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1.  CTNNA3 and SEMA3D: promising loci for asthma exacerbation identified through multiple GWAS 
BACKGROUND
Asthma exacerbations are a major cause of morbidity and medical cost.
OBJECTIVE
The objective of this study was to identify genetic predictors of exacerbations in subjects with asthma.
METHODS
We performed GWAS meta analysis of acute asthma exacerbation in two pediatric clinical trials: Childhood Asthma Management Program (CAMP, n=581) and Childhood Asthma Research and Education (CARE, n=205) network trials. Acute asthma exacerbations was defined as treatment with a five-day course of oral steroids. We obtained a replication cohort from BioVU (n=786), the Vanderbilt University electronic medical record-linked DNA biobank. We used CD4+ lymphocyte genome-wide mRNA expression profiling to identify associations of top SNPs with mRNA abundance of nearby genes.
RESULTS
A locus in CTNNA3 reached genome-wide significance (rs7915695, p=2.19*10-8, mean exacerbations 6.05 for minor alleles vs. 3.71 for homozygous major). Among four top SNPs replicated in BioVU, rs993312 in SEMA3D was significant (p=0.0083), and displayed stronger association among African Americans (p=0.0004 in BioVU, mean exacerbations 3.91 vs. 1.53; p=0.0089 in CAMP, mean exacerbations 6.0 vs. 3.25). CTNNA3 variants did not replicate in BioVU. A regulatory variant in the CTNNA3 locus was associated with CTNNA3 mRNA expression in CD4+ cells from asthmatics (p=0.00079). CTNNA3 appears to be active in immune response, and SEMA3D has a plausible role in airway remodeling. We also provide a replication of a previous association of P2RX7 with asthma exacerbation.
CONCLUSIONS
We identified two loci associated with exacerbations through GWAS. CTNNA3 met genome-wide significance thresholds and SEMA3D replicated in a clinical Biobank database.
doi:10.1016/j.jaci.2015.04.039
PMCID: PMC4676949  PMID: 26073756
Asthma; Exacerbation; GWAS; eQTL; CTNNA3; SEMA3D; BioBank; Childhood Asthma
2.  Chronic cat-allergen exposure induces a TH2 cell-dependent IgG4 response related to low-sensitization 
Background
In human subjects, allergen-tolerance has been observed after high dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T cell response that leads to the induction of IgG4 during chronic allergen exposure remains poorly understood.
Objective
To evaluate the relationship between cat allergen-specific T cell frequency, cat allergen-specific IgE and IgG4 titers and clinical status in cat allergic adults with and without cat ownership and the cellular mechanism by which IgG4 is produced.
Methods
Fel d 1, Fel d 4, Fel d 7 and Fel d 8- specific T cell responses were characterized by CD154 expression after antigen stimulation.
Results
In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4) specific TH2 cells (sTH2 cells) correlates with IgE level and is linked to asthma. Paradoxically, we observed that cat allergic subjects with chronic cat exposure maintain high frequency of sTH2 cells, which correlates with IgG4 level and low-sensitization. B cells from allergic, but not from non-allergic subjects, are able to produce IgG4 after cognate interactions with sTH2 clones, and Fel d 1 peptide or the Fel d 1 recombinant protein.
Conclusion
These experiments suggest that 1) allergen-experienced B cells with capacity to produce IgG4 are present in allergic subjects; and 2) cat-allergen exposure induces an IgG4 response in a TH2 cell-dependent manner. Thus, IgG4 accumulation could be mediated by chronic activation of the TH2 response, which in turn drives desensitization.
doi:10.1016/j.jaci.2015.07.031
PMCID: PMC4679456  PMID: 26371841
Cat allergy; Fel d 1; Fel d 4; TH2 cells; allergen tolerance; asthma; class II tetramer; CD154; IgG4; allergen exposure
3.  Increased expression of the epithelial anion transporter Pendrin/SLC26A4 in nasal polyps of patients with Chronic Rhinosinusitis 
Background
Chronic rhinosinusitis (CRS) is a multifactorial disease of unknown etiology characterized by sinonasal inflammation, increased mucus production and defective mucociliary clearance. Pendrin, an epithelial anion transporter, is increased in asthma and chronic obstructive pulmonary disease. Pendrin increases mucus production and regulates mucociliary clearance.
Objectives
We sought to investigate the expression of pendrin and the mucus-related protein Muc5AC in sinonasal tissues of control and CRS patients, and to evaluate the regulation of pendrin expression in nasal epithelial cells (NECs) in vitro.
Methods
The expression and distribution of pendrin in sinonasal tissues was analyzed using real-time PCR, immunoblot analysis and immunohistochemistry. Differentiated NECs were used to study the regulation of pendrin expression.
Results
Increased pendrin was observed in NP tissue of CRS patients. Immunohistochemistry analysis revealed that pendrin was largely restricted to the epithelial layer. Pendrin expression significantly correlated with inflammatory cell markers, suggesting that the factors made by these cells may induce pendrin expression. Furthermore, both pendrin and periostin (a biomarker in asthma) correlated with IL-13, suggesting that pendrin may be induced by this cytokine in sinonasal tissues. The mucus component protein Muc5AC, correlated weakly with pendrin, indicating that pendrin might modulate mucus production in NPs. In cultured NECs, pendrin expression was induced by Th2 cytokines and was induced synergistically when Th2 cytokines were combined with IL-17A. Interestingly, human rhinovirus had a potentiating effect on IL-13 induced pendrin expression. Dexamethasone suppressed pendrin expression suggesting that the therapeutic benefit of dexamethasone in asthma and CRS may involve regulation of pendrin expression.
Conclusions
Th2-mediated pendrin expression is increased in nasal polyps of patients with CRS and may lead to increased inflammation, mucus production and a decreased mucociliary clearance.
doi:10.1016/j.jaci.2015.05.024
PMCID: PMC4679496  PMID: 26143180
Pendrin; SLC26A4; Periostin; Muc5AC; Chronic rhinosinusitis; nasal polyp; mucus; mucociliary clearance; nasal epithelial cells
4.  Targeted Deep Sequencing Identifies Rare ‘loss-of-function’ Variants in IFNGR1 for Risk of Atopic Dermatitis Complicated by Eczema Herpeticum 
Background
A subset of atopic dermatitis (AD) is associated with increased susceptibility to eczema herpeticum (ADEH+). We previously reported that common single nucleotide polymorphisms (SNPs) in interferon-gamma (IFNG) and receptor 1 (IFNGR1) were associated with ADEH+ phenotype.
Objective
To interrogate the role of rare variants in IFN-pathway genes for risk of ADEH+.
Methods
We performed targeted sequencing of interferon-pathway genes (IFNG, IFNGR1, IFNAR1 and IL12RB1) in 228 European American (EA) AD patients selected according to their EH status and severity measured by Eczema Area and Severity Index (EASI). Replication genotyping was performed in independent samples of 219 EA and 333 African Americans (AA). Functional investigation of ‘loss-of-function’ variants was conducted using site-directed mutagenesis.
Results
We identified 494 single nucleotide variants (SNVs) encompassing 105kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency (MAF) <5%) and 86 (17.4%) novel variants, of which 2.8% were coding-synonymous, 93.3% were non-coding (64.6% intronic), and 3.8% were missense. We identified six rare IFNGR1 missense including three damaging variants (Val14Met (V14M), Val61Ile and Tyr397Cys (Y397C)) conferring a higher risk for ADEH+ (P=0.031). Variants V14M and Y397C were confirmed to be deleterious leading to partial IFNGR1 deficiency. Seven common IFNGR1 SNPs, along with common protective haplotypes (2 to 7-SNPs) conferred a reduced risk of ADEH+ (P=0.015-0.002, P=0.0015-0.0004, respectively), and both SNP and haplotype associations were replicated in an independent AA sample (P=0.004-0.0001 and P=0.001-0.0001, respectively).
Conclusion
Our results provide evidence that both genetic variants in the gene encoding IFNGR1 are implicated in susceptibility to the ADEH+ phenotype.
CAPSULE SUMMARY
We provided the first evidence that rare functional IFNGR1 mutations contribute to a defective systemic IFN-γ immune response that accounts for the propensity of AD patients to disseminated viral skin infections.
doi:10.1016/j.jaci.2015.06.047
PMCID: PMC4679503  PMID: 26343451
IFNGR1; genetic variants; atopic dermatitis; eczema herpeticum
5.  Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations 
Background
Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure.
Objective
We sought to compare (1) omalizumab with placebo and (2) omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school.
Methods
A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations (clincaltrials.gov #NCT01430403).
Guidelines-based therapy was continued over a 4- to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-α responses to rhinovirus in PBMCs were examined.
Results
Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio [OR], 0.48; % CI, 0.25–.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33–1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02–0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002–0.98). Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01–0.88). Adverse events were rare and similar among arms.
Conclusions
Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation.
doi:10.1016/j.jaci.2015.09.008
PMCID: PMC4679705  PMID: 26518090
Asthma; fall season; omalizumab; inhaled corticosteroid; asthma exacerbations; rhinovirus; IFN-α
6.  Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis 
Background
The management of children with pediatric mastocytosis poses a challenge. This is because there is limited information as to the application of clinical and laboratory findings and bone marrow histopathology as they relate to medical intervention and communication.
Objective
We sought to examine clinical aspects of pediatric mastocytosis in relationship to serum tryptase levels and bone marrow pathology to provide practical guidance for management.
Methods
Between 1986 and 2012, 105 children were evaluated at the National Institutes of Health. Organomegaly was confirmed by means of ultrasound. Baseline tryptase levels and at least 1 subsequent tryptase measurement was available in 84 and 37 of these children, respectively. Fifty-three children underwent a bone marrow examination. These data were used to examine relationships between clinical findings, tryptase levels, and marrow histopathology.
Results
In patients with high tryptase levels and severe mediator symptoms, all with organomegaly had systemic disease, and none without organomegaly had systemic disease. Serum tryptase levels differed significantly between patients with urticaria pigmentosa and those with diffuse cutaneous (P < .0001) and systemic mastocytosis (P < .0001) and in all 3 categories versus control subjects (P < .0001). Tryptase levels and symptoms decreased over time in most patients, and tryptase levels correlated with bone marrow mast cell burden in patients with systemic mastocytosis (P < .0001). There was a significant relationship between clinical resolution and the percentage decrease in tryptase levels (P = .0014).
Conclusions
The majority of children experienced major or complete disease resolution (57%), whereas These remainder exhibited partial improvement. Organomegaly was a strong indicator of systemic disease. Serum tryptase levels furthered classification and reflected clinicopathologic findings, while sequential tryptase measurements were useful in supplementing clinical judgment as to disease course.
doi:10.1016/j.jaci.2015.04.024
PMCID: PMC4984538  PMID: 26044856
Mast cells; tryptase; urticaria pigmentosa; cutaneous mastocytosis; diffuse cutaneous mastocytosis; mastocytosis; bone marrow examination
9.  The Future of Biologics: Applications for Food Allergy 
Allergic diseases affects millions worldwide, with growing evidence of an increase in allergy occurrence over the past few decades. Current treatments for allergy include corticosteroids to reduce inflammation and allergen immunotherapy (AIT); however, some individuals experience treatment-resistant inflammation or adverse reactions to these treatments, and neither are currently approved for the treatment of food allergy. There is a dire need for new therapeutic approaches for individuals with poorly controlled atopic diseases and to improve the safety and effectiveness of AIT. Improved understanding of allergy through animal models and clinical trials has unveiled potential targets for new therapies, leading to the development of several biologics to treat allergic diseases. This review focuses on the mechanisms that contribute to allergy, with an emphasis on future targets for biologics for the treatment of food allergy. These biologics include immunotherapy with novel anti-IgE antibodies and analogs, small molecule inhibitors of cell signaling, anti-type 2 cytokine monoclonal antibodies and Th1-promoting adjuvants.
doi:10.1016/j.jaci.2014.12.1908
PMCID: PMC5108659  PMID: 25662303
food allergy; immunotherapy; anti-IgE; oral tolerance; allergen sensitization; anaphylaxis; biologics
10.  Filaggrin Mutations That Confer Risk of Atopic Dermatitis Confer Greater Risk for Eczema Herpeticum 
Background
Loss-of-function null mutations R501X and 2282del4 in the skin barrier gene, filaggrin (FLG), represent the most replicated genetic risk factors for atopic dermatitis (AD). Associations have not been reported in African ancestry populations. Eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous HSV infections.
Objective
We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility.
Methods
Two common loss-of-function mutations plus nine FLG single nucleotide polymorphisms (SNPs) were genotyped in 278 European American AD patients, of whom 112 had ADEH, and 157non-atopic controls. Replication was performed on 339 African Americans.
Results
Significant associations were observed for both the R501X and 2282del4 mutations and AD among European Americans (P=1.46×10−5,3.87×10−5, respectively), but the frequency of the R501X mutation was three times higher (25.% vs 9%) for ADEH compared to AD without EH (odds ratio [OR]=3.4 (1.7–6.8), P=0.0002). Associations with ADEH were stronger with the combined null mutations (OR=10.1 (4.7–22.1), P=1.99×10−11). Associations with the R501X mutation were replicated in the African American population; the null mutation was absent among healthy African Americans, but present among AD (3.2%, P=0.035) and common among ADEH (9.4%; P=0.0049) patients. However, the 2282del4 mutation was absent among African American ADEH patients and rare (<1%) among healthy individuals.
Conclusion
The R501X mutation in the gene encoding filaggrin, one of the strongest genetic predictors of AD, confers an even greater risk for ADEH in both European and African ancestry populations, suggesting a role for defective skin barrier in this devastating condition.
Clinical Implications
The Filaggrin (FLG) R501X Mutation, a major risk factor for atopic dermatitis, confers a greater risk of the severe, HSV-associated complication, eczema herpeticum in diverse ethnic groups.
Capsule Summary
Mutations in the skin barrier function protein, filaggrin, are strong predictors of atopic dermatitis. This report demonstrates an even greater association between one of these mutations (R501X) and eczema herpeticum in ethnically diverse American populations.
doi:10.1016/j.jaci.2009.07.034
PMCID: PMC5103856  PMID: 19733298
Atopic dermatitis; Eczema herpeticum; filaggrin; R501X; 2282del4; Single Nucleotide Polymorphisms
11.  Analysis of glutathione S-transferase allergen cross-reactivity in a North American population: relevance for molecular diagnosis 
Background
It is not clear if cross-reactivity or co-sensitization to glutathione S-transferases (GST) occurs in tropical and subtropical environments. In the United States, Bla g 5 is the most important GST allergen, and lack of co-exposure to GST from certain species allows a better assessment of cross-reactivity.
Objectives
To examine the molecular structure of GST allergens from cockroach (Bla g 5), dust mites (Der p 8, Blo t 8) and helminth (Asc s 13) for potential cross-reactive sites, and to assess the IgE cross-reactivity of sensitized patients from a temperate climate for these allergens for molecular diagnostic purposes.
Methods
Four crystal structures were determined. Sera from cockroach and mite allergic patients were tested for IgE reactivity to these GST. A panel of six murine anti-Bla g 5 mAb was assessed for cross-reactivity with the other three GST using antibody binding assays.
Results
Comparisons of the allergen structures, formed by two-domain monomers that dimerize, revealed few contiguous regions of similar exposed residues, rendering cross-reactivity unlikely. Accordingly, anti-Bla g 5 or anti-Der p 8 IgE from North American patients did not recognize Der p 8 or Bla g 5, respectively, and neither showed binding to Blo t 8 or Asc s 13. A weaker binding of anti-Bla g 5 IgE to Der p 8 versus Bla g 5 (~100-fold) was observed by inhibition assays, similar to a weak recognition of Der p 8 by anti-Bla g 5 mAb. Patients from tropical Colombia had IgE to all four GST.
Conclusions
The lack of significant IgE cross-reactivity among the four GST is in agreement with the low shared amino acid identity at the molecular surface. Each GST is needed for accurate molecular diagnosis in different geographic areas.
doi:10.1016/j.jaci.2015.03.015
PMCID: PMC4624055  PMID: 25930195
Cockroach; house dust mite; helminth; glutathione S-transferases (GST); cross-reactivity; diagnosis
12.  Skin DC Induce Follicular Helper T Cells and Protective Humoral Immune Responses 
Background
The contribution of individual subsets of dendritic cells (DC) to the generation of adaptive immunity is central to understanding immune homeostasis and protective immune responses.
Objective
We sought to define functions for steady-state skin DC.
Methods
Herein we present an approach in which we restrict antigen presentation to individual DC subsets in the skin and monitor the effects on endogenous antigen-specific CD4+ T and B cell responses.
Results
Presentation of foreign antigen by Langerhans cells (LC) in the absence of exogenous adjuvant led to a large expansion of T follicular helper cells (Tfh). This was accompanied by B cell activation, germinal center formation and protective antibody responses against influenza. The expansion of Tfh and antibody responses could be elicited by both systemic and topical skin immunization. Tfh induction was not restricted to LC and occurred in response to antigen presentation by CD103+ dermal DC. CD103+ DC despite inducing similar Tfh responses as LC, were less efficient in induction of GC B cells and humoral immune responses. We also found that skin DC are sufficient to expand CXCR5+ Tfh through an IL-6 and IFNAR independent mechanism, but B cells were required for sustained Bcl6+ expression.
Conclusions
These data demonstrate that a major unappreciated function of skin DC is their promotion of Tfh and humoral immune responses that potentially represent an efficient approach for vaccination.
Clinical Implications
Our findings suggest that targeting antigen without adjuvants to a specific skin DC subset either by systemic or topical application will be an efficient approach to generate protective, antibody-based vaccines.
doi:10.1016/j.jaci.2015.04.001
PMCID: PMC4639468  PMID: 25962902
steady-state conditions; skin dendritic cells; T follicular helper cells; protective humoral immune responses
13.  Broad spectrum of autoantibodies in Wiskott-Aldrich Syndrome (WAS) and X-linked Thrombocytopenia (XLT) 
Summary
Using a protein microarray, a broad spectrum of autoantibodies were demonstrated in patients with either Wiskott-Aldrich syndrome (WAS) or with X-linked thrombocytopenia (XLT), indicating that immune dysregulation is an integral component of both diseases.
doi:10.1016/j.jaci.2015.08.010
PMCID: PMC4640933  PMID: 26409660
Wiskott-Aldrich syndrome; X-linked thrombocytopenia; autoantibodies; BAFF
14.  Association between Vitamin D and Allergy-Related Outcomes Vary by Race and other Factors 
Background
Allergy-related studies that include biological measurements of vitamin D preceding well-measured outcomes are needed.
Objective
Examine the associations between early life vitamin D levels and the development of allergy-related outcomes in the racially diverse WHEALS birth cohort.
Methods
25-hydroxyvitamin D [25(OH)D] was measured in stored blood samples from pregnancy, cord blood and age 2 years. Logistic regression models were used to calculate odds ratios (OR) with 95% confidence intervals (CI) for a 5 ng/ml increase in 25(OH)D level for the outcomes at age 2 years: eczema, skin prick tests (SPT), elevated allergen-specific IgE (sIgE≥0.35IU/ml), and doctor diagnosis of asthma (3–6 years).
Results
Prenatal 25(OH)D was inversely associated with eczema (OR=0.85, 95% CI 0.75, 0.96). The association was stronger in White children (White: OR=0.79, 95% CI 0.57, 1.09; Black: OR=0.96, 95% CI 0.82, 1.12), although this was not statistically significant. Cord blood 25(OH)D was inversely associated with having ≥1 positive SPT and aeroallergen sensitization. Both associations were statistically significant in White children (SPT: OR=0.50, 95% CI 0.32, 0.80; ≥1 aeroallergen: OR=0.50, 95% CI 0.28, 0.92) in contrast with Black children (SPT:OR=0.88, 95% CI 0.68, 1.14; aeroallergen: OR=0.85, 95% CI 0.65, 1.11). 25(OH)D measured concurrent with outcome assessment was inversely associated with aeroallergen sensitization (OR=0.79, 95% CI 0.66, 0.96) only among Black children (White children: OR=1.21, 95% CI 0.87, 1.69).
Conclusions
Prenatal and cord 25(OH)D were associated with some allergy-related outcomes with a general pattern indicating that children with higher 25(OH)D tend to have fewer allergy-related outcomes.
doi:10.1016/j.jaci.2015.04.017
PMCID: PMC4640935  PMID: 26078105
vitamin D; allergy; eczema; asthma; IgE; racial differences
15.  Impaired Efferocytosis in Human Chronic Granulomatous Disease is Reversed by Pioglitazone Treatment 
doi:10.1016/j.jaci.2015.07.034
PMCID: PMC4640967  PMID: 26386811
Chronic Granulomatous Disease; efferocytosis; monocytes; macrophages; PPARγ; pioglitazone; oxidants
16.  Single-cell systems level analysis of human Toll-Like-Receptor activation defines a chemokine signature in Systemic Lupus Erythematosus 
Background
Activation of Toll-Like Receptors (TLRs) induces inflammatory responses involved in immunity to pathogens and autoimmune pathogenesis, such as in Systemic Lupus Erythematosus (SLE). Although TLRs are differentially expressed across the immune system, a comprehensive analysis of how multiple immune cell subsets respond in a system-wide manner has previously not been described.
Objective
To characterize TLR activation across multiple immune cell subsets and individuals, with the goal of establishing a reference framework against which to compare pathological processes.
Methods
Peripheral whole blood samples were stimulated with TLR ligands, and analyzed by mass cytometry simultaneously for surface marker expression, activation states of intracellular signaling proteins, and cytokine production. We developed a novel data visualization tool to provide an integrated view of TLR signaling networks with single-cell resolution. We studied seventeen healthy volunteer donors and eight newly diagnosed untreated SLE patients.
Results
Our data revealed the diversity of TLR-induced responses within cell types, with TLR ligand specificity. Subsets of NK and T cells selectively induced NF-κB in response to TLR2 ligands. CD14hi monocytes exhibited the most polyfunctional cytokine expression patterns, with over 80 distinct cytokine combinations. Monocytic TLR-induced cytokine patterns were shared amongst a group of healthy donors, with minimal intra- and inter- individual variability. Furthermore, autoimmune disease altered baseline cytokine production, as newly diagnosed untreated SLE patients shared a distinct monocytic chemokine signature, despite clinical heterogeneity.
Conclusion
Mass cytometry analysis defined a systems-level reference framework for human TLR activation, which can be applied to study perturbations in inflammatory disease, such as SLE.
doi:10.1016/j.jaci.2015.04.008
PMCID: PMC4640970  PMID: 26037552
Mass cytometry; Toll-Like-Receptors; systemic lupus erythematosus; inflammation; monocytes; MCP1
17.  Peripheral Blood Eosinophilia and Hypersensitivity Reactions among Patients Receiving Outpatient Parenteral Antibiotics 
Background
While drug-induced peripheral eosinophilia complicates antimicrobial therapy, little is known about its frequency and implications.
Objective
We aimed to determine the frequency and predictors of antibiotic-induced eosinophilia and subsequent hypersensitivity reactions (HSRs).
Methods
We evaluated a prospective cohort of former inpatients receiving intravenous antibiotic therapy as outpatients with at least one differential blood count. We used multivariate Cox proportional hazards models, with time-varying antibiotic treatment indicators, to assess the impact of demographic data and antibiotic exposures on eosinophilia and subsequent HSR, including documented rash, renal injury, and liver injury. Possible Drug Rash Eosinophilia and Systemic Symptoms (DRESS) syndrome cases were identified and manually validated.
Results
Of 824 patients (60% male, median age 60 years, median therapy duration 41 days), 210 (25%) developed eosinophilia with median peak absolute eosinophil count of 726/mL [IQR: 594–990/mL]. Use of vancomycin, penicillin, rifampin, and linezolid were associated with a higher hazard of developing eosinophilia. There was subsequent HSR in 64/210 (30%) patients with eosinophilia, including rash (N=32), renal injury (N=31), and liver injury (N=13). Patients with eosinophilia were significantly more likely to develop rash (HR = 4.16 [2.54, 6.83]; p<0.0001) and renal injury (HR = 2.13 [1.36, 3.33]; p=0.0009), but not liver injury (HR = 1.75 [0.92, 3.33]; p=0.09). Possible DRESS syndrome occurred in 7/824 (0.8%) patients; 4 (57%) were on vancomycin.
Conclusions
Drug-induced eosinophilia is common with parenteral antibiotics. While most patients with eosinophilia do not develop an HSR, eosinophilia increases the hazard rate of developing rash and renal injury. DRESS syndrome was more common than previously described.
doi:10.1016/j.jaci.2015.04.005
PMCID: PMC4640981  PMID: 25981739
allergy; antibiotic; drug; eosinophilia; hypersensitivity; DRESS syndrome; vancomycin; metronidazole; OPAT
18.  Human seroreactivity to gut microbiota antigens 
Background
While immune responses directed against antigens from the intestinal microbiota are observed in certain diseases, the normal human adaptive immune response to intestinal microbiota is poorly defined.
Objective
Our goal was to assess the adaptive immune response to the intestinal microbiota present in 143 healthy adults and compare this response to the immune response observed in 52 children and their mothers at risk of having allergic disease.
Methods
Human serum was collected from adults and from children followed from birth to seven years of age, and the serum IgG response to a panel of intestinal microbiota antigens was assessed using a novel protein microarray.
Results
Nearly every individual tested, regardless of health status, had serum IgG that recognized a common set of antigens. Seroreactivity to the panel of antigens was significantly lower in atopic adults. Healthy infants expressed the highest level of IgG seroreactivity to intestinal microbiota antigens. This adaptive response developed between 6 and 12 months of age, and peaked around 2 years of age. Low IgG responses to certain clusters of microbiota antigens during infancy were associated with allergy development during childhood.
Conclusions
There is an observed perturbation of the adaptive response to antigens from the microbiota in allergic individuals. These perturbations are observable even in childhood, suggesting that optimal stimulation of the adaptive immune system by the microbiota may be needed to prevent certain immune-mediated diseases.
doi:10.1016/j.jaci.2015.03.036
PMCID: PMC4640988  PMID: 26014812
Adaptive; atopy; allergy; childhood; IgG; microarray; microbiota; Antigens, Bacterial; Antibodies, Bacterial
19.  Endemic Mycoses in Patients with STAT3 Mutated Hyperimmunoglobulin E (Job’s) Syndrome 
doi:10.1016/j.jaci.2015.07.003
PMCID: PMC4641001  PMID: 26292779
Job’s; Hyper-IgE Syndrome; Cryptococcus; Histoplasmosis; Coccidioidomycosis
20.  Radiation-Sensitive Severe Combined Immunodeficiency: The arguments for and against conditioning prior to hematopoietic cell transplantation – What to do? 
Defects in DCLRE1C, PRKDC, LIG4, NHEJ1, and NBS1, involving the non-homologous end joining (NHEJ) DNA repair pathway, result in radiation-sensitive severe combined immunodeficiency (RS-SCID). Results of hematopoietic cell transplantation for RS-SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of pre-conditioning with alkylating agents is associated with a greater likelihood of full T and B cell reconstitution compared to no conditioning or immunosuppression alone. A reduced intensity regimen using fludarabine and low dose cyclophosphamide may be effective for patients with LIG4, NHEJ1 and NBS1 defects although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose alkylating agents without significant late effects. Until non-chemotherapy agents, e.g., anti-CD45 or anti-CD117 become available, options include minimizing exposure to alkylators, e.g., single agent low dose targeted Busulfan or achieving T cell reconstitution followed several years later with a conditioning regimen to restore B cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and GvHD. Prospective multi- center studies are needed to evaluate these approaches in this rare but highly vulnerable patient population.
doi:10.1016/j.jaci.2015.04.027
PMCID: PMC4641002  PMID: 26055221
SCID; radiation sensitivity; hematopoietic cell transplantation; non-homologous end joining; DNA repair
21.  Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts 
Introduction
Long-term, intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decrements in bone mineral accretion (BMA). We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma.
Methods
We first performed a gene by OCS interaction genome-wide association study (GWAS) of BMA in 489 white participants in the Childhood Asthma Management Program trial, who took short-term oral prednisone bursts when they experienced acute asthma exacerbations. We selected the top-ranked 2,000 single nucleotide polymorphisms (SNPs) in the GWAS and determined whether these SNPs also had cis-regulatory effects on dexamethasone-induced gene expression in osteoblast cells.
Results
We identified two SNPs (rs9896933 and rs2074439) associated with decreased BMA and related to the tubulin γ pathway. Rs9896933 met criteria for genome-wide significance (P = 3.15 ×10−8 in GWAS) and is located on the intron of tubulin folding cofactor D gene. Rs2074439 (P = 2.74 × 10−4 in GWAS) showed strong cis-regulatory effects on dexamethasone-induced tubulin γ gene expression in osteoblast cells (P = 8.64 × 10−4). Interestingly, we found that BMA worsened with increased dose of prednisone as the number of mutant alleles of the two SNPs increased.
Conclusions
We have identified two novel tubulin γ pathway SNPs, rs9896933 and rs2074439, showing independent interactive effects with cumulative corticosteroid dose on BMA in children with asthma receiving multiple OCS bursts.
doi:10.1016/j.jaci.2015.04.014
PMCID: PMC4641004  PMID: 26025128
Asthma; Bone mineral density; Child; Corticosteroids
22.  Insights into Primary Immune Deficiency from quantitative microscopy analysis 
Recent advances in genomics based technology have resulted in an increase in our understanding of the molecular basis of many primary immune deficiencies. Along with this increased knowledge comes an increased responsibility to understand the underlying mechanism of disease, and thus increasingly sophisticated technologies are being used to investigate the cell biology of human immune deficiencies. One such technology, which has, itself, undergone a recent explosion in innovation, is that of high-resolution microscopy and image analysis. These advances complement innovative studies that have previously shed light on critical cell biological processes that are perturbed by single gene mutations in primary immune deficiency. Here, we highlight advances made specifically in the following cell biological processes: 1) cytoskeletal-related processes; 2) cell signaling; 3) intercellular trafficking; and 4) cellular host defense.
doi:10.1016/j.jaci.2015.03.049
PMCID: PMC4641025  PMID: 26078103
Primary Immune Deficiency; microscopy; cell biology; cytoskeleton; host defence
23.  TNFRSF13B hemizygosity reveals TACI haploinsufficiency at later stages of B-cell development 
Background
Heterozygous C104R or A181E TNFRSF13B mutations impair the removal of autoreactive B cells, weaken B-cell activation and convey to common variable immune deficiency (CVID) patients an increased risk for autoimmunity. How mutant TACI influences wildtype TACI function is unclear; different models suggest either a dominant-negative effect or haploinsufficiency.
Objective
We investigated potential TACI haploinsufficiency by analyzing antibody-deficient Smith-Magenis Syndrome (SMS) patients, who possess only one TNFRSF13B allele and antibody-deficient patients carrying one c.204insA TNFRSF13B null mutation.
Methods
We tested the reactivity of antibodies isolated from single B cells from SMS patients and patients with a c.204insA TNFRSF13B mutation and compared them with counterparts from CVID patients with heterozygous C104R or A181E TNFRSF13B missense mutations. We also assessed if loss of a TNFRSF13B allele induced haploinsufficiency in naïve and memory B cells recapitulate abnormal immunological features typical of CVID patients with heterozygous TNFRSF13B missense mutations.
Results
We found loss of a TNFRSF13B allele does not impact TACI expression, activation responses, or establishment of central B-cell tolerance in naïve B cells. Additionally, SMS patients and patients with a c.204insA TNFRSF13B mutation display normal Treg function and peripheral B-cell tolerance. The lack of a TNFRSF13B allele did result in decreased TACI expression on memory B cells, resulting in impaired activation and antibody secretion.
Conclusion
TNFRSF13B hemizygosity does not recapitulate autoimmune features of CVID-associated C104R and A181E TNFRSF13B mutations, which likely encode dominant-negative products, but instead reveals selective TACI haploinsufficiency at later stages of B-cell development.
doi:10.1016/j.jaci.2015.05.012
PMCID: PMC4641026  PMID: 26100089
TNFRSF13B; TACI; B-cell tolerance; Common variable immune deficiency; Smith-Magenis Syndrome
24.  Genetic errors of the human CARD-BCL10-MALT1 (CBM) complex: molecular, immunological, and clinical heterogeneity 
Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These three CARD-BCL10-MALT1 (CBM) complexes activate NF-κB in both the innate and adaptive arms of immunity. Human inherited defects of the three components of the CBM complex, including the two adaptors CARD9 and CARD11 and the two core components BCL10 and MALT1, have recently been reported. Bi-allelic loss-of-function (LOF) mutant alleles underlie several different immunological and clinical phenotypes, which can be assigned to two distinct categories. Isolated invasive fungal infections, of unclear cellular basis, are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1 and BCL10 deficiencies. Interestingly, humans with these mutations have some features in common with the corresponding knockout mice, but other features are different between humans and mice. Moreover, germline and somatic gain-of-function (GOF) mutations of MALT1, BCL10 and CARD11 have also been found in other patients with lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including LOF and GOF mutations, highlights the contribution of each of the components of the CBM to human immunity.
doi:10.1016/j.jaci.2015.06.031
PMCID: PMC4894862  PMID: 26277595
Primary immunodeficiency; combined immunodeficiency; BCL10; MALT1; CARMA1; CARD9
25.  Creation and implementation of SAMPRO™: A school-based asthma management program 
Clinicians who care for children with asthma have an obligation to coordinate asthma care with the schools. Aside from routine clinical care of asthmatic children, providers must educate the family and child about the need for an asthma treatment plan in school and support the school nurse meeting the needs of the student requiring school-based asthma care. The following article was developed by multiple stakeholders to address this need. It describes the 4 components of the School-based Asthma Management Program (SAMPRO™). SAMPRO™ details elements necessary for the education of children, families, clinicians, and school-based personnel based on a “circle of support” that would enhance multidirectional communication and promote better care for children with asthma within the school setting.
doi:10.1016/j.jaci.2016.06.015
PMCID: PMC5085063  PMID: 27596707
Asthma; school; school nurse; children; asthma action plan; education; environment; triggers

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