Volume 122, Issue 3, Pages 475-480 (September 2008)

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ABSTRACT

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New perspectives on mechanisms underlying chronic allergic inflammation and asthma in 2007

Received 16 June 2008; accepted 19 June 2008. published online 11 August 2008.

This review summarizes selected articles appearing from January to December 2007 in the Journal of Allergy and Clinical Immunology. Articles were chosen that related to advances in mechanisms of chronic allergic inflammation and asthma, including those describing gene association studies, mast cells, IgE, eosinophils, cytokines, the inception of allergy, airway remodeling, preclinical therapeutic targets, and virally induced asthma.

Article Outline

• Abstract

• Gene association studies

• Mast cells and IgE

• Mast cells

• IgE

• Histamine and histamine receptors

• Eosinophils

• T2 immune response

• Cytokines

• IL-13

• IL-17/IL-25 (IL-17E)

• Inception of allergy/asthma

• Airway remodeling

• Corticosteroid-resistant asthma

• Preclinical novel therapeutic targets

• Cigarette smoke, chronic obstructive pulmonary disease, and asthma

• Viruses and asthma

• Conclusion

• References

• Copyright

In this review, we focus on selected articles from the Journal of Allergy and Clinical Immunology in 2007 that focus on mechanisms of chronic allergic inflammation and asthma.

Gene association studies

Several studies investigated the association of genetic polymorphisms with asthma and identified positive associations with IL13,1 IL4RA,2 and filaggrin3 and inverse associations with Clara cell protein 10 (CC10)4 and the myosin light chain kinase gene.5

Ermers et al1 investigated whether polymorphisms in the IL13 gene could distinguish between the majority of children who have transient wheezing after lower respiratory tract respiratory syncytial virus (RSV) infection and the minority of children who have persistent or late wheezing. They followed a cohort of 101 children hospitalized for lower respiratory tract RSV infection prospectively for 6 years and identified that an IL13 genetic polymorphism (ie, the IL13 Gln allele) was associated with the development of late wheezing at age 6 years but not early wheezing after RSV-induced bronchiolitis. The authors concluded that late wheezing after RSV infection at age 6 years represents a distinct asthma phenotype and is not related to early postbronchiolitis wheezing. Studies by Hunninghake et al6 also demonstrated that polymorphisms in IL13 were significantly associated with serum total IgE levels and eosinophil counts in 2 populations.

Studies investigating an association of genetic polymorphisms in IL4RA with asthma have provided conflicting results. Loza and Chang2 therefore performed a meta-analysis of 9 studies of the IL-4 receptor α chain and asthma and demonstrated a small but statistically significant association of atopic asthma with the R551 IL4 receptor variant. Studies by Ueta et al7 in a small cohort of Japanese patients suggest an association between IL4R polymorphisms and the Stevens-Johnson syndrome.

Lee et al8 demonstrated that although polymorphisms in the chemokine CCR3 were not associated with asthma susceptibility, the CCR3 haplotype ht2 showed a negative gene dose effect on the eosinophil count.

In addition to genes having a positive association with asthma, several genes have been associated with a reduced frequency of asthma. These include polymorphisms in CC10, which are associated with infrequent wheezing and lower CC10 levels,4 as well as single nucleotide polymorphisms (SNPs) in the myosin light chain kinase gene, which have an inverse correlation with asthma in populations of African ancestry.5 In addition to gene association studies of CC10, Johansson et al9 demonstrate that CC16 inhibits TH2 cell differentiation through effects on dendritic cells.

Koehm et al10 used HLA-DR humanized transgenic mice to demonstrate that the HLA-DR2 genotypes (DRB1∗1501 and DRB1∗1503) played a major role in the development of pulmonary allergic inflammation in response to Aspergillus species antigens, whereas the HLA-DR2 genotype DRB1∗1502 mediated a nonallergic TH1 immune response to the organism.

The protein filaggrin facilitates the terminal differentiation of the epidermis and the formation of the skin barrier.3 Loss-of-function mutations in the filaggrin gene have been strongly associated with atopic dermatitis. Studies have also investigated whether filaggrin mutations are associated with asthma. Palmer et al3 demonstrated an association of the filaggrin gene with eczema-associated asthma and asthma severity independent of eczema status. However, not all studies demonstrate that mutations of the filaggrin gene associate with asthma.11

Another eczema-associated gene is IL31, which, when overexpressed in transgenic mice, induces severe itching and dermatitis resembling human eczema. In studies of nonatopic eczema, Schulz et al12 demonstrated that polymorphisms in the IL31 gene associate with nonatopic eczema in 3 independent European populations.

Mast cells and IgE

Mast cells

Yang et al13 demonstrated a novel mechanism of non–IgE-dependent mast cell activation induced by the calcium-binding protein S100A12 (also known as calgranulin C; extracellular newly identified RAGE-binding protein). S100A12 induced mucosal and connective tissue mast cell degranulation in vitro and in vivo and amplified IgE-mediated responses.13 S100A12 can be detected in asthmatic sputum, as well as in eosinophils and neutrophils, suggesting a pathway for inflammatory cells to activate mast cells through non–IgE-dependent pathways in nonatopic individuals.

IgE

Studies have previously demonstrated that IgE can be synthesized locally in the airway mucosa. Balzar et al14 demonstrated that eosinophilia in subjects with severe asthma is associated with significantly higher levels of local IgE production in the airways compared with that seen in subjects with severe asthma who did not have eosinophilia. Interestingly, both groups of subjects with severe asthma had similar systemic blood levels of IgE.14 Higher local IgE levels were associated with more severe exacerbations of asthma.14 Crestani et al15 have also noted an association between IgE levels and the eosinophil-active cytokine IL-5 in infants and their parents.

Analysis of mitochondrial haplogroups provides insight into the maternal contribution to a particular phenotype because mitochondria are inherited exclusively through the maternal line. Studies by Raby et al16 demonstrated that carriers of European mitochondrial haplogroup U (frequency, 11%) have higher total serum IgE levels compared with noncarriers (approximately 684 vs 389 IU/L). These findings might provide insight into the influence of maternal history of atopy on the development of atopy in offspring. In addition to levels of IgE, Gieras et al17 demonstrated that the number of IgE epitopes on an allergen molecule determines the extent of mast cell degranulation. Platts-Mills et al18 demonstrated that the prevalence of a high titer of IgE (>10 IU/mL) to mouse allergens is more frequently detected in minority populations (3.4%) compared with diverse populations (1.3%). In addition, Erwin et al19 demonstrated that allergen-specific IgE to dust mite contributes to high total IgE levels in wheezing children in New Zealand, whereas in northern Sweden, where exposure to dust mite is much lower, allergen-specific IgE antibodies appear to make little contribution to high total serum IgE levels. Studies of IgE to cat allergen by Adédoyin et al20 demonstrate that individuals with cat allergy make IgE not only to cat allergens, such as Fel d 1, but also to cat IgA.

In an open-label study by Carter et al21 of 3 subjects with systemic mastocytosis, anti-IgE decreased the frequency of unprovoked episodes of hypotension, whereas Siebenhaar et al22 described a patient with cutaneous mastocytosis and Meniere's disease whose skin symptoms, as well as nausea and dizziness, improved with anti-IgE. The mechanism by which anti-IgE decreases episodes of mast cell–dependent hypotension in these patients with mastocytosis remains unknown but might relate to a decrease in the activation state of mast cells concurrent with a decrease in surface IgE levels and associated decreases in FcɛRI receptor numbers.

Histamine and histamine receptors

Histamine might play a role in airway remodeling through its known effect on inducing fibroblast proliferation. Kunzmann et al23 have demonstrated that histamine also induces expression of connective tissue growth factor by fibroblasts, providing an additional pathway for histamine to potentially influence airway remodeling.

Once histamine is released, it can bind to 4 known histamine receptors (H1, H2, H3, and H4). Although activation of histamine receptors induces proinflammatory effects, studies by Dijksta et al24 suggest that stimulation of H4 receptors might be anti-inflammatory.For example, stimulation of H4 receptors on human monocytes downregulates expression of the monocyte chemoattractant CCL2 (also known as monocyte chemoattractant protein 1), which would decrease additional monocyte recruitment.24 Thus histamine released at sites of allergic inflammation might also limit ongoing monocyte recruitment through activation of H4 receptors on monocytes. H4 receptors have also been implicated in the migration of mast cell precursors to CXCL12.25

Basophils from different subjects that express equal densities of IgE can have extreme differences in mediator release in response to stimulation with anti-IgE. MacGlashan26 demonstrated that basophil expression of early intracellular signaling elements (ie, spleen tyrosine kinase [Syk] and phosphatidylinositol 5′ phosphatase) correlated with maximum histamine release or basophil sensitivity. In a multiple regression analysis, Syk and phosphatidylinositol 5′ phosphatase together could account for 67% of population basophil response variance, although most of the variance was explained by Syk expression.26 These findings suggests a mechanism for differences in basophil contribution to the severity of atopic diseases in different subjects.

Eosinophils

Cysteinyl leukotriene (CysLT) antagonism and anti-IgE therapy reduce the number of eosinophils in the airway, although not to the same degree as corticosteroid therapy. Studies by Meliton et al27 provide evidence that CysLT antagonism blocks eosinophil adhesion in response to selected, but not all, stimuli. For example, in vitro studies by Meliton et al demonstrated that incubating eosinophils with a CysLT receptor 1 antagonist or a 5-lipoxygenase inhibitor blocks LTB4–induced, but not IL-5– or eotaxin 1–induced, eosinophil β2-integrin adhesion function.27 This helps to explain the partial blockade of eosinophil adhesion and migration by CysLT antagonism in diseases such as asthma, in which multiple mediators in addition to CysLTs contribute to eosinophil tissue recruitment.

Anti-IgE reduces levels of eosinophils in the sputum during the late-phase response to allergen challenge and has been investigated by Foroughi et al28 in the therapy of eosinophil-associated gastrointestinal disorders. In an open-label study of 9 subjects with eosinophil-associated gastrointestinal disorders, anti-IgE significantly decreased peripheral blood eosinophil counts (34%) but did not show a statistically significant effect in reducing esophageal or gastrointestinal tissue eosinophils.28

Kanters et al29 noted increased expression of FcγRII on peripheral blood eosinophils after allergen challenge in asthmatic subjects experiencing a late asthmatic response but not in asthmatic subjects with a single early response. These studies suggest that eosinophils in subjects with a late-phase response to inhaled allergen have a primed phenotype.

Additional studies of eosinophils by Kwatia et al30 demonstrated that eosinophils might contribute to surfactant dysfunction in asthma mediated through the combined activity of secretory phospholipase A2 and eosinophil lysophospholipases, whereas Munitz and Levi-Schaffer31 reviewed the role of inhibitory receptors expressed by eosinophils.

TH2 immune response

Pollen proteins (eg, Amb a 1 and Lol p) are well-recognized causes of allergy and TH2 immune responses. Valenta and Niederberger32 reviewed the current status of the development of recombinant allergens for skin testing and immunotherapy. Metz-Favre et al33 used a recombinant hybrid molecule consisting of 4 major allergens from timothy grass (Phl p 1, 2, 5, and 6) to detect timothy grass pollen allergy by means of skin testing in 32 patients with grass pollen allergy and 9 control subjects.

Recently, studies have identified lipids in pollen allergens that might modulate TH2 immune responses. For example, studies by Gutermuth et al34 demonstrated that aqueous extracts of white birch pollen instilled intranasally into mice in vivo induce increased TH2 immune responses and decreased TH1 immune responses. One of the lipid components of aqueous extracts of white birch pollen is the plant hormone phytoprostane,34 which, when instilled intranasally in mice in vivo, inhibits both TH2 and TH1 immune responses. These studies provide evidence for immune-modulating properties of nonprotein components of allergens, such as lipids. Further studies are needed to determine their relevance to immunotherapy, in which they could either be beneficial or harmful depending on their effect on the immune response.

Studies of fungal proteins by Kiss et al35 have demonstrated that in mice a fungus-associated allergenic proteinase can induce recruitment of TH2 cells and eosinophils to the airway independent of adaptive immune cells, complement, or Toll receptor signaling. These studies suggest proteinase-associated mechanisms by which allergens can initiate allergic responses.35 Additional studies by Daines et al36 demonstrated that house dust mite allergen can also function as a protease and directly cleave IL-13 receptor α2 (IL-13Rα2) in vitro. Lower levels of IL-13Rα2 were also noted in bronchoalveolar lavage fluid from subjects with asthma versus control subjects.36 House dust mite–dependent degradation of IL-13Rα2 could theoretically contribute to the pathogenesis of allergic inflammation because of the loss of IL-13Rα2–mediated inhibition of IL-13 responses.

Weber-Chrysochoou et al37 demonstrated that the development of either dust mite–positive immediate hypersensitivity skin test results or asthma at age 5 years was associated with dust mite–induced PBMC IL-5 responses at ages 3 and 5 years. In contrast, TH1 cytokine (IFN-γ), and regulatory T-cell cytokine (IL-10) responses to dust mite were not associated with either dust mite–positive immediate hypersensitivity skin test results or asthma at age 5 years.37 This study suggests that the T-cell response to dust mite is acquired over the first years of life and might play an important role in the development of asthma. In other studies evaluating TH1 cytokines and risk of wheezing, Stern et al38 demonstrated that the risk of wheezing between 2 and 13 years of age was significantly higher for subjects with low IFN-γ production at 9 months of age.

Cytokines

IL-13

IL-13 has been implicated in the pathogenesis of asthma, and recent studies suggest an important role for IL-13 in eosinophilic esophagitis (EE). Blanchard et al39 demonstrated that IL13 mRNA levels are markedly increased (16-fold) in esophageal biopsy specimens from patients with EE compared with those from healthy individuals. Furthermore, incubation of primary esophageal epithelial cells with IL-13 induced a transcript profile that overlapped significantly with an EE-specific esophageal transcriptome. This expression profile included eotaxin-3, a chemokine previously detected to be highly expressed in EE.

IL-17/IL-25 (IL-17E)

IL-25, a member of the IL-17 family of cytokines, has been implicated in TH2 immune responses. Ballantyne et al40 demonstrated that administration of anti–IL-25 antibody to mice inhibited eosinophilic inflammation and TH2 cytokine responses and reduced airway responsiveness, suggesting that administration of anti–IL-25 might represent a novel therapeutic strategy in asthma. Although IL-17E plays a role in allergic inflammation, Kawaguchi et al41 demonstrated that IL-17F induces bronchial epithelial cells in vitro to express IFN-γ–inducible protein 10 (IP-10), a CXC chemokine that preferentially attracts TH1 lymphocytes.

Inception of allergy/asthma

Stimulation of the innate immune response by microbes, farm milk, and helminths has been investigated to determine whether they influence the development of allergy. Adlerberth et al42 characterized intestinal bacteria identified in stool cultures from infants from the first week of life through 12 months of age and did not identify any specific intestinal bacteria that were associated with the development of sensitization to foods, atopic eczema, or both in 3 different European birth cohorts. These studies suggest that acquisition of the particular intestinal bacteria investigated in this study does not modulate the frequency of food sensitization or atopic eczema in children.

Consumption of farm milk in early life is associated with less asthma and allergy. Bieli et al43 demonstrated that children consuming farm milk carrying the A allele of the CD14/−1721 SNP had a lower incidence of allergic disease than those children homozygous for the G allele. Additional studies by Stern et al44 investigated whether living on farms, exposure to stables/farm milk, or both in the first year of life modulated levels of allergen-specific IgE in children. They demonstrated that such exposures reduced IgE responses to grass pollen (Phl p 1 and 5) but did not significantly influence IgE responses to house dust mite (Der p 2) or cat (Fel d 1).

The relationship between infections with helminths and the subsequent development of either atopy or asthma is controversial. A recent cross-sectional study by Hunninghake et al45 examined this relationship in 439 children with asthma aged 6 to 14 years. Sensitization to the helminth Ascaris lumbricoides was associated with increased airway responsiveness and hospitalizations for asthma in the previous year.

Airway remodeling

Several cell types, including mast cells, can contribute to angiogenesis, a feature of airway remodeling in asthma. Support for mast cells contributing to angiogenesis is derived from studies by Zanini et al46 demonstrating that chymase-positive mast cells in human airways expressed the proangiogenic mediator vascular endothelial growth factor. In addition, the number of chymase-positive mast cells correlated with the vascular area. Interestingly, a 6-week course of inhaled corticosteroids reduced the number of chymase-positive mast cells but did not reduce the number of peribronchial blood vessels.46 Studies by Siddiqui et al47 have also demonstrated that vascular remodeling is a feature of both asthma and eosinophilic bronchitis.

The a disintegrin and metalloproteinase (ADAM) family comprises more than 30 proteins that are a subgroup of the zinc-dependent metalloproteinase superfamily. SNPs in ADAM33 have been associated with a more rapid decrease in lung function, suggesting a potential role for ADAM33 in airway remodeling. Studies by Foley et al48 detected increased ADAM33 levels in the airways of patients with moderate-to-severe asthma compared with those seen in patients with mild asthma and nonasthmatic control subjects, with increased ADAM8 levels also noted.

Studies by Southam et al49 in a mouse model of chronic allergen exposure demonstrated that the initial increase in airway hyperresponsiveness was associated with increased eosinophil counts, whereas the late increase in airway responsiveness was associated with remodeling changes (ie, collagen deposition and smooth muscle changes).

Studies have demonstrated that LTs might play a role in the development of airway remodeling in asthma. Further support for LTs in airway remodeling are derived from in vitro studies by Yoshisue et al50 demonstrating that LTD4 increased bronchial fibroblast proliferation induced by epidermal growth factor. Interestingly, bronchial fibroblasts do not express CysLT receptors 1 or 2. The effect of LTD4 on fibroblasts involved a protein kinase C–mediated intracellular pathway, which was blocked by neither CysLT receptor 1 nor dual-receptor antagonists, suggesting the need for novel therapies to block this pathway.50 Lee et al51 demonstrated in a mouse model that CysLTs upregulate IL-11, a profibrotic cytokine, suggesting another pathway for LTs to mediate airway remodeling.

Corticosteroid-resistant asthma

Corticosteroid-resistant asthma can lead to irreversible airway remodeling. Studies by Goleva et al52 demonstrated that bronchodilator reversibility is impaired in patients with corticosteroid-resistant asthma and that this is associated with an increase in the matrix metalloproteinase 9/tissue inhibitor of metalloproteinase 1 ratio, which potentially promotes proteolytic activity and remodeling.

Pégorier et al53 reported increased levels of endothelin-1 in the bronchial epithelium of patients with corticosteroid-resistant asthma. The levels of endothelin-1 in patients with corticosteroid-resistant asthma correlated with airway smooth muscle area, suggesting a role for endothelin-1 in smooth muscle remodeling.

Preclinical novel therapeutic targets

Patients with moderate-to-severe asthma comprise those with the greatest need for novel therapies. Studies by the National Heart, Lung, and Blood Institute Severe Asthma Research Program54 have demonstrated that although severe asthma is characterized by reduced lung function and persistent symptoms, lung function abnormalities are reversible in most patients with severe asthma, suggesting that intervention with novel therapies could improve lung function, even in this group of patients with severe asthma.

A recently described anti-inflammatory protein, glucocorticoid-induced leucine zipper (GILZ), interferes with transcription of proinflammatory genes by nuclear factor κB. Studies by Eddleston et al55 using human airway epithelium have demonstrated that knockdown of GILZ by means of small interfering RNA inhibits the anti-inflammatory effects of corticosteroids. Thus therapeutic strategies that upregulate GILZ might be novel anti-inflammatory therapies in asthma.

Ragweed extract contains reduced nicotinamide adenine dinucleotide phosphate oxidases, which induce oxidative stress that augments antigen-induced allergic airway inflammation. Dharajiya et al56 demonstrated that antioxidants significantly reduce levels of eosinophils and mucus in the airways in a mouse model of ragweed-induced asthma.

Prior studies have demonstrated an important role for the transcription factor T-bet in regulating TH1 cell differentiation. In adoptive transfer studies of T-bet–deficient CD4+ cells in mice, Fujiwara et al57 demonstrate that T-bet is vital for the inhibition of antigen-induced eosinophilic inflammation, as well as for inhibition of antigen-induced recruitment of neutrophils to the airway. Thus targeting T-bet might play an important role in reducing both eosinophilic and neutrophilic airway inflammation.

In a rat model of asthma, Esnault et al58 demonstrated that administration of juglone (5-hydroxy-1,4-naphthoquinone), a pharmacologic inhibitor of Pin-1, significantly reduced pulmonary eosinophilia without changes in levels of other immune and inflammatory cell populations.

Cigarette smoke, chronic obstructive pulmonary disease, and asthma

Bergeron et al59 demonstrated increased expression of arginase I in asthmatic subjects who smoke compared with that seen in asthmatic subjects who do not smoke. Because arginase converts arginine to ornithine, a precursor of proline (a constituent of collagen), high arginase activity could promote collagen synthesis and greater remodeling in asthmatic subjects who smoke.59

Studies by Borger et al60 of CCAAT/enhancer-binding proteins, which control cell proliferation, suggest that subjects with asthma and chronic obstructive pulmonary disease (COPD) express different isoforms of CCAAT/enhancer-binding proteins, with asthmatic subjects expressing the α isoform and subjects with COPD expressing the δ isoform. Thus in addition to disease-specific gene products being expressed in patients with asthma versus those with COPD, the same gene with different isoforms might distinguish asthma from COPD.

Miller et al61 have demonstrated that in subjects with the emphysematous form of COPD diagnosed based on chest computed tomographic scan, the extent of COPD, as well the presence of a bronchodilator response, was associated with increased levels of eotaxin-1.

Viruses and asthma

Kusel et al62 investigated the role of acute respiratory tract infections in the first year of life in 198 children at high risk for atopic disease on the subsequent development of atopy, wheeze, and asthma at age 5 years. The most common viruses detected in postnasal aspirates at the time of infection in the first year of life were rhinoviruses (48%) and RSV (11%). At 5 years of age, 28% of children had current wheeze, which was significantly associated with febrile lower respiratory tract viral infections in the first year of life. Interestingly, these associations were restricted to children who displayed early sensitization (<2 years old) and were not observed in nonatopic patients or those sensitized later. The authors suggest that protection of “high-risk” children against severe respiratory tract infections during infancy might represent an effective strategy for primary asthma prevention. Ramsey et al63 also reported that physician-diagnosed bronchiolitis before age 1 year was significantly associated with asthma at age 7 years.

IP-10 is produced by rhinovirus-infected airway epithelial cells. Wark et al64 demonstrated that serum IP-10 levels were increased to a greater degree in acute virus-induced asthma compared with levels seen in those with non–virus-induced acute asthma. Increased IP-10 levels were associated with more severe asthma.

Conclusion

This review summarized selected articles related to advances in mechanisms of chronic allergic inflammation and asthma that appeared in 2007 in the Journal of Allergy and Clinical Immunology. Table I highlights several advances in gene association studies, mast cell biology, eosinophils, the inception of allergy, preclinical therapeutic targets, and virally induced asthma.

Table I.

Key advances in mechanisms of chronic allergic inflammation and asthma in 2007

	1. IL-13
	IL13 Gln allele is associated with late wheezing after RSV-induced bronchiolitis.1
	Increased IL-13 levels are seen in patients with EE.39
	2. Mast cells/basophils
	Non–IgE-dependent mast cell activation is induced by the calcium-binding protein S100A12 present in eosinophils and neutrophils.13
	Basophil expression of Syk correlates with basophil sensitivity to anti-IgE.26
	3. Viruses/atopy and development of asthma
	Wheeze at 5 years is associated with viral infections in the first year of life in early sensitized children (<2 years old).62
	4. Eosinophils
	Anti–IL-25 reduces eosinophilic inflammation and AHR in a mouse model.40
	Increased expression of FcγRII is seen on eosinophils after allergen challenge in asthmatic subjects experiencing a late asthmatic response.29

References

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29. 29Kanters D, ten Hove W, Luijk B, et al. Expression of activated FcγRII discriminates between multiple granulocyte-priming phenotypes in peripheral blood of allergic asthmatic subjects. J Allergy Clin Immunol. 2007;120:1073–1081. Abstract | Full Text | Full-Text PDF (311 KB) | CrossRef

30. 30Kwatia MA, Doyle CB, Cho W, et al. Combined activities of secretory phospholipases and eosinophil lysophospholipases induce pulmonary surfactant dysfunction by phospholipid hydrolysis. J Allergy Clin Immunol. 2007;119:838–847. Abstract | Full Text | Full-Text PDF (713 KB) | CrossRef

31. 31Munitz A, Levi-Schaffer F. Inhibitory receptors on eosinophils: a direct hit to a possible Achilles heel?. J Allergy Clin Immunol. 2007;119:1382–1387. Abstract | Full Text | Full-Text PDF (486 KB) | CrossRef

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Department of Medicine, University of California San Diego, La Jolla, Calif

Reprint requests: David Broide, MB, ChB, Department of Medicine, University of California San Diego, Biomedical Sciences Building, Room 5090, 9500 Gilman Dr, La Jolla, CA 92093-0635.

Disclosure of potential conflict of interest: D. Broide has consulting arrangements with Indoor Biotech, Allergen, and Amylin and has received research support from the National Institutes of Health, Immune Tolerance Network, and the Food Allergy and Anaphylaxis Network.

PII: S0091-6749(08)01174-3

doi:10.1016/j.jaci.2008.06.025

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