In this chapter, the terms antigen and allergen are first defined and differentiated from one another. Sensitization and atopy are also defined within the context of allergy, and the process of allergic inflammation is described. This includes the biochemical mediators of allergic inflammation as well as the clinical outcome of an allergic reaction. The molecular structure of an allergen, its affinity toward an antibody, the route and amount of allergen exposure, and the presence of underlying allergic sensitization are crucial components of an allergic reaction. However, while all proteins may be antigens and stimulate an immune response, not all antigens become allergens. It is likely that a combination of genetics and environmental factors influence the loss of immunologic tolerance and subsequent production of IgE against a particular antigen. Further research is needed to identify these genetic and environmental components.

Objective IgG Fc receptors (FcγRs) play important roles in immune responses. It is not clear whether FcγR receptors play a role in human asthma and allergy. The aim of current study was to investigate whether functional single nucleotide polymorphisms (SNPs) of FcγR genes (FCGR) are associated with human asthma and allergy. Methods Functional SNPs of FCGR2A (FcγRIIA-131His>Arg, rs1801274), FCGR2B (FcγRIIB-187Ile>Thr, rs1050501), FCGR2C (FcγRIIC-13Gln>Stop, rs10917661), FCGR3A (FcγRIIIA-158Val>Phe, rs396991), and FCGR3B variants (FcγRIIIB NA1 and NA2) were genotyped in an asthma family cohort including 370 atopy positive, 239 atopy negative, and 169 asthma positive subjects. The genotype and phenotype data (asthma, bronchial hyper-responsiveness, and atopy) of subjects were analyzed using family-based association tests (FBAT) and logistic regression adjusted for age and sex. Result The FcγRIIA-131His>Arg SNP is significantly associated with atopy in a family-based association test (P = 0.00287) and in a logistic regression analysis (P = 0.0269, OR 0.732, 95% CI: 0.555–0.965). The FcγRIIA-131His (or rs1801274-A) allele capable of binding human IgG2 has a protective role against atopy. In addition, the rare FcγRIIB-187Thr (or rs1050501-C) allele defective for the receptor-mediated inhibitory signals is a risk factor for atopy (P = 0.0031, OR 1.758, 95% CI: 1.209–2.556) and IgE production (P<0.001). However, variants of activating FcγRIIIA (rs396991), and FcγRIIIB (NA1 and NA2), and FcγRIIC (rs10917661) are not associated with asthma, BHR, and atopy (P>0.05). Conclusions FcγRIIA and FcγRIIB functional polymorphisms may have a role in the pathogenesis of allergy.

Association of the neurotransmitter serotonin (5-HT) with the pathogenesis of allergic asthma is well recognized and its role as a chemoattractant for eosinophils (Eos) in vitro and in vivo has been previously demonstrated. Here we have examined the regulation of 5-HT-induced human and murine Eos trafficking and migration at a cellular and molecular level. Eos from allergic donors and bone marrow-derived murine Eos (BM-Eos) were found to predominantly express the 5-HT2A receptor. Exposure to 5-HT or 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-HT2A/C selective agonist, induced rolling of human Eos and AML14.3D10 human Eos-like cells on vascular cell adhesion molecule (VCAM)-1 under conditions of flow in vitro coupled with distinct cytoskeletal and cell shape changes as well as phosphorylation of MAPK. Blockade of 5-HT2A or of ROCK MAPK, PI3K, PKC and calmodulin, but not G(αi)-proteins, with specific inhibitors inhibited DOI-induced rolling, actin polymerization and changes in morphology of VCAM-1-adherent AML14.3D10 cells. More extensive studies with murine BM-Eos demonstrated the role of 5-HT in promoting rolling in vivo within inflamed post-capillary venules of the mouse cremaster microcirculation and confirmed that down-stream signaling of 5-HT2A activation involves ROCK, MAPK, PI3K, PKC and calmodulin similar to AML14.3D10 cells. DOI-induced migration of BM-Eos is also dependent on these signaling molecules and requires Ca(2+). Further, activation of 5-HT2A with DOI led to an increase in intracellular Ca(2+) levels in murine BM-Eos. Overall, these data demonstrate that 5-HT (or DOI)/5-HT2A interaction regulates Eos trafficking and migration by promoting actin polymerization associated with changes in cell shape/morphology that favor cellular trafficking and recruitment via activation of specific intracellular signaling molecules (ROCK, MAPK, PI3K and the PKC-calmodulin pathway).

INSTRUCTIONS Credit can now be obtained, free for a limited time, by reading the review article in this issue and completing all activity components. Please note the instructions listed below: •Review the target audience, learning objectives, and all disclosures. •Complete the pre-test online at http://www.annallergy.org (click on the CME heading). •Follow the online instructions to read the full version of the article; reflect on all content as to how it may be applicable to your practice. •Complete the post-test/evaluation and claim credit earned; at this time, you will have earned up to 1.0 AMA PRA Category 1 Credit™. Please note that the minimum passing score on the post-test is 70%. Release Date: February 1, 2012 Expiration Date: January 31, 2014 Estimated Time to Complete: 60 minutes Target Audience: Physicians involved in providing patient care in the field of allergy/asthma/immunology Learning Objectives: At the conclusion of this activity, participants should be able to: •Discuss that asthma, allergies and their associated conditions are complex, resulting from both genetic and non-genetic factors. •Recognize that the interplay between genetic and non-genetic factors can provide guidance as to the prevention and therapeutic management of these conditions and perhaps eventually lead to possible cures of these increasingly common syndromes. Accreditation: The American College of Allergy, Asthma & Immunology (ACAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation: The American College of Allergy, Asthma & Immunology (ACAAI) designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Planning Committee Members: Malcolm N. Blumenthal, MD (Author) Gailen D. Marshall, Jr, MD, PhD (Editor-in-Chief) Disclosure of Relevant Financial Relationships: M.N. Blumenthal and G.D. Marshall have nothing to disclose. No unapproved/investigative use of a product/device is discussed. Recognition of Commercial Support: This activity has not received external commercial support. Copyright Statement: Copyright © 2012-2013 ACAAI. All rights reserved. CME Inquiries: Contact the American College of Allergy, Asthma & Immunology at [email protected] or 847-427-1200. INSTRUCTIONS Credit can now be obtained, free for a limited time, by reading the review article in this issue and completing all activity components. Please note the instructions listed below: •Review the target audience, learning objectives, and all disclosures. •Complete the pre-test online at http://www.annallergy.org (click on the CME heading). •Follow the online instructions to read the full version of the article; reflect on all content as to how it may be applicable to your practice. •Complete the post-test/evaluation and claim credit earned; at this time, you will have earned up to 1.0 AMA PRA Category 1 Credit™. Please note that the minimum passing score on the post-test is 70%. Release Date: February 1, 2012 Expiration Date: January 31, 2014 Estimated Time to Complete: 60 minutes Target Audience: Physicians involved in providing patient care in the field of allergy/asthma/immunology Learning Objectives: At the conclusion of this activity, participants should be able to: •Discuss that asthma, allergies and their associated conditions are complex, resulting from both genetic and non-genetic factors. •Recognize that the interplay between genetic and non-genetic factors can provide guidance as to the prevention and therapeutic management of these conditions and perhaps eventually lead to possible cures of these increasingly common syndromes. Accreditation: The American College of Allergy, Asthma & Immunology (ACAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation: The American College of Allergy, Asthma & Immunology (ACAAI) designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Planning Committee Members: Malcolm N. Blumenthal, MD (Author) Gailen D. Marshall, Jr, MD, PhD (Editor-in-Chief) Disclosure of Relevant Financial Relationships: M.N. Blumenthal and G.D. Marshall have nothing to disclose. No unapproved/investigative use of a product/device is discussed. Recognition of Commercial Support: This activity has not received external commercial support. Copyright Statement: Copyright © 2012-2013 ACAAI. All rights reserved. CME Inquiries: Contact the American College of Allergy, Asthma & Immunology at [email protected] or 847-427-1200.

In this issue of Annals of Allergy, Asthma & Immunology, Selivanoca et al 1 suggest that the differential expressions of the 2adrenoceptor (ADRB2), M3 cholinoreceptor (CHRM3), and corticosteroids are associated with asthma, chronic obstructive pulmonary disease (COPD), and their response to treatment. 1 Increased levels of the ADRB2 gene were demonstrated in patients with severe asthma and COPD as compared with those having mild and moderate diseases. Higher levels of ADRB2 messenger RNA levels occurred in patients with severe asthma with persistent airflow limitation. Lower levels of CHRM3 occurred in patients with COPD as compared with asthma. The CHRM3 gene expression was more elevated in COPD patients with bronchial hyperresponsiveness than in those without. Many problems impede the diagnosis and therapy of these conditions and the resulting conclusions. These include definitions, pathogenesis, and the role of genetic, epigenetic, and environmental factors. 2,3 The definitions of asthma and COPD are imprecise, with asthma having variable airflow obstruction, hyperinflammation, airway plugs, and eosinophilia and COPD having progressive deterioration of lung function and excessive mucus, macrophages, and neutrophils. Both diseases may be the extreme ends of a single condition. 3 Bron

Trafficking and recruitment of eosinophils during allergic airway inflammation is mediated by the phosphatidylinositol 3-kinase (PI3K) family of signaling molecules. The role played by the p110δ subunit of PI3K (PI3K p110δ) in regulating eosinophil trafficking and recruitment was investigated using a selective pharmacological inhibitor (IC87114). Treatment with the PI3K p110δ inhibitor significantly reduced murine bone marrow-derived eosinophil (BM-Eos) adhesion to VCAM-1 as well as ICAM-1 and inhibited activation-induced changes in cell morphology associated with reduced Mac-1 expression and aberrant cell surface localization/distribution of Mac-1 and α4. Infused BM-Eos demonstrated significantly decreased rolling and adhesion in inflamed cremaster muscle microvessels of mice treated with IC87114 compared with vehicle-treated mice. Furthermore, inhibition of PI3K p110δ significantly attenuated eotaxin-1-induced BM-Eos migration and prevented eotaxin-1-induced changes in the cytoskeleton and cell morphology. Knockdown of PI3K p110δ with siRNA in BM-Eos resulted in reduced rolling, adhesion, and migration, as well as inhibition of activation-induced changes in cell morphology, validating its role in regulating trafficking and migration. Finally, in a mouse model of cockroach antigen-induced allergic airway inflammation, oral administration of the PI3K p110δ inhibitor significantly inhibited airway eosinophil recruitment, resulting in attenuation of airway hyperresponsiveness in response to methacholine, reduced mucus secretion, and expression of proinflammatory molecules (found in inflammatory zone-1 and intelectin-1). Overall, these findings indicate the important role played by PI3K p110δ in mediating BM-Eos trafficking and migration by regulating adhesion molecule expression and localization/distribution as well as promoting changes in cell morphology that favor recruitment during inflammation.

Asthma is a complex disease with many phenotypes. Its definition and treatment by a number of cultures around the world may play a role in the efficacy of such treatments. Western medicine defines asthma based on inflammation, obstruction, and mucus production which are reversible with treatment. A number of studies focusing on natural products, mind body medicine, manipulative therapy, and others have not been able to reproducibly demonstrate efficacy in treating asthma. This may be due to a number of factors including methodology, study design, and-most importantly-the definition of asthma used for each study. The Western definition of asthma may differ greatly from the definition used by those cultures which originally created the therapies used in studies of complementary and alternative medicine (CAM). Because of this difference, the outcome of the studies may not be an accurate reflection of the ability of these therapies to treat the disease process they were originally designed to treat. Future studies in CAM will likely need to address these differences.

RATIONALE: Atopy has been defined as a positive reaction in testing to one or more common allergens. We conducted a prospective investigation on the results of skin testing as part of the CSGA study in 1995 and 2007. METHODS: The allergens tested in the CSGA study included indoor allergens (D psteronysinus, cat, dog, cockroach mix), pollens (Pariplaneta americana, Lolium perenne, Ambrosia artemisiifolia, Betula populifolia, Artemisia vulgaris, Quercus alba) and molds (Cladosprium herbarum, Aspergillus fumigatus, Alternaria tenuis). RESULTS: Of 371 testing negative to all allergens in 1995, 257(69%) remained negative in 2007 while 114(31%) became positive. Of 167 who tested positive to all allergens in 1995, 40(24%) became negative while 76% stayed positive in 2007. Of the 274 subjects who were negative for pollens in 1995, 211(77%) remained negative while 63(23%) became positive. Of 181 subjects who tested positive for pollens in 1995, 44(25%) became negative and 135(75%) remained positive. Of the 227 subjects who tested negative to pollens in 1995, 164(72%) remained negative while 63(28%) became positive. Of the 46 positive to molds in 1995, 33(72%) remained positive while 13(28%) became negative. CONCLUSIONS: The skin response to the common indoor and outdoor allergens varied with time. The percentage of subjects who converted from positive to negative or negative to positive for any given allergen tested was 23% to 31%. Factors that may affect the skin test response include exposure, test standardization, time, and subject age. Genetic studies may reveal the reason skin test reactivity changes over time.

RATIONALE: Due to the wide variation in prevalence and factors associated with difficult to control asthma, it is vital that common clinical characteristics be identified.METHODS: This is a retrospective chart review of 100 pediatric patients classified as having uncontrolled asthma based on NHBLI guidelines.An inclusion criterion was use of daily high doses of inhaled steroids, intermittent systemic steroid bursts, or daily use of oral steroids.Asthmatics patients with other chronic lung condition such as bronchopulmonary dysplasia, or restrictive lung disease were excluded. RESULTS:The following clinical characteristics were observed in this group: 95% are atopic based on history of allergic rhinitis, eczema, positive allergy prick skin test or RAST (radioallergosorbent test), 66% are African Americans, 27% have exposure to tobacco smoke (ETS), 51% have moderate to severe airway obstruction based on FEV1, 47% have sinusitis, 43% have GERD, 55% have a BMI percentile of 85 or above, 33% are obese.CONCLUSIONS: The great majority of pediatrics patients with difficult to control asthma are atopic and almost half of them have sinusitis and GERD as co-morbidities, 33% are also obese.Identifying the atopic condition and co-morbidities of asthma patients who continue to be symptomatic despite adequate therapy may help improve quality of life and better asthma control.

Asthma is a respiratory condition of the lower respiratory tract that affects approximately 8% to 12% of the general population. It is characterized by symptoms of cough, wheeze, and shortness of breath associated with airway obstruction with reversibility or bronchial hyperreactivity. 1 Szczeklik A. Nizankowska-Mogilnicka E. Sanak M. Hypersensitivity to aspirin and non-steroidal antiinflammatory drug. in: Adkinson Jr, N.F. Bochner B.S. Bussse W.W. Holgate S.T. Lemasnske Jr, R.F. Simons F.E. Middleton's Allergy Principles and Practice. 7th ed. Mosby Elsevier, St Louis, MO2009: 1227-1243 Crossref Google Scholar Rhinitis is a condition of the upper nose characterized by symptoms of sneezing, nasal congestion, and nasal discharge. It affects 21% to 40% of the general population. Both conditions are relatively common, are related to inflammation, and are associated with nasal polyps and eosinophilia and other factors (allergic and nonallergic and genetic and environmental). 2 Orban N.T. Sale H. Durham S.R. Allergic and non-allergic rhinitis. in: Atkinson Jr, N.F. Bochner B.S. Busse W.W. Holgate T. Lamasnke R.F. Simon F.E. Middleton's Allergy Principles and Practice. 7th ed. Mosby Elsevier, St Louis, MO2009: 893-990 Google Scholar

Background: Six asthma candidate genes, ADAM33, NPSR1, PHF11, DPP10, HLA-G, and CYFIP2, located at different chromosome regions have been positionally cloned following the reported linkage studies. For ADAM33, NPSR1, and CYFIP2, the associations with asthma or asthma-related phenotypes have been studied in East Asian populations such as Chinese and Japanese. However, for PHF11, DPP10, and HLA-G, none of the association studies have been conducted in Asian populations. Therefore, the aim of the present study is to test the associations between these three positionally cloned genes and asthma or asthma-related phenotypes in a Chinese population. Methods: Two, five, and two single nucleotide polymorphisms (SNPs) in the identified top regions of PHF11, DPP10, and HLA-G, respectively, were genotyped in 1183 independent samples. The study samples were selected based on asthma affectation status and extreme values in at least one of the following three asthma-related phenotypes: total serum immunoglobulin E levels, bronchial responsiveness test, and skin prick test. Results: Single SNP and haplotype analyses revealed that PHF11 was associated with positive skin reactions to antigens; DPP10 was associated with bronchial hyperresponsiveness (BHR) and BHR asthma; and HLA-G was associated with BHR asthma. Conclusions: Our study is the first one to support the roles of PHF11, DPP10, and HLA-G in influencing asthma and asthma-related phenotypes, such as skin prick test and BHR, in a Chinese population.

Objective: To identify genes involved in phenotypes that increase one’s risk for developing asthma, a complex disease that is likely genetically heterogeneous. Unlike other approaches to locus discovery in the presence of heterogeneity, this method seeks loci that segregate in all or most ascertained families while recognizing that other genes and environmental factors that modify the action of the common gene may vary across families. Methods: The method is based on seeking groups of families that differ, between groups, in the way affected idndividuals express the genotype. Then we use the distance of each individual to the cluster center for his family to define a quantitative trait. This quantitative trait is then subjected to a genome scan using variance components methods. Results: The method is applied to a data set of 27 multigenerational families with asthma, and a novel locus at 2q33 (at 210 cM) is identified. Conclusions: The proposed method has the potential to identify loci near genes that increase risk for asthma related phenotypes. The method could be used for other complex disorders that exhibit locus heterogeneity.

Inherited atopic diseases of humans arise from adverse adaptive humoral responses to noninfectious environmental allergens. We previously reported that allergen-specific IgG1 provides more reliable heritability estimates for responses to allergens than total IgE. Genome scans were done for 91 Caucasian nuclear families with history of atopy for total IgE and IgG1 produced against a common major allergen from house dust mite, Der p 1. Suggestive associations for Der p 1-IgG1 production were found at 7 quantitative trait loci (QTL) (logarithm of the odds, LOD > or = 1.23; p < or = 0.009) with QTL-specific heritabilities of 73%-80%. Scans using total IgE found suggestive associations for 12 QTLs (LOD > or = 1.44; p < or = 0.004), but QTL-specific heritabilities only in the range of 30%-35%. Allergen-specific IgG1 is a suitable "endophenotype" to be used in searches for genes associated with atopy-associated humoral immune responses to common aeroallergens.

As part of an assessment of schoolchildren's environmental exposures and health, a probability sample of 136 children from diverse racial/ethnic backgrounds was drawn from grades 2-5 of two inner-urban Minneapolis schools (Whittier, Lyndale). Questionnaires were administered to a parent/guardian; blood samples for IgE and lung function tests were obtained. Overall adjusted rates for lifetime asthma (15.4%; 95%CI 9.3-21.5%), asthma in the last 12 months (13.6%; 7.8-19.4%), and current asthma medication use (10.5%; 5.3-15.7%) were higher than reported US national rates. Adjusted rates for lifetime physician-diagnosed asthma differed significantly among racial/ethnic groups (P<0.01): African-Americans (25.9%), White/Others (25.8%), Hispanics (9.3%), Somalis (1.8%), Asians (0%). Corresponding rates for atopy (total IgE>100 IU/mL or an allergen-specific IgE>0.35 IU/mL) were: African-Americans (66.6%), White/Others (100%), Hispanics (77.2%), Somalis (78.1%), Asians (81.8%). Lung function (FEV1, FVC) was analyzed by linear regression using log-transformed data: significant race-specific differences in lung function were found relative to White/Others (P<0.001 for each racial/ethnic group): African-Americans (FEV1 -16.5%, FVC -16.9%), Somalis (-22.7%, -26.8%), Hispanics (-12.2%, -11.4%) and Asians (-11.1%, -12.4%). Females had significantly lower FEV1 (-8.8%) and FVC (-11.0%) than males. An unexplained, significant difference in children's lung function was found between the two schools. A history of physician-diagnosed asthma was not associated with decreased lung function. Factors other than poverty, inner-urban living, and IgE levels (atopy) need to be considered in the development of childhood asthma.

Quantitative phenotypes correlated with a complex disorder offer increased power to detect linkage in comparison to affected–unaffected classifications. Asthma is a complex disorder characterized by periods of bronchial obstruction and increased bronchial hyper reactivity. In childhood and early adulthood, asthma is frequently associated also with quantitative measures of atopy. Genome wide quantitative multipoint linkage analysis was conducted for serum IgE levels and percentage of positive skin prick test (SPTper) using three large groups of families originally ascertained for asthma. In this report, 438 and 429 asthma families were informative for linkage using IgE and SPTper which represents 690 independent families. Suggestive linkage (LOD ≥ 2) was found on chromosomes 1, 3, and 8q with maximum LODs of 2.34 (IgE), 2.03 (SPTper), and 2.25 (IgE) near markers D1S1653, D3S2322–D3S1764, and D8S2324, respectively. The results from chromosomes 1 and 3 replicate previous reports of linkage. We also replicate linkage to 5q with peak LODs of 1.96 (SPTper) and 1.77 (IgE) at or near marker D5S1480. Our results provide further evidence implicating chromosomes 1, 3, and 5q. The current report represents one of the biggest genome scans so far reported for asthma related phenotypes. This study also demonstrates the utility of increased sample sizes and quantitative phenotypes in linkage analysis of complex disorders.