sequences reported by their group in a new set of samples obtained from 10 patients with septal deviation (controls) and 14 patients with chronic rhinosinusitis without nasal polyps (CRSsNP). With regard to TGF-β1, with our primers, we could again only identify positive expression in a limited number of samples, for an expression frequency of 50% in CRSsNP and 70% in controls, which is comparable to our previous results. Using the primers constructed according to the description by their group, we were able to detect the expression of TGF-β1 in all samples, but the expression intensity was relatively weak. Such discrepancy might be a result of the different amplification efficiencies between different primers. Furthermore, when using the primers of their group, TGF-β1 mRNA expression levels were almost 2-fold lower in CRSsNP compared with controls, which again confirms our previous findings, but not those reported by Zhang et al.

Component-resolved diagnosis of kiwifruit allergy with purified natural and recombinant kiwifruit allergens - Corrected Proof

2010-01-11

Background: Kiwifruit is one of the most common causes of food allergic reactions. Component-resolved diagnostics may enable significantly improved detection of sensitization to kiwifruit.Objective: To evaluate the use of individual allergens for component-resolved in vitro diagnosis of kiwifruit allergy.Methods: Thirty patients with a positive double-blind placebo-controlled food challenge to kiwifruit, 10 atopic subjects with negative open provocation to kiwifruit, and 5 nonatopic subjects were enrolled in the study. Specific IgE to 7 individual allergens (nAct d 1-5 and rAct d 8-9) and allergen extracts was measured by ImmunoCAP.Results: The diagnostic sensitivities of the commercial extract and of the sum of single allergens were 17% and 77%, respectively, whereas diagnostic specificities were 100% and 30%. A combination of the kiwi allergens Act d 1, Act d 2, Act d 4, and Act d 5 gave a diagnostic sensitivity of 40%, whereas diagnostic specificity remained high (90%). Exclusion of the Bet v 1 homolog recombinant (r) Act d 8 and profilin rAct d 9 from this allergen panel reduced sensitivity to 50% but increased specificity to 40%. Kiwifruit-monosensitized patients reacted more frequently (P < .001) with Act d 1 than polysensitized patients, whereas the latter group reacted more frequently with rAct d 8 (P = .004).Conclusion: Use of single kiwifruit allergen ImmunoCAP increases the quantitative test performance and diagnostic sensitivity compared with the commercial extract. Bet v 1 homolog and profilin are important allergens in pollen-related kiwifruit allergy, whereas actinidin is important in monoallergy to kiwifruit, in which symptoms are often more severe.

Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes - Corrected Proof

2010-01-11

Background: Systemic mastocytosis (SM) is a heterogeneous group of disorders with distinct clinical and biological behavior. Despite this, little is known about the immunophenotypic features of the distinct diagnostic categories of SM.Objective: To analyze the immunophenotypic characteristics of bone marrow (BM) mast cells (MCs) of different subtypes of SM.Methods: Bone marrow samples from 123 patients with different subtypes of SM and 92 controls were analyzed for a broad panel of immunophenotypic markers by flow cytometry.Results: Three clearly different maturation-associated immunophenotypic profiles were found for BMMCs in SM. These different profiles were associated with both genetic markers of the disease and its clinical behavior. BMMCs from poor-prognosis categories of SM (aggressive SM and MC leukemia) typically showed an immature phenotype with clonal involvement of all myeloid lineages by the D816V stem cell growth factor receptor gene (KIT) mutation. In turn, a mature activated versus resting BMMC immunophenotype was commonly found among patients with good-prognosis subtypes of SM depending on whether they carried (indolent SM and clonal MC activation disorders) or not (well differentiated SM) the D816V KIT mutation.Conclusion: Bone marrow MCs from SM show 3 different maturation-related immunophenotypic profiles that are associated with both the genetic markers of the disease and its clinical behavior.

Ovalbumin content in 2009 to 2010 seasonal and H1N1 monovalent influenza vaccines - Corrected Proof

Kirk H. Waibel, Robert Gomez — 2010-01-11

To the Editor: For the 2009 to 2010 influenza season, 34 manufacturers in 19 countries are manufacturing influenza vaccines. In the United States, there are 5 manufacturers producing 1 nasal and 5 injectable Food and Drug Administration (FDA)–approved seasonal influenza vaccines. These manufacturers are also producing 1 nasal and 4 injectable H1N1 (hemagglutinin 1, neuraminidase 1) monovalent vaccines. Because influenza vaccines are developed by inoculating embryonated chicken eggs with virus, the final product has always contained ovalbumin, which can pose a risk in children and adults with egg allergy. However, because manufacturers do not report final lot ovalbumin content, allergists are directed to start with skin prick and intradermal skin testing to the vaccine followed by either a 2-dose or a graded multidose vaccine administration protocol. However, these recommendations may be too conservative, because all but 1 manufacturer for the 2009 to 2010 FDA-approved influenza vaccines state a maximum ovalbumin content of ≤1 μg per dose (≤2 μg/mL), and improvements such as ultracentrifugation have resulted in lower ovalbumin content in vaccines like FluMist (MedImmune LLC, Gaithersburg, Md).

15. Primary immunodeficiencies - Corrected Proof

Luigi D. Notarangelo — 2009-12-30

In the last years, advances in molecular genetics and immunology have resulted in the identification of a growing number of genes causing primary immunodeficiencies (PIDs) in human subjects and a better understanding of the pathophysiology of these disorders. Characterization of the molecular mechanisms of PIDs has also facilitated the development of novel diagnostic assays based on analysis of the expression of the protein encoded by the PID-specific gene. Pilot newborn screening programs for the identification of infants with severe combined immunodeficiency have been initiated. Finally, significant advances have been made in the treatment of PIDs based on the use of subcutaneous immunoglobulins, hematopoietic cell transplantation from unrelated donors and cord blood, and gene therapy. In this review we will discuss the pathogenesis, diagnosis, and treatment of PIDs, with special attention to recent advances in the field.

10. Food allergy - Corrected Proof

Scott H. Sicherer, Hugh A. Sampson — 2009-12-30

Adverse immune responses to foods affect approximately 5% of young children and 3% to 4% of adults in westernized countries and appear to have increased in prevalence. Food-induced allergic reactions are responsible for a variety of symptoms and disorders involving the skin and gastrointestinal and respiratory tracts and can be attributed to IgE-mediated and non–IgE-mediated (cellular) mechanisms. Genetic disposition and environmental factors might abrogate oral tolerance, leading to food allergy. Disease outcomes are influenced by the characteristics of the immune response and of the triggering allergen. Diagnosis is complicated by the observation that detection of food-specific IgE (sensitization) does not necessarily indicate clinical allergy. Therefore diagnosis requires a careful medical history, laboratory studies, and, in many cases, an oral food challenge to confirm a diagnosis. Novel diagnostic methods, including ones that focus on immune responses to specific food proteins or epitopes of specific proteins, are under study. Currently, management of food allergies consists of educating the patient to avoid ingesting the responsible allergen and to initiate therapy (eg, with injected epinephrine for anaphylaxis) in case of an unintended ingestion. Improved therapeutic strategies under study include oral and sublingual immunotherapy, Chinese herbal medicine, anti-IgE antibodies, and modified vaccines.

16.Secondary immunodeficiencies, including HIV infection - Corrected Proof

Javier Chinen, William T. Shearer — 2009-12-30

Extrinsic factors can adversely affect immune responses, producing states of secondary immunodeficiency and consequent increased risk of infections. These immunodeficiencies, which can be encountered in routine clinical practice, arise from a number of conditions, such as treatment with glucocorticoids and immunomodulatory drugs, surgery and trauma, extreme environmental conditions, and chronic infections, such as those caused by HIV. The most common cause of immunodeficiency is malnutrition, affecting many communities around the world with restricted access to food resources. Protein-calorie deficiency and micronutrient deficiencies have been shown to alter immune responses; of note, recent progress has been made in the influence of vitamin D deficiency in causing failure of immune activation. Other categories of disease that might present with secondary immunodeficiency include metabolic diseases and genetic multisystemic syndromes. The immune defects observed in secondary immunodeficiency are usually heterogeneous in their clinical presentation, and their prognosis depends on the severity of the immune defect. Management of the primary condition often results in improvement of the immunodeficiency; however, this is sometimes not possible, and the risk of infections can be reduced with prompt antimicrobial treatment and prophylaxis.

26. Laboratory evaluation of primary immunodeficiencies - Corrected Proof

João B. Oliveira, Thomas A. Fleisher — 2009-12-30

Primary immunodeficiencies are congenital disorders caused by defects in different elements of the immune system. Affected patients usually present clinically with recurrent infections, severe infections, or both, as well as autoimmune phenomena that are associated with many of these disorders. Early diagnosis is essential for referral to specialized care centers and the prompt initiation of appropriate therapy. In this article the authors describe a general approach for the investigation of the most common primary immunodeficiencies, outlining the typical clinical symptoms and most appropriate laboratory investigations.

Josiah F. Wedgwood (1950-2009) - Corrected Proof

2009-12-30

To the Editor: With the death of Josiah F. Wedgwood on November 27, 2009, the primary immunodeficiency (PID) and autoimmunity research communities lost a strong advocate and a dear friend. Josiah received a Bachelors of Arts magna cum laude, 1971, and a PhD in Biochemistry and Molecular Biology, 1978, from Harvard University. He earned an MD from George Washington University School of Medicine in 1980 and trained in pediatrics and pediatric infectious diseases at New York Hospital/Cornell University Medical Center and in neonatology/perinatology at Long Island Jewish Medical Center. From 1991 to 1998, he was an assistant professor of Pediatrics at Mount Sinai Medical Center in New York. From 1998 until 2002, Josiah served as director of Newborn Services, Hospital of Saint Raphael at Yale Medical School. Josiah was the primary author of more than 25 journal articles and 5 book chapters in neonatology, immunology, and pediatric infectious diseases.

28. Immunomodulator therapy: Monoclonal antibodies, fusion proteins, cytokines, and immunoglobulins - Corrected Proof

Susan J. Lee, Javier Chinen, Arthur Kavanaugh — 2009-12-28

The immune system consists of a diverse array of immunocompetent cells and inflammatory mediators that exist in complex networks. These components interact through cascades and feedback circuits, maintaining physiologic inflammation (eg, tissue repair) and immunosurveillance. In various autoimmune and allergic diseases, a foreign antigen or autoantigen might upset this fine balance, leading to dysregulated immunity, persistent inflammation, and ultimately pathologic sequelae. In recent years, there has been tremendous progress delineating the specific components of the immune system that contribute to various aspects of normal immunity and specific disease states. With this greater understanding of pathogenesis coupled with advances in biotechnology, many immunomodulatory agents commonly called “biologic agents” have been introduced into the clinic for the treatment of various conditions, including immune globulins and cytokines. The 2 most common classes of approved biologic agents are mAbs and fusion proteins with exquisite specificity. These agents have the potential both to optimize outcomes through more thorough modulation of specific parts of the dysregulated immune response and to minimize toxicity compared with less specific methods of immunosuppression.

Color-coded real-time cellular imaging of lung T-lymphocyte accumulation and focus formation in a mouse asthma model - Corrected Proof

2009-12-25

Background: A critical role for CD4+TH2 cells in the pathogenesis of acute asthma has been demonstrated in the studies of human asthma as well as of animal models of asthma. TH2-cell migration into the lung is crucial for the initiation of asthma phenotype, but the dynamics of this process are poorly understood because it has been difficult to visualize this process.Objective: Our aim was to image the cellular dynamics of the migration of TH2 cells into the lung of living animals in a mouse model of asthma and identify the cellular processes required for the initiation of the asthma phenotype.Methods: We developed a color-coded real-time imaging model of cell migration into the lung using green fluorescent protein (GFP) and red fluorescent protein (RFP) transgenic CD4 T cells.Results: Selective accumulation of antigen-specific CD4 T cells in the lungs was quantitatively imaged in a mouse model of asthma. The inhibition of accumulation by dexamethasone was imaged. Accumulating GFP+ TH2 cells formed foci in the lungs from 6 to 20 hours after antigen inhalation. This process was also inhibited by the administration of anti–intercellular adhesion molecule 1 or anti–vascular cell adhesion molecule 1 mAbs. Two days after inhalation of antigen, GFP+ TH2 cells were detected in the area of eosinophil infiltration.Conclusion: Focus formation generated by accumulating antigen-specific TH2 cells in the lung appeared to be a critical process in the initiation of the asthma phenotype. This new model enables the study of in vivo cell biology of airway inflammation and novel drug discovery for lung inflammatory diseases.

Effects of budesonide and formoterol on allergen-induced airway responses, inflammation, and airway remodeling in asthma - Corrected Proof

2009-12-07

Background: Combining inhaled corticosteroids with long-acting β2-agonists results in improved asthma symptom control and fewer asthma exacerbations compared with those seen after inhaled corticosteroids alone. However, there are limited data as to whether these beneficial effects are due to enhanced anti-inflammatory actions or whether such combination therapies affect airway remodeling in patients with asthma.Objective: We sought to determine the effects of inhaled budesonide/formoterol combination therapy versus inhaled budesonide alone or inhaled placebo on allergen-induced airway responses, airway inflammation, and airway remodeling.Methods: Fourteen asthmatic subjects with dual responses after allergen inhalation were included in this prospective, randomized, double-blind, 3-period crossover study. Outcomes included early and late asthmatic responses, changes in airway responsiveness, sputum eosinophilia measured before and after allergen challenge, numbers of airway submucosal myofibroblasts, and smooth muscle area measured before and after study treatment.Results: Allergen-induced sputum eosinophilia was significantly reduced by combination treatment to a greater extent than by budesonide alone. Allergen inhalation resulted in a significant increase in submucosal tissue myofibroblast numbers and produced a significant decrease in percentage smooth muscle area. Combination therapy, but not budesonide monotherapy, significantly attenuated these changes in myofibroblast numbers and smooth muscle area.Conclusions: The effects on allergen-induced changes in sputum eosinophils, airway myofibroblast numbers, and smooth muscle seen with combination therapy suggest that the benefits associated with this treatment might relate to effects on airway inflammation and remodeling. The attenuation of early asthmatic responses and airway hyperresponsiveness by combination treatment was likely due to the known functional antagonistic effect of formoterol.

Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge - Corrected Proof

2009-12-07

Background: Omalizumab treatment suppresses FcεRI expression faster on blood basophils than skin mast cells.Objective: We used omalizumab to elucidate the relative contributions of basophil versus mast cell FcεRI activation in a nasal allergen challenge (NAC) model.Methods: Eighteen subjects with cat allergy were enrolled in a 3.5-month, double-blind, randomized (3.5:1), placebo-controlled trial of omalizumab using standard dosing. At baseline, subjects underwent NAC with lavage for prostaglandin D2 measurement, skin prick test titration (SPTT), and blood sampling for basophil histamine release (BHR) and basophil IgE/FcεRI measurements. Basophil studies were repeated at day 3 and then weekly until cat allergen–induced BHR was <20% of baseline or until day 45. Baseline visit procedures were repeated after the BHR reduction (midstudy NAC) and at the treatment period's completion (final NAC).Results: Subjects treated with omalizumab who completed all NACs (n = 12) demonstrated significant mean reduction in BHR to an optimal dose of cat allergen by midstudy NAC compared with baseline (74% decrease; P = .001). In addition, these subjects demonstrated significant decreases in mean combined nasal symptom scores (50% decrease; P = .007) and total sneeze counts (59% decrease; P = .01) by midstudy NAC relative to baseline NAC. In contrast, measures of mast cell response (SPTT and nasal lavage prostaglandin D2) were only significantly reduced by the final NAC. Subjects on placebo (n = 4) did not experience a shift in basophil, NAC symptom, or mast cell measures.Conclusion: Reduction in nasal symptom scores occurred when the basophil, but not mast cell, response was reduced on omalizumab, implicating a role for basophils in the acute NAC response.

Early-life EBV infection protects against persistent IgE sensitization - Corrected Proof

2009-12-07

Background: Infection with EBV has previously been implicated in influencing allergic disorders, but its precise role remains contradictory. The timing of primary infection may contribute to the discrepancies.Objective: This study aimed at investigating whether the time-point of primary EBV infection during childhood could be of importance in modulating the risk of developing IgE sensitization.Methods: A total of 219 Swedish infants were followed prospectively to 5 years of age with clinical examinations, skin prick testing, specific IgE analyses, and determination of serostatus against EBV.Results: After analysis of the children's EBV serostatus, we found that 5-year-olds who were infected with EBV before the age of 2 years were at a significantly lower risk of being persistently IgE-sensitized—that is, sensitized at both 2 and 5 years of age (adjusted odds ratio, 0.34; 95% CI, 0.12-0.94). In contrast, contraction of EBV after 2 years of age was highly associated with late-onset IgE sensitization (adjusted odds ratio, 4.64; 95% CI, 1.57-13.69). Persistently sensitized 5-year-olds had higher specific-IgE levels than children with late-onset IgE sensitization (P < .01).Conclusion: Our data support the value of early-life microbial exposure for protection against the development of IgE sensitization and underscore the proximate postnatal years as an important period during which EBV could contribute to an allergo-protective immune profile.

12. Allergic skin diseases - Corrected Proof

Luz S. Fonacier, Stephen C. Dreskin, Donald Y.M. Leung — 2009-11-25

The skin is one of the largest immunologic organs and is affected by both external and internal factors, as well as innate and adaptive immune responses. Many skin disorders, such as atopic dermatitis, contact dermatitis, urticaria, angioedema, psoriasis, and autoimmune blistering disorders, are immune mediated. Most of these diseases are chronic, inflammatory, and proliferative, in which both genetic and environmental factors play important roles. These immunologic mechanisms might have implications for potential targets of future therapeutic interventions.

18. Vasculitis - Corrected Proof

Carol A. Langford — 2009-11-25

Vasculitis is defined by the presence of blood vessel inflammation. It can be observed in a wide variety of settings, which can be broadly grouped as secondary vasculitides, which occur in association with an underlying disease or trigger, or primary vasculitides, in which vasculitis is occurring for as-yet unknown causes. The primary systemic vasculitides comprise a range of disease entities that are uniquely identified by their clinical, histopathologic, and therapeutic characteristics. Individual diseases predominantly affect blood vessels of a particular size, which influences their clinical manifestations and has been used in their classification. The vasculitides can also differ in their severity, extending from self-limited illnesses to those that can be life-threatening in the absence of prompt initiation of treatment. Immunosuppressive agents are used to treat many vasculitic diseases. Although such approaches can be effective, the patient's long-term course can be influenced by organ damage from their initial presentation, disease relapses, and medication toxicity. Recent investigations have focused on understanding disease pathophysiology and the exploration of novel therapeutic approaches.

5. Immunologic messenger molecules: Cytokines, interferons, and chemokines - Corrected Proof

Scott P. Commins, Larry Borish, John W. Steinke — 2009-11-25

Cytokines and chemokines are secreted proteins involved in numerous aspects of cell growth, differentiation, and activation. A prominent feature of these molecules is their effect on the immune system with regard to cell trafficking and development of immune tissue and organs. The nature of an immune response determines which cytokines are produced and ultimately whether the response is cytotoxic, humoral, cell mediated, or allergic. For this chapter, cytokines are grouped according to those that are predominantly antigen-presenting cell or T lymphocyte derived; that mediate cytotoxic, humoral, cell mediated, and allergic immunity; or that are immunosuppressive. A discussion of chemokine function and their role in cell trafficking and disease follows.

2. Innate immunity - Corrected Proof

Stuart E. Turvey, David H. Broide — 2009-11-25

Recent years have witnessed an explosion of interest in the innate immune system. Questions about how the innate immune system senses infection and empowers a protective immune response are being answered at the molecular level. These basic science discoveries are being translated into a more complete understanding of the central role innate immunity plays in the pathogenesis of many human infectious and inflammatory diseases. It is particularly exciting that we are already seeing a return on these scientific investments with the emergence of novel therapies to harness the power of the innate immune system. In this review we explore the defining characteristics of the innate immune system, and through more detailed examples, we highlight recent breakthroughs that have advanced our understanding of the role of innate immunity in human health and disease.

A genome-wide association study on African-ancestry populations for asthma - Corrected Proof

2009-11-12

Background: Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed.Objectives: We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma.Methods: We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore–Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma.Results: A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10−5 in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the α-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 × 10−6); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 × 10−6); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies.Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated.Conclusions: This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.

Evaluation of candidate genes in a genome-wide association study of childhood asthma in Mexicans - Corrected Proof

2009-11-12

Background: More than 200 asthma candidate genes have been examined in human association studies or identified with knockout mouse approaches. However, many have not been systematically replicated in human populations, especially those containing a large number of tagging single nucleotide polymorphisms (SNPs).Objective: We comprehensively evaluated the association of previously implicated asthma candidate genes with childhood asthma in a Mexico City population.Methods: From the literature, we identified candidate genes with at least 1 positive report of association with asthma phenotypes in human subjects or implicated in asthma pathogenesis using knockout mouse experiments. We performed a genome-wide association study in 492 asthmatic children aged 5 to 17 years and both parents using the Illumina HumanHap 550v3 BeadChip. Separate candidate gene analyses were performed for 2933 autosomal SNPs in the 237 selected genes by using the log-linear method with a log-additive risk model.Results: Sixty-one of the 237 genes had at least 1 SNP with a P value of less than .05 for association with asthma. The 9 most significant results were observed for rs2241715 in the gene encoding TGF-β1 (TGFB1; P = 3.3 × 10−5), rs13431828 and rs1041973 in the gene encoding IL-1 receptor–like 1 (IL1RL1; P = 2 × 10−4 and 3.5 × 10−4), 5 SNPs in the gene encoding dipeptidyl-peptidase 10 (DPP10; P = 1.6 × 10−4 to 4.5 × 10−4), and rs17599222 in the gene encoding cytoplasmic FMR1 interacting protein 2 (CYFIP2; P = 4.1 × 10−4). False discovery rates were less than 0.1 for all 9 SNPs. Multimarker analysis identified TGFB1, IL1RL1, the gene encoding IL-18 receptor 1 (IL18R1), and DPP10 as the genes most significantly associated with asthma.Conclusions: This comprehensive analysis of literature-based candidate genes suggests that SNPs in several candidate genes, including TGFB1, IL1RL1, IL18R1, and DPP10, might contribute to childhood asthma susceptibility in a Mexican population.

Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease - Corrected Proof

2009-10-28

Background: Bronchial asthma is a chronic inflammatory disorder of the airways characterized by increased expression of multiple inflammatory genes. Acetylation of histones by histone acetyltransferases is associated with increased gene transcription, whereas hypoacetylation induced by histone deacetylases is associated with suppression of gene expression. Sirtuin 1 (SIRT1) is a member of the silent information regulator 2 family that belongs to class III histone deacetylase.Objective: This study aimed to investigate the role of SIRT1 and the related molecular mechanisms in the pathogenesis of allergic airway disease.Methods: By using a murine model of ovalbumin (OVA)–induced allergic airway disease and murine tracheal epithelial cells, this study investigated the involvement of SIRT1 and its signaling networks in allergic airway inflammation and hyperresponsiveness.Results: In this study with mice after inhalation of OVA, the increased levels of SIRT1, hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor protein in the lungs after OVA inhalation were decreased substantially by the administration of a SIRT1 inhibitor, sirtinol. We also showed that the administration of sirtinol reduced significantly the increased numbers of inflammatory cells of the airways; airway hyperresponsiveness; increased levels of IL-4, IL-5, and IL-13; and increased vascular permeability in the lungs after OVA inhalation. In addition, we have found that inhibition of SIRT1 reduced OVA-induced upregulation of HIF-1α in airway epithelial cells.Conclusions: These results indicate that inhibition of SIRT1 might attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular endothelial growth factor expression mediated by HIF-1α in mice.

WITHDRAWN: Endoscopic evaluation of resistant rhinosinusitis (before and after surgery) is now available on the American Academy of Allergy, Asthma & Immunology Web site - Corrected Proof

Wellington S. Tichenor, Allen Adinoff, Brian Smart, Daniel L. Hamilos — 2007-05-26

This article has been withdrawn consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.