The Journal of Allergy and Clinical Immunology

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2013-05-01

Brief Overview of This Month's JACI

2013-05-01

Editorial Board

2013-05-01

Information for Readers

2013-05-01

News & Notes

2013-05-01

With: Robert F. Lemanske, Jr., MD, FAAAAI Dr. Robert Lemanske is a Professor of Pediatrics and Medicine at the University of Wisconsin School of Medicine and Public Health (UWSMPH) in Madison, where he is the Head of the Division of Pediatric Allergy, Immunology and Rheumatology. Dr. Lemanske is currently serving as AAAAI Secretary-Treasurer.

CME Activities Calendar

2013-05-01

Visit the AAAAI Continuing Education Center for all your CME needs:

News Beyond our Pages

Marc E. Rothenberg, Jean Bousquet, Patricia C. Fulkerson — 2013-05-01

Omalizumab resulted in a significantly reduced itch severity score in a dose-dependent manner

T cells in asthma: Influences of genetics, environment, and T-cell plasticity

Clare M. Lloyd, Sejal Saglani — 2013-03-29

Asthma is classically considered the archetypal TH2 disease, with increased circulating IgE levels and eosinophilic inflammation being caused by increased levels of TH2-type cytokines. However, this paradigm has been challenged because of the realization that strategies designed to suppress TH2 function are not effective for all patients. The clinical phenotype of asthma is notoriously heterogeneous and is affected by genetic and environmental exposures in addition to interactions between airway structural cells, including epithelial cells, and the immune system, as well as contributions from cells other than TH2 cells. A combination of genetic and environmental factors is thought to influence whether inflammation resolves or progresses, and the pulmonary epithelium is increasingly recognized to play a key role in this process. This complex interplay has made it increasingly apparent that immune responses are tailored to the individual patient and determined by the weight of each influence, and thus the label of asthma as a TH2 disease is too conservative. Indeed, an important concept that needs to be addressed, both in animal models and clinically, is that of T-cell plasticity and how lymphocytic responses are determined by environmental influences.

T cells in asthma: Influences of genetics, environment, and T-cell plasticity

2013-05-01

Mechanisms underlying helper T-cell plasticity: Implications for immune-mediated disease

2013-05-01

CD4 helper T cells are critical for proper immune cell homeostasis and host defense but are also major contributors to immune and inflammatory disease. Arising from a simple biphasic model of differentiation (ie, TH1 and TH2 cells). A bewildering number of fates seem possible for helper T cells. To what extent different helper cell subsets maintain their characteristic gene expression profiles or exhibit functional plasticity is a hotly debated topic. In this review we will discuss how the expression of “signature cytokines” and “master regulator” transcription factors do not neatly conform to a simple helper T-cell paradigm. Although this might seem confusing, the good news is that the newly recognized complexity fits better with our understanding of immunopathogenesis. Finally, we will discuss factors, including epigenetic regulation and metabolic alterations, that contribute to helper cell specificity and plasticity.

Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report

2013-03-15

Allergy immunotherapy (AIT) is an effective treatment for allergic asthma and rhinitis, as well as venom-induced anaphylaxis. In addition to reducing symptoms, AIT can change the course of allergic disease and induce allergen-specific immune tolerance. In current clinical practice immunotherapy is delivered either subcutaneously or sublingually; some allergens, such as grass pollen, can be delivered through either route, whereas others, such as venoms, are only delivered subcutaneously. Both subcutaneous and sublingual immunotherapy appear to have a duration of efficacy of up to 12 years, and both can prevent the development of asthma and new allergen sensitivities. In spite of the advances with AIT, safer and more effective AIT strategies are needed, especially for patients with asthma, atopic dermatitis, or food allergy. Novel approaches to improve AIT include use of adjuvants or recombinant allergens and alternate routes of administration. As part of the PRACTALL initiatives, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology nominated an expert team to develop a comprehensive consensus report on the mechanisms of AIT and its use in clinical practice, as well as unmet needs and ongoing developments in AIT. This resulting report is endorsed by both academies.

Partial defects of T-cell development associated with poor T-cell function

Luigi D. Notarangelo — 2013-03-05

For many years, severe combined immune deficiency diseases, which are characterized by virtual lack of circulating T cells and severe predisposition to infections since early in life, have been considered the prototypic forms of genetic defects of T-cell development. More recently, advances in genome sequencing have allowed identification of a growing number of gene defects that cause severe but incomplete defects in T-cell development, function, or both. Along with recurrent and severe infections, especially cutaneous viral infections, the clinical phenotype of these conditions is characterized by prominent immune dysregulation.

Unresolved issues in hematopoietic stem cell transplantation for severe combined immunodeficiency: Need for safer conditioning and reduced late effects

Biljana Horn, Morton J. Cowan — 2013-05-01

In this review we discuss recent outcomes of hematopoietic cell transplantation (HCT) for patients with severe combined immunodeficiency (SCID), including survival, T- and B-cell reconstitution, and late effects, particularly those related to genotype, use of conditioning regimen, and use of alternative donors. We identify the following issues that require additional data, which can be obtained through cooperative studies: outcomes of patients with SCID who did not receive conditioning before alternative donor HCT; outcomes of patients with SCID who did not receive graft-versus-host disease prophylaxis after T cell–replete HCT; late effects of HCT for patients with SCID, including neurocognitive outcomes, growth, and development; and their relationship to genotype and use of alkylating agents for conditioning. Careful follow-up of outcomes of all newborns receiving diagnoses based on newborn screening programs for SCID is essential because data are scarce on the effects of conditioning regimens in very young patients. A consensus on the definition of T- and B-cell recovery, criteria for additional “boosts,” pharmacokinetic data of chemotherapy agents used in young children, and uniformity of the use of various chemotherapy agents are needed to compare results among institutions. Finally, development of new nontoxic conditioning regimens for HCT that can be safely used in very young children is required.

The Editors' Choice

Donald Y.M. Leung, Stanley J. Szefler, Associate Editors of the JACI — 2013-05-01

Chronic rhinosinusitis (CRS) is a common inflammatory condition of the paranasal sinuses with an unclear cause. The factors and illnesses associated with the development of CRS have not been examined longitudinally. In this issue Tan et al (p 1350) study the epidemiology of CRS using a case-control study on incident CRS cases. By using 10 years of electronic health records from the Geisinger Clinic, which serves a primary care population of a geographically large and demographically stable population in central Pennsylvania, the authors were able to examine patterns of diagnoses and health resource use preceding a new diagnosis of CRS. Their results found a stable incidence of both CRS with and CRS without nasal polyps between 2001 and 2009. Additionally, there was a significantly increased odds of illnesses of the upper and lower airways preceding CRS (see Figure). Outside the airway, there were also significant, although more modest, increases in diagnoses of gastroesophageal reflux and conditions affecting the eye, urinary tract, and skin. Further analysis showed that even before having CRS, subjects saw their physicians and received antibiotics at higher frequency than control subjects. However, CRS was frequently diagnosed without use of confirmatory, guideline-recommended testing, such as nasal endoscopy or computed tomographic imaging.

Lung T-cell responses to nontypeable Haemophilus influenzae in patients with chronic obstructive pulmonary disease

2012-11-12

Background: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation that persists after the cessation of smoking. T cells have a major role in driving inflammation in patients with COPD and are activated by specific antigens to produce mediators, such as cytokines. The antigens that activate lung T cells have not been clearly defined. Nontypeable Haemophilus influenzae (NTHi) is the dominant bacterium isolated from the lungs of patients with COPD. Objective: We sought to measure the response of lung tissue T cells to stimulation with NTHi.Methods: We obtained lung tissue from 69 subjects having lobectomies for lung cancer. Of the group, 39 subjects had COPD, and 30 without COPD were classified as control subjects. The lung tissue was dispersed into single-cell suspensions and stimulated with live NTHi. Cells were labeled with antibodies for 5 important inflammatory mediators in patients with COPD and analyzed by using flow cytometry.Results: NTHi produced strong activation of both TH cells and cytotoxic T cells in the COPD cohort. The COPD cohort had significantly higher levels of cells producing TNF-α, IL-13, and IL-17 in both T-cell subsets. When control subjects were divided into those with and without a significant smoking history and compared with patients with COPD, there was a progressive increase in the numbers of T cells producing cytokines from nonsmoking control subjects to smoking control subjects to patients with COPD.Conclusion: NTHi activates lung T cells in patients with COPD. This proinflammatory profibrotic response might be a key cause of inflammation in patients with COPD and has implications for treatment.

Peripheral lung function in patients with stable and unstable asthma

2013-04-04

Background: Exacerbations of asthma are thought to be caused by airflow obstruction resulting from airway inflammation, bronchospasm, and mucus plugging. Histologic evidence suggests the small airways, including acinar air spaces, are involved; however, this has not been corroborated in vivo by measurements of peripheral small-airway function.Objective: We sought to determine whether asthma severity is linked to small-airway function, particularly in patients with acute severe asthma.Methods: Eighteen subjects admitted for an asthma exacerbation underwent lung function testing, including measures of acinar ventilation heterogeneity (Sacin) and conductive ventilation heterogeneity (Scond) using the multiple-breath nitrogen washout. Treatment requirement was defined according to Global Initiative for Asthma scores. Data were compared with those obtained in 19 patients with stable asthma.Results: For the asthma exacerbation group, the median FEV1 was 59% of predicted value (95% CI, 45% to 75% of predicted value), the median Scond value was 185% of predicted value (95% CI, 119% to 245% of predicted value), and the median Sacin value was 225% of predicted value (95% CI, 143% to 392% of predicted value). FEV1 (percent predicted) was correlated with Sacin (percent predicted) values (Spearman rho = −0.67, P = .006) but not with Scond (percent predicted) values (P > .1). The Global Initiative for Asthma score was significantly related to Sacin (percent predicted) (Spearman rho = 0.59, P = .016) but not to Scond (percent predicted) values (P > .1). The unstable group was characterized by considerably lower forced vital capacity (P < .001) and higher Scond (P = .001) values than the unstable group. In a subgroup of 11 unstable patients who could be reviewed after 4 weeks, FEV1, forced vital capacity, Sacin, and Scond values showed marked improvements.Conclusion: Our findings suggest that unstable asthma is characterized by a combined abnormality in the acinar and conductive lung zones, both of which are partly reversible. Functional abnormality in the acinar lung zone in particular showed a direct correlation with airflow obstruction and treatment requirement in patients with acute severe asthma.

Multiple breath nitrogen washout profiles in asthmatic patients: What do they mean clinically?

David A. Kaminsky — 2013-03-29

Mounting evidence over the years has clearly demonstrated abnormalities of structure and function in the lung periphery in asthmatic patients, involving both the small airways and the lung parenchyma. Although the anatomic evidence comes from tissue biopsy or postmortem studies, the functional evidence comes from both classic and novel means to probe the lung periphery, some of which are amenable to clinical implementation in our patients. This information leads to 2 important questions: What do these measurements mean, and what is their clinical significance?

Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice

2013-04-04

Background: Respiratory tract viruses are a major environmental risk factor for both the inception and exacerbations of asthma. Genetic defects in Toll-like receptor (TLR) 7–mediated signaling, impaired type I interferon responses, or both have been reported in asthmatic patients, although their contribution to the onset and exacerbation of asthma remains poorly understood.Objective: We sought to determine whether Pneumovirus infection in the absence of TLR7 predisposes to bronchiolitis and the inception of asthma.Methods: Wild-type and TLR7-deficient (TLR7−/−) mice were inoculated with the rodent-specific pathogen pneumonia virus of mice at 1 (primary), 7 (secondary), and 13 (tertiary) weeks of age, and pathologic features of bronchiolitis or asthma were assessed. In some experiments infected mice were exposed to low-dose cockroach antigen.Results: TLR7 deficiency increased viral load in the airway epithelium, which became sloughed and necrotic, and promoted an IFN-α/βlow, IL-12p70low, IL-1βhigh, IL-25high, and IL-33high cytokine microenvironment that was associated with the recruitment of type 2 innate lymphoid cells/nuocytes and increased TH2-type cytokine production. Viral challenge of TLR7−/− mice induced all of the cardinal pathophysiologic features of asthma, including tissue eosinophilia, mast cell hyperplasia, IgE production, airway smooth muscle alterations, and airways hyperreactivity in a memory CD4+ T cell–dependent manner. Importantly, infections with pneumonia virus of mice promoted allergic sensitization to inhaled cockroach antigen in the absence but not the presence of TLR7.Conclusion: TLR7 gene defects and Pneumovirus infection interact to establish an aberrant adaptive response that might underlie virus-induced asthma exacerbations in later life.

Evidence mounts that viruses drive atopic development

Jerome A. Sigua, Mitchell H. Grayson — 2013-04-04

Viral respiratory tract infections, especially early in life, have been associated with a markedly increased risk of both allergic disease and asthma. Although much effort has been focused on understanding this risk, the mechanisms linking a viral respiratory tract infection with atopic development still have not been fully elucidated. Hypothesizing that defects in the antiviral immune response might underlie the development of postviral atopic disease, Kaiko et al explored the effect of Toll-like receptor (TLR) 7 deficiency on disease development.

Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults

2013-05-01

Background: In North America and Europe, millions of patients experience symptoms of allergic rhinitis with or without conjunctivitis (AR/C) on exposure to ragweed pollen. The disease burden can be significant, with most patients relying on symptomatic medications without disease-modifying potential. However, novel sublingual immunomodulatory treatment options may potentially play an important role if efficacy and side effect profiles allow the convenience of self-administration.Objectives: This study evaluated an allergy immunotherapy tablet (AIT; SCH 39641/MK-3641) for treatment of ragweed-induced AR/C in the first large randomized, double-blind multinational trial of this therapeutic modality for ragweed allergy.Methods: Adults (n = 784) with short ragweed-induced AR/C were randomly assigned to approximately 52 weeks of daily self-administered ragweed AIT of 1.5, 6, or 12 units of Ambrosia artemisiifolia major allergen 1 (Amb a 1-U) or placebo. Subjects could use as-needed allergy rescue medication. Symptoms and medications were recorded daily. The primary efficacy end point was total combined daily symptom/medication score (TCS) during peak ragweed season. Safety was monitored through adverse event diaries maintained through study duration.Results: During peak ragweed season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 9% (−0.76; P = .22), 19% (−1.58; P = .01), and 24% (−2.04; P = .002) compared with placebo. During the entire season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 12% (−0.88; P = .09), 18% (−1.28; P = .01), and 27% (−1.92; P < .001) compared with placebo. Treatment was well tolerated; no systemic allergic reactions occurred.Conclusions: In this trial, ragweed AIT of 12 Amb a 1-U was effective and tolerable with a safety profile that permitted daily self-administration of ragweed allergen immunotherapy.

Incidence and associated premorbid diagnoses of patients with chronic rhinosinusitis

2013-03-29

Background: Chronic rhinosinusitis (CRS) is a prevalent condition with underexplored risk factors.Objectives: We sought to determine CRS incidence and evaluate associations with a range of premorbid medical conditions for chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) using real-world clinical practice data.Methods: Electronic health records data from 446,480 Geisinger Clinic primary care patients were used for a retrospective longitudinal cohort study for data from 2001-2010. By using logistic regression, newly diagnosed CRS cases between 2007 and 2009 were compared with frequency-matched control subjects on premorbid factors in the immediate (0-6 months), intermediate (7-24 months), and entire observed timeframes before diagnosis.Results: The average incidence of CRS was 83 ± 13 CRSwNP cases per 100,000 person-years and 1048 ± 78 CRSsNP cases per 100,000 person-years. Between 2007 and 2009, 595 patients with incident CRSwNP and 7523 patients with incident CRSsNP were identified and compared with 8118 control subjects. Compared with control subjects and patients with CRSsNP, patients with CRSwNP were older and more likely to be male. Before diagnosis, patients with CRS had a higher prevalence of acute rhinosinusitis, allergic rhinitis, chronic rhinitis, asthma, gastroesophageal reflux disease, adenotonsillitis, sleep apnea, anxiety, and headaches (all P < .001). Patients with CRSsNP had a higher premorbid prevalence of infections of the upper and lower airway, skin/soft tissue, and urinary tract (all P < .001). In the immediate and intermediate timeframes analyzed, patients with CRS had more outpatient encounters and antibiotic prescriptions (P < .001), but guideline-recommended diagnostic testing was performed in a minority of cases.Conclusions: Patients who are given a diagnosis of CRS have a higher premorbid prevalence of anxiety, headaches, gastroesophageal reflux disease, sleep apnea, and infections of the respiratory system and some nonrespiratory sites, which results in higher antibiotic, corticosteroid, and health care use. The use of guideline-recommended diagnostic testing for confirmation of CRS remains poor.

Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: A systematic review and indirect comparison

2013-04-03

Background: Severe allergic rhinitis uncontrolled by pharmacotherapy can adversely affect quality of life. Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have demonstrated effectiveness in this patient group; however, it remains uncertain which route of administration is more effective.Objectives: We sought to update existing systematic reviews on the clinical effectiveness of SCIT and SLIT versus placebo, to undertake a systematic review of head-to-head trials, and to compare the relative effectiveness of SCIT and SLIT in an adjusted indirect comparison.Methods: Standard systematic review methods aimed at minimizing bias were used. Double-blind, randomized, placebo-controlled trials of SCIT or SLIT or trials of SCIT versus SLIT were included. Meta-analysis and indirect comparison meta-analysis with meta-regression were performed.Results: Updated meta-analyses confirmed statistically significant benefits for SCIT and SLIT compared with placebo in adults and, to a lesser extent, in children. Only 1 head-to-head trial met the inclusion criteria; both this and the indirect comparisons did not provide conclusive results in favor of either SCIT or SLIT based on symptom-medication or quality-of-life scores. There was a trend toward favoring SCIT for symptom and medication scores.Conclusions: Although there is clear evidence of effectiveness of both SCIT and SLIT, superiority of one mode of administration over the other could not be consistently demonstrated through indirect comparison, and further research is needed to establish the comparative effectiveness of SCIT versus SLIT.

Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity

2013-04-08

Background: Ataxia telangiectasia (AT) is a multisystem DNA-repair disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. Patients with AT have reduced B- and T-cell numbers and a highly variable immunodeficiency. ATM is important for V(D)J recombination and immunoglobulin class-switch recombination (CSR); however, little is known about the mechanisms resulting in antibody deficiency severity.Objective: We sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT.Methods: In this study we included patients with classical AT plus early-onset hypogammaglobulinemia (n = 3), classical AT (n = 8), and variant AT (late onset, n = 4). We studied peripheral B- and T-cell subsets, B-cell subset replication history, somatic hypermutation frequencies, CSR patterns, B-cell repertoire, and ATM kinase activity.Results: Patients with classical AT lacked ATM kinase activity, whereas patients with variant AT showed residual function. Most patients had disturbed naive B-cell and T-cell homeostasis, as evidenced by low cell numbers, increased proliferation, a large proportion CD21lowCD38low anergic B cells, and decreased antigen receptor repertoire diversity. Impaired formation of T cell–dependent memory B cells was predominantly found in patients with AT plus hypogammaglobulinemia. These patients had extremely low naive CD4+ T-cell counts, which were more severely reduced compared with those seen in patients with classical AT without hypogammaglobulinemia. Finally, AT deficiency resulted in defective CSR to distal constant regions that might reflect an impaired ability of B cells to undergo multiple germinal center reactions.Conclusion: The severity of the antibody deficiency in patients with AT correlates with disturbances in B- and T-cell homeostasis resulting in reduced immune repertoire diversity, which consequently affects the chance of successful antigen-dependent cognate B-T interaction.

Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency

2013-04-05

Background: Primary immunodeficiencies represent model diseases for the mechanistic understanding of the human innate and adaptive immune response. They are clinically highly relevant per se because in patients with severe combined immunodeficiency (SCID), infections caused by opportunistic pathogens are typically life-threatening early in life.Objectives: We aimed at defining and functionally characterizing a novel form of SCID in an infant of consanguineous parents who presented with life-threatening Pneumocystis jirovecii pneumonia using a comprehensive immunologic and whole-exome genetic diagnostic strategy.Methods: Analysis of leukocyte subpopulations was performed by using multicolor flow cytometry and was combined with stimulation tests for T-cell function. The search for a disease-causing mutation was performed with diagnostic whole-exome sequencing and systematic variant categorization. Reconstitution assays were used for validating the loss-of-function mutation.Results: The novel entity of SCID was characterized by agammaglobulinemia and profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes. Genetic analysis revealed a single pathogenic homozygous nonsense mutation of the caspase recruitment domain 11 (CARD11) gene. In reconstitution assays we demonstrated that the patient-derived truncated CARD11 protein is defective in antigen receptor signaling and nuclear factor κB activation.Conclusion: We show that an inactivating CARD11 mutation links defective nuclear factor κB signaling to a novel cause of autosomal recessive SCID.

Cor a 1–reactive T cells and IgE are predominantly cross-reactive to Bet v 1 in patients with birch pollen–associated food allergy to hazelnut

2012-12-13

Background: IgE- and T-cell cross-reactivity contribute to the birch pollen–food syndrome.Objectives: We performed a comprehensive analysis of T-cell cross-reactivity in primary cell cultures, facilitating the identification of allergen-specific T-cell subpopulations from individual patients.Methods: Patients with birch pollen allergy and associated food allergy to hazelnuts, carrots, or both were analyzed for IgE cross-reactivity, T-cell responses, and T-cell cross-reactivity to recombinant Bet v 1.0101 (Bet v 1; birch), Cor a 1.0401 (Cor a 1; hazelnut), and Dau c 1.0104 (Dau c 1; carrot). A novel flow cytometry–based method using a 2-step staining process with fluorescent dyes was established to identify subpopulations of cross-reactive T cells.Results: IgE-binding inhibition tests of individual sera revealed that the vast majority of Cor a 1–reactive IgE was cross-reactive to Bet v 1, whereas Bet v 1–reactive IgE was only partially inhibited by preincubation with Cor a 1. Primary stimulation of T cells with Bet v 1 or Cor a 1 resulted in a significant increase in specific responses to Cor a 1 or Bet v 1 after secondary stimulation, respectively, indicating T-cell cross-reactivity between birch and hazelnut allergens in all patients of the study cohort. Preactivation with Dau c 1 induced less pronounced effects. A novel flow cytometry–based proliferation assay identified a predominant Cor a 1/Bet v 1–cross-reactive T-cell subpopulation within highly Bet v 1/Cor a 1–responsive T cells.Conclusion: Analysis of primary allergen-specific T cells combined with flow cytometry–based proliferation assays facilitates investigation of allergen-specific T-cell subpopulations in subjects and might be helpful to evaluate the effect of birch-specific immunotherapy on pollen-associated food allergies.

Olea europaea pollen lipids activate invariant natural killer T cells by upregulating CD1d expression on dendritic cells

2012-12-26

Background: Invariant natural killer T (iNKT) cells recognize lipids presented by CD1d and have been implicated in the pathogenesis of allergic asthma. Recognition of plant pollen lipids by iNKT cells and their role in allergic responses are poorly defined.Objective: Our goal was to investigate whether iNKT cells can be activated by monocyte-derived dendritic cells (DCs) exposed to lipid antigens from Olea europaea.Methods: DCs generated in vitro were exposed to O europaea pollen grains or lipids isolated from them. Expression of lipid-presenting molecules (CD1), as well as maturation markers (HLA-DR, HLA-I, CD86, and CD80 molecules), on DCs was analyzed. iNKT cell activation after coculture with DCs was evaluated based on expansion, cytokine production, and cytotoxicity tests.Results: DCs upregulated CD1d and CD86 expression and downregulated CD1a expression after exposure to a whole extract of olive pollen lipids. CD1d and CD1a were regulated at the transcriptional level in a peroxisome proliferator-activated receptor γ activation–dependent manner. Polar lipids, diacylglycerols, free fatty acids, and triacylglycerols isolated from pollen grains upregulate CD1d. The increase in CD1d expression on the DC cell surface induced by polar lipids was not regulated at the RNA level. iNKT cells efficiently recognize DCs treated with the different lipids isolated from olive pollen grains.Conclusions: Lipids from O europaea pollen upregulate CD1d and CD86 molecules on DCs, which are then able to activate iNKT cells through a CD1d-dependent pathway.

Human mast cells drive memory CD4+ T cells toward an inflammatory IL-22+ phenotype

Nicolas Gaudenzio, Camille Laurent, Salvatore Valitutti, Eric Espinosa — 2013-03-20

Background: Mast cells are key components of the skin microenvironment in psoriasis, yet their functional role in this T-cell–mediated inflammatory disorder remains to be elucidated.Objective: To define the impact of T-cell/mast-cell cognate interactions on the cytokines produced by TH cells.Methods: We used human primary mast cells and effector/memory CD4+ T cells for in vitro coculture experiments, and we analyzed TH cells responses by using cytometry. CD4+ T-cell/mast-cell conjugates in skin lesions from patients with psoriasis were analyzed by using 3-color immunohistochemistry and confocal microscopy.Results: We show that IFN-γ–primed human mast cells formed productive immunologic synapses with antigen-experienced CD4+ T cells. These interactions promoted the generation of TH22 and IL-22/IFN-γ–producing TH cells from the circulating memory CD4+ T-cell pool via a TNF-α/IL-6–dependent mechanism. An analysis of human psoriatic skin biopsies showed a rich infiltrate of IL-22+CD4+ T cells frequently found in contact with mast cells. Moreover, most of these mast-cell–conjugated lymphocytes coexpressed IFN-γ, suggesting that IL-22+IFN-γ+ CD4+ T cells are generated in vivo on interaction with mast cells.Conclusions: Our findings identify human mast cells as functional partners of TH cells, shaping their responses toward IL-22 production.

A novel splice variant of FcγRIIa: A risk factor for anaphylaxis in patients with hypogammaglobulinemia

2013-04-01

Background: Our index case was a patient with common variable immunodeficiency (CVID). She had anaphylactoid reactions on administration of intravenous immunoglobulin (IVIg) associated with the presence of IgG antibodies against IgA.Objective: We sought to determine the role of Fcγ receptor (FcγR) IIa in IVIg-induced anaphylactoid reactions.Methods: Neutrophils and PBMCs were isolated from healthy subjects and IVIg-treated patients. FcγRIIa mRNA and DNA were analyzed by using real-time PCR and sequencing. IgG-mediated elastase release and intracellular Ca2+ mobilization were determined in neutrophils and transfected cell lines, respectively.Results: A novel splice variant of FcγRIIa containing an expressed cryptic exon 6* (FcγRIIaexon6∗) was identified in our index patient. This exon is normally spliced out of all FcγRII isoforms, except the inhibitory FcγRIIb1. Compared with healthy control subjects, the heterozygous FCGR2Ac.742+871A>G mutation was more frequent in patients with CVID (n = 53, P G allele–positive patients with Kawasaki disease (n = 208) and 1 patient with idiopathic thrombocytopenia (n = 93). None had adverse reactions to IVIg. Moreover, FcγRIIaexon6∗ was also demonstrated in asymptomatic family members. Functional studies in primary cells and transfected murine cells demonstrated enhanced cellular activation by FcγRIIaexon6∗ compared with its native form, as shown by increased elastase release and intracellular calcium mobilization.Conclusion: A novel splice variant, FcγRIIaexon6∗, was characterized as a low-frequency allele, coding for a gain-of-function receptor for IgG. In the presence of immune complexes, FcγRIIaexon6∗ can contribute to anaphylaxis in patients with CVID.

Hygiene and the cytokine jungle in Brazil

Petra Ina Pfefferle, Erika von Mutius — 2013-04-01

Cytokines are important mediators of immune responses and play an important role in the development of allergy and asthma. Diverging concepts of immune development have been proposed. One perception proposes antagonistic regulation of opposing signals emanating from TH1 and TH2 cells, respectively. According to this view, TH2-derived cytokines mediate the onset of atopy by promoting specific IgE responses to allergens, whereas TH1 cytokines antagonize this move. However, this paradigm does not go along with epidemiologic observations of increasing temporal trends in allergic and autoimmune diseases, the latter being related to increased TH1 responses. An overarching paradigm to reconcile these apparently paradoxical approaches states that regulatory factors, in particular IL-10 and TGF-β, contribute to containing the immunologic balance. Although pro and con arguments can be derived from manipulating sophisticated animal models, not much is known from human populations.

Tolerant beekeepers display venom-specific functional IgG4 antibodies in the absence of specific IgE

2012-10-15

Beekeepers are exposed to multiple stings in season although they are immune to the effects apart from local swellings at the site of the sting. This is in contrast to venom-allergic individuals who are in general stung only occasionally yet remain at risk of IgE-mediated anaphylaxis. To assess the mechanism of tolerance in beekeepers, we measured their serum allergen-specific IgE and IgG4 levels. We measured the ability of their serum to form bee venom IgE-allergen complexes (the IgE-facilitated-allergen binding [FAB] assay). Results were compared to those in bee venom–allergic subjects (positive control) and normal healthy individuals (negative control). We also measured the ability of serum from tolerant beekeepers to inhibit allergen-IgE binding in the IgE-FAB assay. To determine whether any observed differences in beekeepers are sustained in the absence of exposure, we compared immunoreactive and functional immunoglobulin levels in beekeepers inside/outside the beekeeping season.

Adult-onset manifestation of idiopathic T-cell lymphopenia due to a heterozygous RAG1 mutation

2012-11-05

We would like to share a relevant and interesting immunodeficiency case that would be of interest to the readers of the Journal of Allergy and Clinical Immunology. This report describes an adult-onset idiopathic T-cell lymphopenia due to recombinase activating gene 1 (RAG1) deficiency in an HIV-negative male patient with no recurrent or opportunistic infections presenting at the age of 38 years with chronic dermatitis, pruritus, and hyperkeratosis. Clinical and immunologic examination revealed eosinophilia with modestly elevated IgE (747 kU/L), normal IgG, IgA, and IgM, profound pan–T-cell lymphopenia, high normal total B cells, and slightly reduced natural killer cells. Genetic analysis revealed a heterozygous frameshift mutation in the RAG1 gene, resulting in a truncated RAG1 protein. This is a late clinical presentation of an idiopathic T-cell lymphopenia secondary to a heterozygous hypomorphic RAG1 mutation and has important implications for the considerable phenotypic variability related to molecular defects in genes typically associated with severe combined immunodeficiency or Omenn syndrome (OS).

Induced bronchospasm after handling of orange flavedo (zest)

2012-11-12

Orange (Citrus sinensis) fruit and juice are widely consumed in Europe. Oranges belong to the Rutaceae family, members of which are found in warm regions worldwide and also include limes, lemons, tangerines, and grapefruit. Despite their wide consumption, sensitization to Rutaceae is rare, but the diagnosis should not be overlooked.

Inhibition of polyethylene glycol–induced histamine release by monomeric ethylene and diethylene glycol: A case of probable polyethylene glycol allergy

2012-12-10

Polyethylene glycols (PEGs) or macrogols are hydrophilic polyethers commonly used in pharmaceutical, cosmetic, food, and household products. Though primarily known as the active ingredient in colonoscopy lavages, PEGs also serve as solvents, excipients, and bulking and dispersing agents. Varying nomenclature exists: often appearing in the terminology is a number (eg, PEG 4000), denoting the rounded average molecular weight of the PEG chains in a given mixture.

Measuring breakthrough exercise-induced bronchoconstriction in young asthmatic children using a jumping castle

2012-11-30

Exercise-induced bronchoconstriction (EIB) has been defined as a transient narrowing of the airways that follows vigorous exercise. EIB is highly specific for asthma in children, and exercise is an indirect provocation test that can be used to diagnose and evaluate asthma. Exercise challenge tests (ECTs) have been studied extensively and are standardized for children older than 8 years. However, performing a safe, effective, and sustainable ECT in younger children is a challenge in itself.

Prevalence of indolent systemic mastocytosis in a Dutch region

2012-12-07

Mastocytosis is a rare disease. Remarkably, incidence or prevalence data of mastocytosis have never been collected. We aimed to generate prevalence data on the indolent and the related smoldering form of systemic mastocytosis (SM) in the adult population of the Groningen region in The Netherlands.

Replication of genome-wide association study loci for allergic rhinitis and house dust mite sensitization in an Asian population of ethnic Chinese in Singapore

2012-12-10

We have read with interest the meta-analysis for allergic rhinitis (AR) and grass sensitization reported by Ramasamy et al in the November issue of the Journal. In this study we aim to replicate the association of the reported single nucleotide polymorphisms (SNPs) to AR and house dust mite (HDM) sensitization in our ethnic Chinese population recruited in Singapore. We performed a case-control study with 3743 subjects who were well defined for sensitization to HDMs and a medical history of allergic phenotypes. Sensitization to HDM species (Dermatophagoides pteronyssinus and Blomia tropicalis) was used instead of grass because HDMs are the major allergens in Southeast Asia and Singapore in particular (see and the section in this article's Online Repository at www.jacionline.org). We have used 2 AR definitions (1) based on self-reported history of AR to be consistent with the definition used in the meta-analysis and (2) based on the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines considering 2 criteria: (1) a positive HDM reaction and (2) 2 or more major AR symptoms (see the section in this article's Online Repository).

Nasopharyngeal carriage with Streptococcus pneumoniae augments the immunizing effect of pneumolysin toxoid B

Daniel R. Neill, Sarah Smeaton, Mathieu Bangert, Aras Kadioglu — 2012-12-20

Streptococcus pneumoniae is a major human pathogen responsible for a spectrum of diseases, including pneumonia, meningitis, and sepsis. Morbidity and mortality linked to pneumococcal disease remain high in sub-Saharan Africa, despite the introduction of protein-polysaccharide conjugate vaccines (PCVs), which offer protection against major disease-causing serotypes. PCVs are limited in their affordability and their efficacy in high-risk groups, such as infants. Furthermore, because the conjugate vaccine is limited in its serotype coverage, the major disease-causing serotypes are being replaced by previously minor serotypes in places where vaccination is widespread. Attempts to overcome the limitations of current vaccination strategies have focused on developing vaccines around conserved pneumococcal proteins that vary minimally between serotypes and are indispensible to bacterial colonization or virulence, such as the cholesterol-binding, pore-forming toxin pneumolysin and its derivatives.

French application of the European guidelines for regulation of allergenic extracts

2013-02-01

As has been implemented in the United States, regulation of allergen extracts (AEs) used for in vivo diagnosis and immunotherapy has also been proposed in Europe. In 2001, Directive 2001/83/EC related to medicinal products for human use was introduced. It also applied to allergen products (APs) that required marketing authorization (MA). However, for some specific cases, Directive 2001/83/EC laid down exemptions. Consequently, the European AP market was divided into 2 categories: (1) industrially produced APs as proprietary medicinal products that are submitted to MA and (2) “named patient products” (NPPs), which are APs produced for an individual patient according to an individual medical prescription (see in this article's Online Repository at www.jacionline.org). They are only regulated at the national level but are represented by up to 75% to 100% of the AP market in some countries.

Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin κ-deleting recombination excision circles

2013-01-02

Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency associated with hypogammaglobulinemia and other various clinical manifestations. CVID was originally reported to be a disease primarily caused by defective B-cell function, with defective terminal B-cell differentiation rendering B cells unable to produce immunoglobulin. However, combined immunodeficiency (CID) involving both defective B and T cells is often misdiagnosed as CVID. Indeed, one study reported that CD4+ T-cell numbers were decreased in 29% of 473 patients with CVID; similarly, another study found that naive T-cell numbers were markedly reduced in 44% (11/25) of patients with CVID. These observations indicated that a subgroup of patients with clinically diagnosed CVID is T-cell deficient. Consistently, some patients with CVID have complications that might be related to T-cell deficiency, including opportunistic infections, autoimmune diseases, and malignancies, which is similar to that observed in patients with CID. Therefore identifying novel markers to better classify CVID and distinguish CID from CVID will be required to best manage medical treatment for CVID.

Homing frequency of human T cells inferred from peripheral blood depletion kinetics after sphingosine-1-phosphate receptor blockade

2013-02-25

Naive and central memory (CM) T cells home through lymph nodes (LNs), whereas T cells with an effector memory (EM) phenotype preferentially screen peripheral tissues in search of cognate antigen. LN entry and egress are distinct and highly regulated processes mediated by an orchestrated interplay of chemokines/chemokine receptors and adhesion molecules. Interaction of peripheral node addressins with L-selectin on T cells allows tethering/rolling along high endothelial venules (HEVs). Interaction of the chemokine receptor CCR7 with its ligands CCL19/CCL21 and CXCR4 with CXCL12 then mediates firm adhesion to HEVs through high-affinity interactions of lymphocyte function–associated antigen 1 and intercellular adhesion molecule 1, permitting transmigration of T cells across the HEV cell layer. Within the LNs, T-cell migration is directed through T-cell zones toward the cortical sinuses. A sphingosine-1-phosphate (S1P) gradient established across the endothelial cells of the cortical sinuses is directing LN egress of T cells through efferent lymph back to the peripheral blood circulation. Acting as a functional antagonist on the S1P receptor, the pharmacologic compound fingolimod, which has shown efficacy in the treatment of multiple sclerosis (MS), blocks this egress. As a consequence, in fingolimod-treated subjects naive and CM T cells are trapped in LNs and reduced in the blood circulation.

Hydroxychloroquine preferentially induces apoptosis of CD45RO+ effector T cells by inhibiting autophagy: A possible mechanism for therapeutic modulation of T cells

2013-03-29

Autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and rheumatoid arthritis, are the result of inappropriate immunes responses against “self.” Hyperactivated, and likely autoreactive, effector T cells are common in autoimmunity, indicating that T-cell homeostasis is disturbed. Impaired apoptosis of self-reactive, effector T cells has been proposed as a driving mechanism of autoimmunity. Consequently, a better understanding of the mechanisms regulating T-cell homeostasis and identifying possible ways to manipulate it pharmacologically for therapeutic purpose remain an unbridged knowledge gap.

Effect of probiotic supplementation during pregnancy and breast-feeding on the allergic sensitization in the infantile eczema

Ahmet Zülfikar Akelma, Emin Mete, Bulent Bozkurt — 2013-03-27

We read with great interest the article by Rautava et al in which they investigated the role of probiotic intervention regimens in reducing the risk of eczema in infants. Mothers with a history of allergic disease and atopic sensitization were randomly assigned to the Lactobacillus rhamnosus LPR and Bifidobacterium longum BL999 (LPR1BL999) group, the Lactobacillus paracasei ST11 and B longum BL999 (ST111BL999) group, or the placebo group during 2 months before and after the expected date of delivery. The authors followed all the infants until the age of 24 months and performed regular clinical examinations scheduled at 1, 3, 6, 12, and 24 months to identify any case of eczema. In addition, they performed skin prick tests at 6, 12, and 24 months to confirm, if any, the diagnosis of atopic sensitization. Ultimately, they found that infants of mothers receiving any of the probiotic supplements developed significantly less episodes of eczema when compared with the placebo group. Skin prick test results, however, were similar between the groups. We have several concerns regarding the interpretation of these results.

Reply

Samuli Rautava, Essi Kainonen, Seppo Salminen, Erika Isolauri — 2013-03-27

We thank Akelma et al for their valuable comments regarding our article. The authors touch upon 3 vitally important and intertwined matters that require further elucidation. Our understanding of the causal interactions leading to atopic sensitization and clinical disease is by no means satisfactory. These shortcomings continue to be reflected in the nomenclature of atopic disease. Last, we need to reach clarity on what may be considered to constitute a preventive effect.

Asthma and the host-microbe interaction

Daniel L. Gilstrap, Monica Kraft — 2013-05-01

Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the instructions listed below:

The Journal of Allergy and Clinical Immunology

Cover 1

Brief Overview of This Month's JACI

Table of Contents

Editorial Board

Information for Readers

News & Notes

CME Activities Calendar

News Beyond our Pages

T cells in asthma: Influences of genetics, environment, and T-cell plasticity

T cells in asthma: Influences of genetics, environment, and T-cell plasticity

Mechanisms underlying helper T-cell plasticity: Implications for immune-mediated disease

Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report

Partial defects of T-cell development associated with poor T-cell function

Unresolved issues in hematopoietic stem cell transplantation for severe combined immunodeficiency: Need for safer conditioning and reduced late effects

The Editors' Choice

Lung T-cell responses to nontypeable Haemophilus influenzae in patients with chronic obstructive pulmonary disease

Peripheral lung function in patients with stable and unstable asthma

Multiple breath nitrogen washout profiles in asthmatic patients: What do they mean clinically?

Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice

Evidence mounts that viruses drive atopic development

Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults

Incidence and associated premorbid diagnoses of patients with chronic rhinosinusitis

Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: A systematic review and indirect comparison

Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity

Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency

Cor a 1–reactive T cells and IgE are predominantly cross-reactive to Bet v 1 in patients with birch pollen–associated food allergy to hazelnut

Olea europaea pollen lipids activate invariant natural killer T cells by upregulating CD1d expression on dendritic cells

Human mast cells drive memory CD4+ T cells toward an inflammatory IL-22+ phenotype

A novel splice variant of FcγRIIa: A risk factor for anaphylaxis in patients with hypogammaglobulinemia

Hygiene and the cytokine jungle in Brazil

Tolerant beekeepers display venom-specific functional IgG4 antibodies in the absence of specific IgE

Adult-onset manifestation of idiopathic T-cell lymphopenia due to a heterozygous RAG1 mutation

Induced bronchospasm after handling of orange flavedo (zest)

Inhibition of polyethylene glycol–induced histamine release by monomeric ethylene and diethylene glycol: A case of probable polyethylene glycol allergy

Measuring breakthrough exercise-induced bronchoconstriction in young asthmatic children using a jumping castle

Prevalence of indolent systemic mastocytosis in a Dutch region

Replication of genome-wide association study loci for allergic rhinitis and house dust mite sensitization in an Asian population of ethnic Chinese in Singapore

Nasopharyngeal carriage with Streptococcus pneumoniae augments the immunizing effect of pneumolysin toxoid B

French application of the European guidelines for regulation of allergenic extracts

Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin κ-deleting recombination excision circles

Homing frequency of human T cells inferred from peripheral blood depletion kinetics after sphingosine-1-phosphate receptor blockade

Hydroxychloroquine preferentially induces apoptosis of CD45RO+ effector T cells by inhibiting autophagy: A possible mechanism for therapeutic modulation of T cells

Effect of probiotic supplementation during pregnancy and breast-feeding on the allergic sensitization in the infantile eczema

Reply

Asthma and the host-microbe interaction