The Journal of Allergy and Clinical Immunology

Cover 1

2010-01-01

A Brief Overview of This Month's JACI

2010-01-01

Editorial Board

2010-01-01

Editor in Chief DONALD Y. M. LEUNG, MD, PhD Denver, Colo Deputy Editor STANLEY J. SZEFLER, MD Denver, Colo

Information for Readers

2010-01-01

Communications regarding original articles and editorial management should be addressed to Donald Y. M. Leung, MD, PhD, Editor in Chief, The Journal of Allergy and Clinical Immunology, National Jewish Medical and Research Center, 1400 Jackson St (J324), Denver, CO 80206; phone 303-398-1963; fax 303-270-2269.

Footnotes1

2010-01-01

This month, Eugenia Hahn, MD, FAAAAI, took time to answer a few questions. Hahn is Chair of the AAAAI's New Allergist/Immunologist Assembly (NAIA). In what ways has membership in the AAAAI benefitted you?Being an active member of the AAAAI keeps me connected to a community of allergists. Also, as developments in the field unfold, being a member helps me to stay current with new ideas, methods and recommendations. For example, the AAAAI Web site has kept me informed regarding pertinent H1N1 information, and a recent broadcast email to members alerted me to the availability of PRE-PEN®.

CME Activities Calendar

2010-01-01

▪ 2009 Virtual Annual Meeting: Unable to attend all of the sessions that you wanted to at the 2009 Annual Meeting? Couldn't make it to Washington, DC? Here is your chance to access the sessions you were not able to attend at your convenience. The 2009 Virtual Annual Meeting offers Webcasts and audio recordings of most Annual Meeting sessions. Earn over 129 CME or 150 CE credits! Credits will be offered until March 2011. For additional information or to place an order, visit annualmeeting.aaaai.org and select the link for “2009 Annual Meeting” from the Attendee tab. Funded through an educational grant from GlaxoSmithKline.

News Beyond Our Pages

Marc E. Rothenberg, Jean Bousquet — 2010-01-01

Gamble et al (Am J Respir Crit Care Med 2009;180:817-22) used pharmacy records to assess adherence with inhaled corticosteroid/long-acting β-agonist combination therapy in 182 patients referred to a difficult asthma clinic in Northern Ireland. Over the previous 6 months, 35% of the patients were found to have filled less than 50% of the medication prescriptions. Women were more apt to be nonadherent than men (42% vs 23%). Those less than 50% adherent had clinically meaningfully lower Asthma Quality of Life scores and were significantly more apt to have been hospitalized 3 or more times in the last year. When adherence to oral corticosteroids was assessed based on measurement of plasma prednisone and cortisol levels, 45% of the 51 patients were found to be nonadherent. Therefore before prescribing expensive therapy for patients with severe refractory asthma, be certain they are taking their prescribed controller therapy.

Recent insights into atopic dermatitis and implications for management of infectious complications

Mark Boguniewicz, Donald Y.M. Leung — 2010-01-01

Atopic dermatitis (AD) is a common complex disease that frequently follows a chronic relapsing course and affects the quality of life of patients and families in a significant manner. New insights into the pathophysiology of AD point to an important role of structural abnormalities in the epidermis combined with immune dysregulation. Patients with AD have a unique predisposition to colonization or infection by a number of microbial organisms, most notably Staphylococcus aureus and herpes simplex virus. A multipronged approach directed at healing or protecting the skin barrier and addressing the immune dysregulation is necessary to improve the likelihood of successful outcomes.

Recent insights into atopic dermatitis and implications for management of infectious complications

2010-01-01

An update on the genetics of atopic dermatitis: Scratching the surface in 2009

Kathleen C. Barnes — 2010-01-01

A genetic basis for atopic dermatitis (AD) has long been recognized. Historic documents allude to family history of disease as a risk factor. Before characterization of the human genome, heritability studies combined with family-based linkage studies supported the definition of AD as a complex trait in that interactions between genes and environmental factors and the interplay between multiple genes contribute to disease manifestation. A summary of more than 100 published reports on genetic association studies through mid-2009 implicates 81 genes, in 46 of which at least 1 positive association with AD has been demonstrated. Of these, the gene encoding filaggrin (FLG) has been most consistently replicated. Most candidate gene studies to date have focused on adaptive and innate immune response genes, but there is increasing interest in skin barrier dysfunction genes. This review examines the methods that have been used to identify susceptibility genes for AD and how the underlying pathology of this disease has been used to select candidate genes. Current challenges and the potential effect of new technologies are discussed.

An update on the genetics of atopic dermatitis: Scratching the surface in 2009

2010-01-01

Air filters and air cleaners: Rostrum by the American Academy of Allergy, Asthma & Immunology Indoor Allergen Committee

2009-11-12

The allergist is generally recognized as possessing the greatest expertise in relating airborne contaminants to respiratory health, both atopic and nonatopic. Consequently, allergists are most often asked for their professional opinions regarding the appropriate use of air-cleaning equipment. This rostrum serves as a resource for the allergist and other health care professionals seeking a better understanding of air filtration.

Secreted virulence factor comparison between methicillin-resistant and methicillin-sensitive Staphylococcus aureus, and its relevance to atopic dermatitis

2010-01-01

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains have emerged as serious health threats in the last 15 years. They are associated with large numbers of atopic dermatitis skin and soft tissue infections, but when they originate from skin and mucous membranes, have the capacity to produce sepsis and highly fatal pulmonary infections characterized as necrotizing pneumonia, purpura fulminans, and postviral toxic shock syndrome. This review is a discussion of the emergence of 3 major CA-MRSA organisms, designated CA-MRSA USA400, followed by USA300, and most recently USA200. CA-MRSA USA300 and USA400 isolates and their methicillin-sensitive counterparts (community-associated methicillin-sensitive S aureus) typically produce highly inflammatory cytolysins α-toxin, γ-toxin, δ-toxin (as representative of the phenol soluble modulin family of cytolysins), and Panton Valentine leukocidin. USA300 isolates produce the superantigens enterotoxin-like Q and a highly pyrogenic deletion variant of toxic shock syndrome toxin 1 (TSST-1), whereas USA400 isolates produce the superantigens staphylococcal enterotoxin B or staphylococcal enterotoxin C. USA200 CA-MRSA isolates produce small amounts of cytolysins but produce high levels of TSST-1. In contrast, their methicillin-sensitive S aureus counterparts produce various cytolysins, apparently in part dependent on the niche occupied in the host and levels of TSST-1 expressed. Significant differences seen in production of secreted virulence factors by CA-MRSA versus hospital-associated methicillin-resistant S aureus and community-associated methicillin-sensitive S aureus strains appear to be a result of the need to specialize as the result of energy drains from both virulence factor production and methicillin resistance.

Dendritic cells: Bridging innate and adaptive immunity in atopic dermatitis

Natalija Novak, Susanne Koch, Jean-Pierre Allam, Thomas Bieber — 2010-01-01

Much knowledge has been gained about the multifaceted functions of dendritic cells (DCs). The central role of various DC subtypes as bridges between innate and adaptive immunity has become more and more evident. However, a high number of differences exist in the expression of pattern-recognition receptors, the first sensors of the innate immune system, in particular Toll-like receptors (TLRs) by distinct DC subtypes (including myeloid and plasmacytoid DCs), their maturation stage, and tissue distribution, as well as state of health or disease. Furthermore, a plethora of variations in human and murine model systems have to be considered. This review sheds some light on this complex and rapidly growing field. It summarizes the most recent findings and deals with the role of TLR-expressing DCs as promoters of chronic inflammatory immune responses in patients with atopic dermatitis, as well as tolerogenic pathways. Therefore TLR-bearing DCs represent promising targets, which might help to improve tolerance induction during immunotherapeutic approaches in the future.

Natural killer cells in atopic and autoimmune diseases of the skin

2010-01-01

Natural killer (NK) cells are best known for their ability to recognize and kill tumor cells and virally infected cells and for their ability to produce large amounts of some cytokines, such as IFN-γ. Recent research has substantially expanded our view on the function of NK cells in the immune system in health and disease. In addition to the better-studied functions in cancer and autoimmunity, contributions from NK cells to allergies and various skin diseases have emerged. We briefly recount the traditional NK cell functions before focusing on their roles in atopic dermatitis, psoriasis, alopecia areata, and pemphigus vulgaris. Although this field is still developing, strong data are available that indicate NK cell involvement. In patients with allergic diseases, the production of TH2 cytokines by NK cells contributes to the known immune deviation. In patients with psoriasis, their pathophysiologic role seems to be especially the production of IFN-γ. NK cell overactivation can be found in patients with alopecia areata and pemphigus vulgaris. Many details are still unclear; however, we believe that there is solid evidence that NK cells actively participate in a number of diseases that have not been traditionally linked to this type of lymphocyte.

Advances in pediatric asthma in 2009: Gaining control of childhood asthma

Stanley J. Szefler — 2010-01-01

This year's summary will focus on recent advances in pediatric asthma as reported in Journal of Allergy and Clinical Immunology publications in 2009. New National Asthma Education and Prevention Program asthma guidelines were released in 2007, with a particular emphasis on asthma control. Now that we have worked with the principals of the guidelines for 2 years, new insights are reported on how to implement the guidelines into clinical practice. This year's report will focus on gaps in management that need to be addressed, including health disparities, methods to improve asthma management through opportunities available in school-based asthma programs, and more information on the development of asthma in childhood. This information brings us closer to the point of managing children with controllable asthma and understanding reasons why asthma is not controlled in the remaining children. If we can close these gaps through better communication, improvements in the health care system, and new insights into treatment, we will move closer to better methods to intervene early in the course of the disease and induce clinical remission as quickly as possible in most children.

Advances in adult asthma diagnosis and treatment in 2009

Andrea J. Apter — 2010-01-01

There is a growing need to standardize and validate outcomes for asthma research. In this review of asthma-related publications from the Journal in 2009, efforts to standardize methodology and reporting of translational research, the influence of the environment, therapeutics, and management of asthma are highlighted.

Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2009

Scott H. Sicherer, Donald Y.M. Leung — 2010-01-01

This review highlights some of the research advances in anaphylaxis and hypersensitivity reactions to foods, drugs, and insects, as well as advances in allergic skin disease that were reported in the Journal in 2009. Among key epidemiologic observations, several westernized countries report that more than 1% of children have peanut allergy, and there is some evidence that environmental exposure to peanut is a risk factor. The role of regulatory T cells, complement, platelet-activating factor, and effector cells in the development and expression of food allergy were explored in several murine models and human studies. Delayed anaphylaxis to mammalian meats appears to be related to IgE binding to the carbohydrate moiety galactose-α-1,3-galactose, which also has implications for hypersensitivity to murine mAb therapeutics containing this oligosaccharide. Oral immunotherapy studies continue to show promise for the treatment of food allergy, but determining whether the treatment causes tolerance (cure) or temporary desensitization remains to be explored. Increased baseline serum tryptase levels might inform the risk of venom anaphylaxis and might indicate a risk for mast cell disorders in persons who have experienced such episodes. Reduced structural and immune barrier function contribute to local and systemic allergen sensitization in patients with atopic dermatitis, as well as increased propensity of skin infections in these patients. The use of increased doses of nonsedating antihistamines and potential usefulness of omalizumab for chronic urticaria was highlighted. These exciting advances reported in the Journal can improve patient care today and provide insights on how we can improve the diagnosis and treatment of these allergic diseases in the future.

The Editors' Choice

Donald Y.M. Leung, Stanley J. Szefler, Associate Editors of the JACI — 2010-01-01

Seasonal allergic rhinitis affects 20% to 25% of the populations of Europe and the United States and has a considerable influence on quality of life in addition to being an independent risk factor for asthma. Specific immunotherapy is the only treatment modality with the potential to modify the course of this disease and provide sustained efficacy in post-treatment years. In a study by Durham et al (p 131), the sustained efficacy after a 3-year period with grass allergy immunotherapy tablet treatment was evaluated 1 year after completion of treatment. Statistically significant and clinically relevant differences in the primary end points in comparison with placebo were found at the 1-year follow-up (see Figure). Significant improvements in quality of life were also reported, both during treatment and during follow-up. No safety issues were identified, the most frequent adverse events being mild local reactions lasting some minutes after tablet intake. This is the first time that disease modification by means of sublingual immunotherapy has been shown in a large-scale, randomized, placebo-controlled trial. The results support allergy tablet immunotherapy as an option in those patients with hay fever whose symptoms remain uncontrolled with symptomatic medications. The observed long-term benefits raise the question of whether the treatment should be considered earlier in the course of the disease.

Ascaris, atopy, and exercise-induced bronchoconstriction in rural and urban South African children

James Calvert, Peter Burney — 2009-12-07

Background: Populations with endemic parasitosis have high levels of IgE but low levels of allergic disease. We investigated the association between infection with the parasite Ascaris allergic sensitization, and exercise-induced bronchospasm (EIB).Objective: We sought to investigate the effect of Ascaris infection on bronchial hyperreactivity, skin testing, and specific IgE levels.Methods: A cross-sectional prevalence survey was conducted in urban and rural South African children to measure levels of EIB. A sample of children was enrolled in a nested case-control study for further investigation based on response to exercise. Analyses used weighted logistic regression.Results: Geometric mean total IgE levels were higher in Ascaris –infected subjects (infected subjects: 451 IU (95% CI, 356-572) vs uninfected subjects: 344 IU (95% CI, 271-437), P = .04), and high levels of total IgE were positively associated with detection of specific IgE to the aeroallergens tested, but there was no significant association between Ascaris infection and titers of specific IgE. Ascaris infection was associated with a decreased risk of a positive skin test response (odds ratio, 0.63; 95% CI, 0.42–0.94; P = .03) but an increased risk of EIB (odds ratio, 1.62; 95% CI, 1.23-2.11; P = .001).Conclusion: In areas of high parasite endemicity, Ascaris might induce an inflammatory response in the lungs independent of its effect on IgE production. This could explain some of the contradictory findings seen in studies examining the association between geohelminth infection, atopy, and asthma.

Differences in asthma between rural and urban communities in South Africa and other developing countries

Thomas A.E. Platts-Mills, Philip J. Cooper — 2010-01-01

Studies on wheezing or asthma in Africa have consistently shown low levels in the villages and increasing prevalence with urbanization. In many of those studies, the authors focused on differences in helminth infection to explain the changes in the prevalence of wheezing. The arguments for this approach are that infestation is common, helminths are known to induce IgE responses, and children in rural Africa generally have high total serum IgE levels despite a low prevalence of allergic symptoms. In contrast, helminths might be less common in many towns because of greater access to sanitation and anthelmintic drugs.

Cord blood cytokines are modulated by maternal farming activities and consumption of farm dairy products during pregnancy: The PASTURE Study

2009-12-07

Background: Traditional farming represents a unique model situation to investigate the relationship of early-life farm-related exposure and allergy protection.Objectives: To investigate associations between maternal farm exposures and cytokine production in cord blood (CB) mononuclear cells in a prospective multinational birth cohort of 299 farm and 326 nonfarm children and their families.Methods: Supernatants from phorbol 12-myristate 13-acetate/ionomycin–stimulated CB mononuclear cells were assessed for the production of IFN-γ, TNF-α, IL-5, IL-10, and IL-12.Results: Significantly higher levels of IFN-γ and TNF-α in farm compared with nonfarm children were found, whereas IL-5, IL-10, and IL-12 levels did not differ between study groups. Maternal contact with different farm animal species and barns and consumption of farm-produced butter during pregnancy enhanced the production of proinflammatory CB cytokines, whereas maternal consumption of farm-produced yogurt resulted in significant lower levels of IFN-γ and TNF-α in umbilical blood.Conclusion: Maternal exposure to farming activities and farm dairy products during pregnancy modulated cytokine production patterns of offspring at birth.

Lower cortisol levels in children with asthma exposed to recurrent maternal distress from birth

2009-12-07

Background: Existing evidence supports associations between exposure to maternal distress and the development of childhood asthma, between exposure to maternal distress and an increased cortisol response in children, and between childhood asthma and an attenuated cortisol response.Objective: To investigate the association between children's cortisol levels and the combined predictors of exposure to maternal distress and childhood asthma.Methods: Serum cortisol levels were examined at age 7 to 10 years in relation to asthma status and exposure to maternal distress in a representative sample of children (n = 503) born in 1995. Data from health care and prescription databases were linked with additional data collected in this longitudinal study. Maternal distress was defined as a physician diagnosis of a depressive or anxiety disorder or a prescription history of related medications as reported in the mothers' health care records. Children's asthma status was determined via examination by 2 pediatric allergists.Results: A multiple linear regression analysis revealed that exposure to maternal distress restricted to the first year of life predicted elevated cortisol levels in children, regardless of asthma status (>40% increase). A significant interaction was discovered in the group of children exposed to maternal distress extending beyond the postnatal period such that no asthma predicted a 25.9% increase in cortisol and a diagnosis of asthma predicted a 5.2% decrease in cortisol. Cortisol levels were further lowered in atopic and bronchial hyperresponsive asthma.Conclusion: Among children exposed to recurrent maternal distress, an elevation in cortisol levels occurs in response to an acute stressor when there is no accompanying diagnosis of asthma, whereas, in comparison, children with asthma tend to exhibit lower cortisol levels.

Trichuris suis ova therapy for allergic rhinitis: A randomized, double-blind, placebo-controlled clinical trial

2009-10-05

Background: Parasitic helminth infections can protect against allergic airway inflammation in experimental models and have been associated with a reduced risk of atopy and a reduced course of asthma in some observational studies. Although no clinical evidence exists to support the use of helminth therapy for allergic disease, the helminth Trichuris suis has demonstrated efficacy in treatment of inflammatory bowel disease.Objective: To determine efficacy of helminth therapy for allergic rhinitis.Methods: We conducted a double-blind, placebo-controlled, parallel group trial in which 100 subjects age 18 to 65 years with grass pollen–induced allergic rhinitis were randomly assigned to ingest a total of 8 doses with 2500 live T suis ova or placebo with an interval of 21 days. The primary outcome was a change in mean daily total symptom score for runny, itchy, sneezing nose (maximum change, 9.0) or in percentage of well days during the grass pollen season.Results: Treatment with T suis ova (N = 49) compared with placebo (N = 47) caused transient diarrhea peaking at day 41 in 33% of participants (placebo, 2%), and increased eosinophil counts (P < .001) and T suis–specific IgE (P < .05), IgG (P < .001), IgG4 (P < .003), and IgA (P < .001), whereas there was no significant change in symptom scores (0.0; 95% CI, –0.5 to 0.4; P = .87), well days (3%; 95% CI, –9% to 14%; P = .63), total histamine (P = .44), grass-specific IgE (P = .76), or diameter of wheal reaction on skin prick testing with grass (P = .85) or 9 other allergens.Conclusion: Repeated treatment with the helminth T suis induced a substantial clinical and immunologic response as evidence of infection, but had no therapeutic effect on allergic rhinitis.

Long-term clinical efficacy in grass pollen–induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet

2010-01-01

Background: Sustained and disease-modifying effects of sublingual immunotherapy have never before been confirmed in a large-scale randomized, double-blind, placebo-controlled trial.Objective: We sought to investigate sustained efficacy 1 year after a 3-year period of daily treatment with the SQ-standardized grass allergy immunotherapy tablet Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU; ALK-Abelló, Hørsholm, Denmark).Methods: A randomized, double-blind, placebo-controlled, phase III trial including adults with a history of moderate-to-severe grass pollen induced rhinoconjunctivitis inadequately controlled by symptomatic medications. The analysis set comprised 257 subjects at the follow-up. Efficacy end points were rhinoconjunctivitis symptom and medication scores, quality of life, and percentages of symptom and medication free days. Immunologic end points included grass pollen–specific serum IgG4 and IgE-blocking factor. Safety was assessed based on adverse events.Results: Significant improvements in efficacy were consistently shown during 3 years' treatment. One year after treatment, the active group showed sustained reductions in mean rhinoconjunctivitis symptom scores (26%, P < .001) and medication scores (29%, P = .022) when compared with placebo. This level was similar to the efficacy observed during the 3-year treatment period. The differences in percentages of symptom- and medication-free days were significant during and 1 year after treatment. The active group also reported sustained and significant improvements in quality of life. Sustained clinical benefit was accompanied by immunologic changes. No safety issues were identified.Conclusion: Three years of treatment with the SQ-standardized grass allergy immunotherapy tablet resulted in consistent clinical improvement and accompanying immunologic changes that were sustained 1 year after treatment, which is indicative of disease modification and associated long-term benefits.

Evidence for the involvement of free light chain immunoglobulins in allergic and nonallergic rhinitis

2009-10-09

Background: Allergic rhinitis is characterized by mast cell degranulation induced by antigen cross-linking of IgE. It has been proposed that some patients with rhinitis show nasal allergy in the absence of systemic markers of atopy, termed entopy. Recent murine studies suggest the existence of an IgE-independent hypersensitivity response involving antigen-induced mast cell activation, mediated by immunoglobulin free light chains (FLCs).Objectives: To determine whether FLC is associated with mast cell–mediated nasal hypersensitivity and its relationship with eosinophilic activity in allergic and nonatopic rhinitis.Methods: Patients with allergy and nonallergic rhinitis with eosinophilia syndrome (NARES) had levels of soluble FLC measured in nasal secretions and serum. In addition, levels of the nasal inflammatory mediators mast cell tryptase and eosinophil cationic protein were quantified. Cellular expression of κ and λ FLC was characterized in the nasal mucosa of allergic and nonatopic idiopathic rhinitis and control subjects by using immunohistochemistry. Immunopositive cells were phenotyped by using laser microdissection and PCR.Results: Free light chain was significantly increased in nasal secretions of subjects with allergy and NARES, and in serum of patients with NARES. Nonatopic patients with allergy showed significantly increased nasal mast cell tryptase and eosinophil cationic protein. FLC-positive cells were significantly increased in allergic and nonatopic mucosa, and were shown to be mast cells and plasma cells.Conclusion: Nasal FLC is significantly increased in allergic and nonatopic rhinitis nasal mucosa, suggesting a role in nasal hypersensitivity. Further studies are needed to identify which allergens trigger FLC-mediated responses in nonatopic rhinitis.

Infected atopic dermatitis lesions contain pharmacologic amounts of lipoteichoic acid

2009-12-07

Background: Bacterial infection with Staphylococcus aureus is a known trigger for worsening of atopic dermatitis (AD); the exact mechanisms by which bacterial infection worsens dermatitis are unknown.Objective: We sought to characterize the amounts of the biologically active bacterial lipoprotein lipoteichoic acid (LTA) in infected AD lesions.Methods: Eighty-nine children with clinically impetiginized lesions of AD were enrolled in this study. A lesion was graded clinically by using the Eczema Area and Severity Index (EASI), wash fluid obtained from the lesion for quantitative bacterial culture, and measurement of LTA and cytokines. The staphylococcal isolate was tested for antibiotic susceptibilities. The patients were treated with a regimen that included topical corticosteroids and systemic antibiotics, and the lesion was reanalyzed after 2 weeks.Results: S aureus was identified in 79 of 89 children enrolled in the study. The bacterial colony-forming unit (CFU) counts correlated with the EASI lesional score (P = .04). LTA levels as high as 9.8 μg/mL were measured in the wash fluid samples, and the amounts correlated with the lesional EASI scores (P = .01) and S aureus CFU (P < .001). Approximately 30% of clinically impetiginized AD lesions contained greater than 1 μg/mL LTA, amounts that exert effects on various cell types in vitro. Moreover, injection of skin tissue ex vivo with amounts of LTA found in AD lesions resulted in epidermal cytokine gene expression.Conclusion: Pharmacologic levels of LTA are found in many infected atopic dermatitis lesions.

Vaccinia virus–specific molecular signature in atopic dermatitis skin

2010-01-01

Background: Eczema vaccinatum (EV), a disseminated viral skin infection, is a life-threatening complication of vaccinia virus (VV) inoculation in patients with atopic dermatitis (AD) and is thought to be associated with a defective innate immune response. However, the precise mechanism or mechanisms and key factor or factors of EV are unknown.Objective: Given that patients with psoriasis, another inflammatory skin disorder, are not susceptible to EV, we compared the global transcriptional response of skin to VV in healthy subjects, patients with psoriasis, and patients with AD, focusing on AD-specific genes. We hypothesized that differences in the transcriptional response to VV between patients with AD and patients with psoriasis or healthy subjects would identify a defective pathway or pathways that might be associated with the development of EV.Methods: Gene expression profiling of sham-treated and VV-treated unaffected skin explants from patients with AD (n = 12), patients with psoriasis (n = 12), or healthy subjects (n = 13) were generated with U133_Plus2 (54,613 probe sets) GeneChips and analyzed with the GCOS_1.4/SAM_2.1/MAPPFinder_2.0 pipeline.Results: Sixty-seven genes were significantly affected by VV in AD skin but not in psoriatic and healthy skin. Genes associated with defense response, response to wounding, and immune response were the most affected by VV in AD skin. All genes in these ontologies were downregulated, including the innate immunity genes leukotriene B4 receptor (LTB4R), orosomucoid 1 (ORM1), coagulation factor II (thrombin) receptor (F2R), complement component 9 (C9), and LPS-binding protein (LBP). These findings were confirmed by means of real-time PCR and validated by means of PubMatrix analysis. ORM1, Toll-like receptor 4 (TLR4), and NLR family pyrin domain containing 1 (NLRP1) genes were also linked to AD severity.Conclusion: This study identified groups of innate immunity genes that are associated with the aberrant response of AD skin to VV and represent potential targets for EV pathogenesis.

Murine atopic dermatitis responds to peroxisome proliferator-activated receptors α and β/δ (but not γ) and liver X receptor activators

2009-10-09

Background: Atopic dermatitis (AD) is a chronic inflammatory dermatosis now increasingly linked to mutations that alter the structure and function of the stratum corneum. Activators of peroxisome proliferator-activated receptors (PPARs) α, β/δ, and γ and liver X receptor (LXR) regulate epidermal protein and lipid production, leading to superior barrier function. Additionally, some of these activators exhibit potent antihyperplastic and anti-inflammatory activity in irritant contact dermatitis and acute allergic contact dermatitis murine models.Objective: We evaluated the efficacy of PPAR/LXR activation in a hapten (oxazolone [Ox])–induced AD-like model (Ox-AD) in hairless mice.Methods: Ox-AD was established with 10 Ox challenges (every other day) on the flank. After the establishment of Ox-AD, twice-daily topical application with individual PPAR/LXR activators was then performed for 4 days, with continued Ox challenges every other day. The efficacy of topical PPAR/LXR activators to reduce parameters of Ox-AD was assessed physiologically, morphologically, and immunologically.Results: Certain topical activators of PPARα, PPARβ/δ, and LXR, but not activators of PPARγ, reversed the clinical dermatosis, significantly improved barrier function, and increased stratum corneum hydration in Ox-AD mice. In addition, the same activators, but again not PPARγ, largely reversed the immunologic abnormalities in Ox-AD mice, including the increased TH2 markers, such as tissue eosinophil/mast cell density, serum thymus and activation-related chemokine levels, the density of chemoattractant receptor–homologous molecule expressed on TH2-positive lymphocytes (but not serum IgE levels), and reduced IL-1α and TNF-α activation, despite ongoing hapten challenges.Conclusion: These results suggest that topical applications of certain activators/ligands of PPARα, PPARβ/δ, and LXR could be useful for the treatment of AD in human subjects.

Chromosome 11q13.5 variant associated with childhood eczema: An effect supplementary to filaggrin mutations

2010-01-01

Background: Atopic eczema is a common inflammatory skin disease with multifactorial etiology. The genetic basis is incompletely understood; however, loss of function mutations in the filaggrin gene (FLG) are the most significant and widely replicated genetic risk factor reported to date. The first genome-wide association study in atopic eczema recently identified 2 novel genetic variants in association with eczema susceptibility: a single nucleotide polymorphism on chromosome 11q13.5 (rs7927894) and a single nucleotide polymorphism (rs877776) within the gene encoding hornerin on chromosome 1q21.Objective: To test the association of these 2 novel variants with pediatric eczema and to investigate their interaction with FLG null mutations.Methods: Case-control study to investigate the association of rs7927894, rs877776 and the 4 most prevalent FLG null mutations with moderate-severe eczema in 511 Irish pediatric cases and 1000 Irish controls. Comprehensive testing for interaction between each of the loci was also performed.Results: The association between rs7927894 and atopic eczema was replicated in this population (P = .0025, χ2 test; odds ratio, 1.27; 95% CI, 1.09-1.49). The 4 most common FLG null variants were strongly associated with atopic eczema (P = 1.26 × 10−50; combined odds ratio, 5.81; 95% CI, 4.51-7.49). Interestingly, the rs7927894 association was independent of the well-established FLG risk alleles and may be multiplicative in its effect. There was no significant association between rs877776 and pediatric eczema in this study.Conclusion: Single nucleotide polymorphism rs7927894 appears to mark a genuine eczema susceptibility locus that will require further elucidation through fine mapping and functional analysis.

Glycation of a food allergen by the Maillard reaction enhances its T-cell immunogenicity: Role of macrophage scavenger receptor class A type I and II

2009-10-28

Background: The Maillard reaction occurs between reducing sugars and proteins during thermal processing of foods. It produces chemically glycated proteins termed advanced glycation end products (AGEs). The glycation structures of AGEs are suggested to function as pathogenesis-related immune epitopes in food allergy.Objective: This study aimed at defining the T-cell immunogenicity of food AGEs by using ovalbumin (OVA) as a model allergen.Methods: AGE-OVA was prepared by means of thermal processing of OVA in the presence of glucose. Activation of OVA-specific CD4+ T cells by AGE-OVA was evaluated in cocultures with bone marrow–derived murine myeloid dendritic cells (mDCs) as antigen-presenting cells. The uptake mechanisms of mDCs for AGE-OVA were investigated by using inhibitors of putative cell-surface receptors for AGEs, as well as mDCs deficient for these receptors.Results: Compared with the controls (native OVA and OVA thermally processed without glucose), AGE-OVA enhanced the activation of OVA-specific CD4+ T cells on coculture with mDCs, indicating that the glycation of OVA enhanced the T-cell immunogenicity of the allergen. The mDC uptake of AGE-OVA was significantly higher than that of the controls. We identified scavenger receptor class A type I and II (SR-AI/II) as a mediator of the AGE-OVA uptake, whereas the receptor for AGEs and galectin-3 were not responsible. Importantly, the activation of OVA-specific CD4+ T cells by AGE-OVA was attenuated on coculture with SR-AI/II–deficient mDCs.Conclusion: SR-AI/II targets AGE-OVA to the MHC class II loading pathway in mDCs, leading to an enhanced CD4+ T-cell activation. The Maillard reaction might thus play an important role in the T-cell immunogenicity of food allergens.

Reassessing the role of hyaluronidase in yellow jacket venom allergy

2009-11-12

Background: Yellow jacket hyaluronidase (YJ-HYA) is considered a major allergen in yellow jacket allergy. It shows 50% homology with the hyaluronidase from honeybee venom, Api m 2. Recently, IgE binding to YJ-HYA and cross-reactivity with Api m 2 has been shown to be due to cross-reactive carbohydrate determinants (CCDs).Objective: We sought to quantify the importance of YJ-HYA in yellow jacket allergy and the cross-reactivity with Api m 2 by discriminating between carbohydrate and peptide epitopes.Methods: IgE binding to Vespula species venom was studied by means of Western blotting in 136 patients with yellow jacket allergy (31 in vitro single positive to yellow jacket venom and 105 in vitro double-positive to yellow jacket-honeybee). Inhibition studies were carried out with MUXF-BSA (isolated bromelain glycopeptides linked to bovine serum albumin) and purified Api m 2.Results: Among yellow jacket single-positive sera, only 1 of 31 bound with YJ-HYA, whereas this was the case in 87% of 105 double-positive sera. Of 83 patients in whom inhibitions were performed, 65% reacted with hyaluronidase through CCDs alone, 27% reacted with both CCDs and peptide epitopes, and 8% reacted only with the hyaluronidase peptide. The protein-specific reactivity with YJ-HYA was cross-inhibited by Api m 2 in 48% (14/29). Antigen 5 and phospholipase A1 were each recognized by around 90% of sera from both groups, together identifying 97% of patients.Conclusion: Hyaluronidase is a minor yellow jacket venom allergen, and only 10% to 15% of patients with yellow jacket allergy are estimated to have IgE against the hyaluronidase protein. Peptide-specific cross-reactivity with Api m 2 occurs in half of these sera. Component-resolved diagnosis with antigen 5 and phospholipase would detect virtually all patients with yellow jacket venom allergy.

Allergy or tolerance in children sensitized to peanut: Prevalence and differentiation using component-resolved diagnostics

2010-01-01

Background: Not all peanut-sensitized children develop allergic reactions on exposure.Objective: To establish by oral food challenge the proportion of children with clinical peanut allergy among those considered peanut-sensitized by using skin prick tests and/or IgE measurement, and to investigate whether component-resolved diagnostics using microarray could differentiate peanut allergy from tolerance.Methods: Within a population-based birth cohort, we ascertained peanut sensitization by skin tests and IgE measurement at age 8 years. Among sensitized children, we determined peanut allergy versus tolerance by oral food challenges. We used open challenge among children consuming peanuts (n = 45); others underwent double-blind placebo-controlled challenge (n = 34). We compared sensitization profiles between children with peanut allergy and peanut-tolerant children by using a microarray with 12 pure components (major peanut and potentially cross-reactive components, including grass allergens).Results: Of 933 children, 110 (11.8%) were peanut-sensitized. Nineteen were not challenged (17 no consent). Twelve with a convincing history of reactions on exposure, IgE ≥15 kUa/L and/or skin test ≥8mm were considered allergic without challenge. Of the remaining 79 children who underwent challenge, 7 had ≥2 objective signs and were designated as having peanut allergy. We estimated the prevalence of clinical peanut allergy among sensitized subjects as 22.4% (95% CI, 14.8% to 32.3%). By using component-resolved diagnostics, we detected marked differences in the pattern of component recognition between children with peanut allergy (n = 29; group enriched with 12 children with allergy) and peanut-tolerant children (n = 52). The peanut component Ara h 2 was the most important predictor of clinical allergy.Conclusion: The majority of children considered peanut-sensitized on the basis of standard tests do not have peanut allergy. Component-resolved diagnostics may facilitate the diagnosis of peanut allergy.

Hepatitis A virus antibodies in immunoglobulin preparations

2009-12-07

Background: Persons with primary immune deficiency receive intravenous immunoglobulin (IVIG) as antibody replacement therapy. These patients depend on the presence of protective antibody levels against circulating pathogens in IVIG.Objectives: The incidence of hepatitis A virus (HAV) infections has been decreasing globally.We investigated whether this decrease in HAV incidence is reflected in human plasma pools and evaluated whether HAV antibody titers in IVIG preparations are still adequate for antibody replacement.Methods: By using ELISA, the HAV antibody titer of 3,953 plasma pools sourced from March 2003 through September 2008 in the European Union (EU) or United States (US) and of 169 IVIG lots manufactured from 2005 through 2007 was determined. The functionality of the HAV antibodies contained in IVIG was assessed by using a microneutralization assay.Results: The results confirm a decrease in HAV antibody titers in EU (−28%) and US (−41%) plasma. Furthermore, the mean HAV antibody content in EU (1.70 ± 0.12 IU/mL) and US (0.82 ± 0.09 IU/mL [mean ± SEM]) plasma was significantly different (P = .0001). A significant difference (P < .0001) was also evident in the IVIG preparations KIOVIG (22.91 ± 0.68 IU/mL) and Gammagard Liquid (14.60 ± 0.48 IU/mL), respectively, made from EU or US plasma. In accordance with the ELISA results, there was a significant difference (P < .0001) in HAV neutralization titer 50% (NT50) values between IVIG produced from EU-sourced (2,477 ± 265 NT50 [1:X]) or US-sourced (844 ± 82 NT50 [1:X]) plasma.Conclusion: Although HAV antibody seroprevalence continues to decrease in Europe and the US, HAV antibody titers in IVIG lots appear to remain adequate for antibody replacement therapy.

Lymphocyte subsets in healthy Malawians: Implications for immunologic assessment of HIV infection in Africa

2009-11-30

Background: CD4+T lymphocyte measurements are the most important indicator of mortality in HIV-infected individuals in resource-limited settings. There is currently a lack of comprehensive immunophenotyping data from African populations to guide the immunologic assessment of HIV infection.Objective: To quantify variation in absolute and relative lymphocyte subsets with age in healthy Malawians.Methods: Lymphocyte subsets in peripheral blood of 539 healthy HIV-uninfected Malawians stratified by age were enumerated by flow cytometry.Results: B and T–lymphocyte and T-lymphocyte subset absolute concentrations peaked in early childhood then decreased to adult levels, whereas lymphocyte subset proportions demonstrated much less variation with age. Adult lymphocyte subsets were similar to those in developed countries. In contrast, high B-lymphocyte and CD8+T-lymphocyte levels among children under 2 years, relative to those in developed countries, resulted in low CD4+T-lymphocyte percentages that varied little between 0 and 5 years (35% to 39%). The CD4+T-lymphocyte percentages in 35% of healthy children under 1 year and 18% of children age 1 to 3 years were below the World Health Organization threshold defining immunodeficiency in HIV-infected children in resource-limited settings. Thirteen percent of healthy children under 18 months old had a CD4:CD8T-lymphocyte ratio <1.0, which is commonly associated with HIV infection. All immunologic parameters except absolute natural killer lymphocyte concentration varied significantly with age, and percentage and overall absolute CD4+T-lymphocyte counts were higher in females than males.Conclusion: Although lymphocyte subsets in Malawian adults are similar to those from developed countries, CD4+T-lymphocyte percentages in young children are comparatively low. These findings need to be considered when assessing the severity of HIV-related immunodeficiency in African children under 3 years.

Defect of regulatory T cells in patients with Omenn syndrome

2010-01-01

Background: Omenn syndrome (OS) is an autosomal-recessive disorder characterized by severe immunodeficiency and T-cell–mediated autoimmunity. The disease is caused by hypomorphic mutations in recombination-activating genes that hamper the process of Variable (V) Diversity (D) Joining (J) recombination, leading to the generation of autoreactive T cells. We have previously shown that in OS the expression of autoimmune regulator, a key factor governing central tolerance, is markedly reduced.Objective: Here, we have addressed the role of peripheral tolerance in the disease pathogenesis.Methods: We have analyzed forkhead box protein P3 (FOXP3) expression in peripheral blood T cells of 4 patients with OS and in lymphoid organs of 8 patients with OS and have tested the suppressive activity of sorted CD4+ CD25high peripheral blood T cells in 2 of these patients.Results: We have observed that CD4+CD25highT cells isolated ex vivo from patients with OS failed to suppress proliferation of autologous or allogenic CD4+ responder T cells. Moreover, despite individual variability in the fraction of circulating FOXP3+ CD4 cells in patients with OS, the immunohistochemical analysis of FOXP3 expression in lymph nodes and thymus of patients with OS demonstrated a severe reduction of this cell subset compared with control tissues.Conclusion: Overall, these results suggest a defect of regulatory T cells in OS leading to a breakdown of peripheral tolerance, which may actively concur to the development of autoimmune manifestations in the disease.

Increased risk of serious pneumococcal disease in patients with atopic conditions other than asthma

2010-01-01

Background: We reported an increased risk of serious pneumococcal disease (SPD) among patients with asthma. It is not known whether this is true for patients with other atopic conditions.Objective: To determine the relationship between atopic conditions other than asthma and SPD.Methods: The study subjects were residents of Rochester, Minn, who developed SPD between 1964 and 1983 and their 2 sex-matched and age-matched controls. We used a population-based computer-linked medical diagnosis system to identify all individuals with potential SPD. All records were reviewed by using explicit predetermined criteria for SPD. All individuals with atopic conditions were identified by the physician diagnoses including atopic dermatitis or eczema, allergic rhinitis, and hay fever documented in medical records. The associations between these atopic conditions and SPD were assessed by using conditional logistic regression.Results: A total of 3941 records were reviewed, and we identified 174 SPD cases. Of these 174 cases, 50.6% were male, and 94.3% were Caucasian. Twenty-six (14.9%) of the SPD cases and 29 (8.3%) of the controls had atopy. Atopic conditions other than asthma were associated with an increased risk of SPD (odds ratio, 2.13; 95% CI, 1.04-4.35; P = .04) after adjusting for smoking status, previous high-risk conditions for SPD, educational status, and ethnicity.Conclusion: Like asthma, other atopic conditions, particularly atopic dermatitis, are associated with an increased risk of SPD. There may be a common immunogenetic mechanism underlying increased risk of SPD among individuals with either asthma or other atopic conditions. Our study findings need to be studied further.

Identification of a novel subset of human circulating memory CD4+ T cells that produce both IL-17A and IL-4

2010-01-01

Background: IL-17A has been suggested to play a pathogenic role in bronchial asthma and other allergic disorders.Objective: Study of the relationship between human IL-17A–producing CD4+ TH cells (TH17) and IL-4–producing CD4+ TH (TH2) cells.Methods: T-cell clones generated from the CCR6+CD161+ fraction of human circulating CD4+ T cells, which contains virtually all TH17 cells, as well as circulating CD4+ T cells from both healthy subjects and patients with asthma, were assessed by flow cytometry for their cytokine production profile.Results: A small proportion of CCR6+CD161+CD4+ T-cell clones showed the ability to produce both IL-17A and IL-4 (TH17/TH2). TH17/TH2 clones also produced IL-5, IL-8, IL-9, IL-13, IL-21, and IL-22 and displayed the ability to induce the in vitro secretion of IgE. A very few TH17/TH2 cells were found among circulating CD4+ T cells from normal subjects, but their proportions were significantly increased in the circulation of patients with chronic asthma. TH17/TH2 cells could not be derived from naive umbilical cord blood CD4+ T cells under any experimental condition. However, when circulating memory CCR6+CD161+CD4+ T cells were cloned under appropriate polarizing conditions, TH17/TH2 clones originated in the presence of IL-4, suggesting that an IL-4–rich microenvironment may induce the shifting of memory TH17 cells into TH17/TH2 cells.Conclusion: Because of its peculiar functional properties and the increased numbers in the circulation of patients with bronchial asthma, this previously unknown population of TH17/TH2 cells may play some role in the pathogenesis of this disease.

Host-microbial interactions in childhood atopy: Toll-like receptor 4 (TLR4), CD14, and fecal Escherichia coli

2010-01-01

Background: Perturbations in the gut microbiota have been linked to atopic diseases. However, the development of atopic diseases depends not only on environmental factors (like microbial stimulation) but also on genetic factors. It is likely that particularly gene-environmental interactions in early life determine the development of atopy.Objective: We examine the interaction between detection of fecal Escherichia coli and genetic variations in the CD14 and Toll-like receptor 4 (TLR4) genes in relation to atopic manifestations.Methods: Within the Child, Parent and Health: Lifestyle and Genetic Constitution (KOALA) Birth Cohort Study, fecal samples of 957 one-month-old infants were collected and quantitatively screened for E coli. Fourteen haplotype-tagging polymorphisms in the genes TLR4 and CD14 were genotyped in 681 of the 957 children. Atopic outcomes were parentally reported eczema in the first 2 years of life and clinically diagnosed eczema and allergic sensitization at age 2 years. Multiple logistic regression was used to evaluate a multiplicative model of interaction.Results: Most of the single nucleotide polymorphisms (SNPs) showed no significant interaction with E coli exposure for both eczema and allergic sensitization. A borderline significant multiplicative interaction was found between E coli and the rs2569190 (CD14/-159) SNP regarding allergic sensitization. Furthermore, a statistically significant multiplicative interaction was found for the TLR4 SNP rs10759932 (P for interaction = .001). E coli colonization was associated with a decreased risk of sensitization only in children with the rs10759932 TT genotype (adjusted odds ratio, 0.31; 95% CI, 0.14-0.68) and not in children with the minor C allele. This interaction remained statistically significant after controlling for multiple testing.Conclusion: The current study is the first to address the potential effect-modifying role of genetic variations in the relationship between the intestinal microbiota and allergy development.

Gap junctions between regulatory T cells and dendritic cells prevent sensitization of CD8+ T cells

2010-01-01

Background: Regulatory T (Treg) cells suppress the sensitization phase of experimental contact hypersensitivity (CHS) reactions when injected before hapten application.Objective: Our aim was to analyze the mechanisms by which Treg cells suppress the sensitization phase of CHS reactions.Methods: Treg cells were labeled with different fluorescent dyes and injected into naive mice directly before sensitization with the hapten 2,4,6-trinitro-1-chlorobenzene. Two days after sensitization, the lymphoid organs were analyzed for the presence of Treg cells and engagement of gap junctions with other cells. Dendritic cells (DCs) and effector CD8+T cells were isolated from the draining lymph nodes (LNs) of the differently treated groups, analyzed by using FACS for activation markers, and assessed for the T-cell stimulatory capacity of the DCs and the priming of effector T cells.Results: Only the LN-homing Treg cells suppressed the sensitization phase in CHS reactions by means of establishing gap junctions with DCs in the dLNs. This gap junctional intercellular communication led to downregulation of T-cell costimulatory molecules on the surface of the DCs, abrogating the priming, activation, and proliferation of hapten-specific CD8+T cells. Consequently, the ear-swelling response induced by challenge with the respective hapten was prevented.Conclusion: Treg cells not only modulate ongoing CD4+T cell–mediated immune reactions at tissue sites but also abrogate the de novo induction of CD8+T cell–driven immune reactions by interfering with T-cell stimulatory activity of DCs through gap junctional intercellular communication.

Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor

2010-01-01

Background: The molecule H22–Fel d 1, which targets cat allergen to FcγRI on dendritic cells (DCs), has the potential to treat cat allergy because of its T-cell modulatory properties.Objective: We sought to investigate whether the T-cell response induced by H22–Fel d 1 is altered in the presence of the TH2-promoting cytokine thymic stromal lymphopoietin (TSLP).Methods: Studies were performed in subjects with cat allergy with and without atopic dermatitis. Monocyte-derived DCs were primed with H22–Fel d 1 in the presence or absence of TSLP, and the resulting T-cell cytokine repertoire was analyzed by flow cytometry. The capacity for H22–Fel d 1 to modulate TSLP receptor expression on DCs was examined by flow cytometry in the presence or absence of inhibitors of Fc receptor signaling molecules.Results: Surprisingly, TSLP alone was a weak inducer of TH2 responses irrespective of atopic status; however, DCs coprimed with TSLP and H22–Fel d 1 selectively and synergistically amplified TH2 responses in highly atopic subjects. This effect was OX40 ligand independent, pointing to an unconventional TSLP-mediated pathway. Expression of TSLP receptor was upregulated on atopic DCs primed with H22–Fel d 1 through a pathway regulated by FcγRI-associated signaling components, including src-related tyrosine kinases and Syk, as well as the downstream molecule phosphoinositide 3–kinase. Inhibition of TSLP receptor upregulation triggered by H22–Fel d 1 blocked TSLP-mediated TH2 responses.Conclusion: Discovery of a novel TH2 regulatory pathway linking FcγRI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines.

Counterregulation of β2-adrenoceptor function in human mast cells by stem cell factor

2009-10-28

Background: Mast cells contribute to the pathophysiology of asthma with the sustained release of both preformed and newly generated mediators in response to allergens and other diverse stimuli. Stem cell factor (SCF) is the key human mast cell growth factor, but also primes mast cells for mediator release. SCF expression is markedly increased in asthmatic airways. Short-acting β2-adrenoceptor drugs such as albuterol inhibit human lung mast cell (HLMC) degranulation in vitro in the absence of SCF, but their effect in the presence of SCF is not known.Objective: The aim of this study was to elucidate the effects of albuterol on HLMC function in the presence of SCF.Methods: Mediator release and KCa3.1 ion channel activity were analyzed in purified HLMC. Intracellular signalling and β2-adrenoceptor phosphorylation and internalization were analyzed in the HMC-1 human mast cell line.Results: β2-Adrenoceptor agonist-dependent inhibition of KCa3.1 ion channels and HLMC mediator release was markedly attenuated in the presence of SCF. Remarkably, albuterol actually potentiated IgE-induced histamine release in a dose-dependent manner when both SCF and IgE were present. These effects were related to the SCF-dependent phosphorylation of Tyr350 on the β2-adrenoceptor with immediate uncoupling of the receptor followed by receptor internalization.Conclusion: The potentially beneficial effects of β2-adrenoceptor agonists in asthmatic airways may be blunted as a result of the high concentrations of SCF present.

Atypical presentation of IL-12 receptor β1 deficiency with pneumococcal sepsis and disseminated nontuberculous mycobacterial infection in a 19-month-old girl born to nonconsanguineous US residents

2009-11-12

To the Editor: Mendelian susceptibility to mycobacterial diseases (OMIM 209950) is a rare primary immunodeficiency resulting from genetic defects in the IFN-γ/IL-12/23 axis. Severe cases are commonly associated with complete absence of IFN-γ receptor 1 expression. We report a severe, unique presentation apparently associated with an IL-12 receptor β1 (IL-12Rβ1) mutation. This previously healthy girl with no family history of immunodeficiency or consanguinity presented at 19 months of age with fever, vomiting, diarrhea, anemia, thrombocytopenia, and massive hepatosplenomegaly. Blood cultures grew Mycobacterium avium complex and Streptococcus pneumoniae. Peripheral blood smear showed moderate poikilocytosis and anisocytosis but no conclusive signs of functional asplenia (ie, Howell-Jolly bodies). Bone marrow aspirate/biopsy demonstrated significant dyserythropoiesis that normalized on subsequent bone marrow evaluations. The underlying explanation for the cytopenias and red blood cell morphologic changes was a large mycobacterial burden in the bone marrow and sepsis. Bone marrow aspirate and stool culture grew M avium complex.

Cross-linking IgE augments human conventional dendritic cell production of CC chemokine ligand 28

Sadia Hayat Khan, Mitchell H. Grayson — 2009-12-07

To the Editor: It has been well documented that infants hospitalized with a severe respiratory viral infection have an increased risk of atopic disease. Whether the viral infection imparts a change in the individual that leads to atopic disease or whether it simply reveals an underlying predisposition to atopic disease remains controversial. However, initial mechanistic information has been obtained by using rodent models of human disease. Recently, we used a mouse model of viral induced atopic disease (the Sendai virus model) to show that expression of the high-affinity receptor for IgE, FcεRI, on lung conventional dendritic cells (cDCs) was critical for accumulation of IL-13–producing TH2 cells in the lung postviral infection. Cross-linking IgE on the cDCs led to production of the TH2-cell and regulatory T-cell chemoattractant CC chemokine ligand (CCL)–28. Neutralization of this chemokine inhibited translation of the viral infection into atopic disease.

Sustained response to mepolizumab in refractory Churg-Strauss syndrome

2010-01-01

To the Editor: Churg-Strauss syndrome (CSS) is a primary small vessel vasculitis characterized by asthma, eosinophilia, multiorgan involvement (lung, peripheral nerves, heart, gastrointestinal tract, skin), and the possible presence of antineutrophil cytoplasmic antibodies (ANCAs). Corticosteroids alone are the classic therapeutic regimen in the absence of poor prognostic factors, and use of cyclophosphamide is recommended for severe disease or corticosteroid-resistant cases. The other therapies tried in CSS (intravenous immunoglobulins, IFN-α, infliximab, rituximab) target the putative pathogenic pathways of ANCA-associated vasculitides without consideration for the hallmarks of CSS compared with other ANCA-associated vasculitides: important blood and tissue eosinophilia and lower prevalence of ANCA.

Persistent rotavirus vaccine shedding in a new case of severe combined immunodeficiency: A reason to screen

2010-01-01

To the Editor: Rotavirus infections in the United States have decreased as a result of vaccination efforts. Before 2006, when the vaccine was implemented, the burden of disease was high, with approximately 27,000 to 70,000 children under 5 years of age hospitalized with rotavirus infection and about 20 to 60 reported deaths annually according to the Centers for Disease Control and Prevention and other studies. Since the introduction of vaccination, rotavirus rates in the United States have diminished by more than 50%, translating to the prevention of 48,000 hospitalizations and 30 deaths. Studies have also shown a delay in the seasonal onset of the disease by 2 to 4 months. Cost savings to the medical community with the vaccines are estimated to be as much as $198,000 per life-year. The question arises, however, as to the unforeseen costs on a population of patients with undiagnosed immune deficiency. In March 2009 there were 2 reported cases by Patel et al of rotavirus infection from RotaTeq (Merck and Co, Inc, Whitehouse Station, NJ) vaccine strains in unknown cases of SCID (severe combined immune deficiency) with adenosine deaminase deficiency and IL-2 receptor-γ deficiency. Werther et al also recently described a 9-month-old girl with a new diagnosis of unspecified SCID who shed the RotaTeq virus strain for 7.5 months and finally cleared it posttransplant. All 3 of these patients presented with gastrointestinal symptoms and failure to thrive. Vaccine strains were identified by RT-PCR.

Cardiorespiratory fitness, adiposity, and incident asthma in adults

2010-01-01

To the Editor: Available large-scale prospective studies on adiposity and asthma used body mass index as an indicator of adiposity. Studies involving more accurate measures of adiposity, such as body fat percentage (BF%), are needed to confirm or contrast body mass index–related results. Cardiorespiratory fitness is a strong predictor of morbidity and mortality, and the available literature suggests that moderate-high cardiorespiratory fitness reduces many of the health hazards associated with obesity. The current study aimed (1) to examine whether cardiorespiratory fitness and/or BF% are associated with subsequent acquisition of asthma in adults, and (2) to test the hypothesis that a high cardiorespiratory fitness level can reduce the risk of incident asthma in individuals with excess adiposity.

Fetal origin of atopic dermatitis

2010-01-01

To the Editor: Environmental challenges during pregnancy and early life events have long been hypothesized to modulate the susceptibility to chronic diseases in later life, which is commonly referred to as “developmental programming.” The unprecedented rise of allergies occurring in industrialized countries over the past 5 decades and the recognition that prenatal and postnatal environmental factors are involved in the risk to develop allergies suggest that atopic diseases may be central in understanding mechanisms involved in developmental programming.

How allergic are “allergic shiners”?

John M. Kelso — 2009-10-28

To the Editor: Chen et al are to be commended for their careful study of so-called “allergic shiners.” This discoloration of the skin below the eyes is often taken to be evidence that the patient, especially a child, must be allergic or atopic, typically meaning that they must have allergic rhinitis. Although the authors have clearly demonstrated that shiners are more common, darker, and larger in children with allergic rhinitis that in normal healthy children, this fact would seem to be of limited usefulness. As the authors state, the phenomenon is “believed to be caused by venous stasis resulting from nasal congestion.” Thus, when presented with a patient with shiners, one may conclude that this is likely secondary to chronic nasal congestion. However, this does not necessarily mean that this nasal congestion is in turn the result of allergic rhinitis. A more appropriate control group would have been children referred for evaluation of chronic rhinitis who were determined not to be allergic, so-called nonallergic rhinitis. Even in the control group of children who had “never been given a diagnosis of allergy, had never presented with any allergic symptom, and had no underlying disease,” 24% had “shiners with significant darkness” (compared with 76% in the children with allergic rhinitis) and 15% had “shiners of significant size” (compared with 61% of children with allergic rhinitis). These percentages are likely to be even higher in children with nonallergic rhinitis than in these healthy children. If shiners were more common (or larger or darker) in children with allergic as opposed to nonallergic rhinitis, then they could be thought of as a useful clinical tool to predict nasal allergy; however, the current study has not shown this to be the case. Given that “allergic” shiners are relatively common even in healthy children, and the probability that they are even more common in children with nonallergic rhinitis than healthy children, using them to predict nasal allergies is not likely to be very accurate.

Reply

Chien-Han Chen, Yu-Tsan Lin, Bor-Luen Chiang — 2009-10-28

To the Editor: We have developed a novel computerized method to quantify allergic shiners and would like to acknowledge Dr Kelso's comment. The allergic shiner is believed to be caused by venous stasis resulting from nasal congestion. Therefore, it is likely that any disorder with nasal obstruction as 1 of its symptoms can result in shiners—for example, chronic rhinosinusitis, nasal polyposis, ciliary dyskinesia syndromes, cystic fibrosis, and nonallergic rhinitis. Not including patients with these conditions as our controls may have overestimated the sensitivity and specificity of shiners for allergic diseases. However, the nature of allergic shiners is largely unknown. Even the causal inference between nasal obstruction and allergic shiners has not yet been clearly confirmed by any animal study or well designed clinical study. Most importantly, our study described a new tool to assess objectively the area and density of shiners, which will be useful for future studies investigating the pathogenesis and therapies for this important cosmetic facial manifestation of allergic rhinitis. We think the priorities should be first to verify the significance of shiners in children with allergic rhinitis and to document the previously unknown correlations of shiners with different severities of nasal and ophthalmic symptoms, instead of directly investigating in the very beginning of a series of studies the additional effect of allergies on shiners. In addition, shiners are referred to as “allergic” shiners only in patients with allergic rhinitis, but not in healthy children and not in children with nonallergic rhinitis. In other word, people do not call shiners “allergic shiners” until they know the person with shiners actually has allergic rhinitis. Hence people may use shiners, but definitely will not use “allergic” shiners, to predict allergic rhinitis. Moreover, we did not intend to use shiners to predict allergies in this study. That is why we did not include children with nonallergic rhinitis. Table II in this study has clearly shown that the sensitivities and specificities of “shiners with significant darkness” and “shiners with significant sizes” for a variety of allergic diseases were not good. Thus, we have not suggested them as signs to predict nasal allergies. Instead, we emphasized that the specificity of “dark shiners” for allergic rhinitis was as high as 100%. “Dark shiners” were defined in our article as shiners darker than two thirds of shiners in patients with allergic rhinitis during their first visit. Therefore it was fairly obvious that we did not use “dark shiners” to detect the presence of allergies. Furthermore, our study showed that there was no significant correlation between the darkness or size of shiners and current eosinophil count, serum total IgE level, and specific IgE level among children with allergic rhinitis. The possible additional effect of allergies on shiners in symptomatic children might be minimal.

Do indications to sublingual immunotherapy need to be revised?

Cristoforo Incorvaia, Marina Mauro — 2010-01-01

To the Editor: The report by Cochard and Eigenmann highlights an important aspect of sublingual immunotherapy (SLIT): its safety in patients with previous reactions to subcutaneous immunotherapy. They describe 2 patients who withdrew from SLIT for repeated side effects with bronchial and nasal reactions, respectively. In both of them, previous subcutaneous immunotherapy treatment had to be discontinued for adverse reactions. This confirms a recent report on 2 patients with similar characteristics who had stopped subcutaneous immunotherapy because of adverse reactions and also had severe, anaphylactic reactions to SLIT. To complicate the issue, in all these patients, SLIT was not performed by conventional schedules: in the first case, an ultrarush schedule using the product Staloral 300 (Stallergenes, Antony, France) was used, whereas in the other report, the patients reacted at the very first dose of the product Grazax (ALK-Abelló, Horsholm, Denmark), which has no updosing phase.

Case reports by Cochard and Eigenmann

James C. Thompson, Mary S. Morris — 2010-01-01

To the Editor: Drs Cochard and Eigenmann are to be applauded for bringing these case reports to light. They show the risk of starting sublingual immunotherapy at a high dose in sensitive patients. In defense of high-dose sublingual immunotherapy, the 14-year-old girl was also sensitive to tree pollens, and the ultrarush therapy for grass was in the context of tree pollen season, which may have primed an immunologic reaction. Further, the 13-year-old boy was sensitized to dust mite, grass, animal danders, and molds, whereas only grass and dust mite therapy were addressed.

Reply

Marie M. Cochard, Philippe A. Eigenmann — 2010-01-01

To the Editor: We thank Drs Incorvaia and Mauro as well as Drs Thompson and Morris for their comments on the 2 patients with systemic side effects to sublingual immunotherapy (SLIT) about whom we reported in a recent Letter to the Editor.

Correction

2010-01-01

With regard to the November 2009 article “Hydroxyurea in the treatment of Churg-Strauss syndrome” (J Allergy Clin Immunol 2009;124:1110-11), the legend for Figure 1 was mistakenly reprinted from another article in the same issue. The correct figure and legend are as follows:

The Journal of Allergy and Clinical Immunology

Cover 1

A Brief Overview of This Month's JACI

Table of Contents

Editorial Board

Information for Readers

Footnotes1

CME Activities Calendar

News Beyond Our Pages

Recent insights into atopic dermatitis and implications for management of infectious complications

Recent insights into atopic dermatitis and implications for management of infectious complications

An update on the genetics of atopic dermatitis: Scratching the surface in 2009

An update on the genetics of atopic dermatitis: Scratching the surface in 2009

Air filters and air cleaners: Rostrum by the American Academy of Allergy, Asthma & Immunology Indoor Allergen Committee

Secreted virulence factor comparison between methicillin-resistant and methicillin-sensitive Staphylococcus aureus, and its relevance to atopic dermatitis

Dendritic cells: Bridging innate and adaptive immunity in atopic dermatitis

Natural killer cells in atopic and autoimmune diseases of the skin

Advances in pediatric asthma in 2009: Gaining control of childhood asthma

Advances in adult asthma diagnosis and treatment in 2009

Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2009

The Editors' Choice

Ascaris, atopy, and exercise-induced bronchoconstriction in rural and urban South African children

Differences in asthma between rural and urban communities in South Africa and other developing countries

Cord blood cytokines are modulated by maternal farming activities and consumption of farm dairy products during pregnancy: The PASTURE Study

Lower cortisol levels in children with asthma exposed to recurrent maternal distress from birth

Trichuris suis ova therapy for allergic rhinitis: A randomized, double-blind, placebo-controlled clinical trial

Long-term clinical efficacy in grass pollen–induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet

Evidence for the involvement of free light chain immunoglobulins in allergic and nonallergic rhinitis

Infected atopic dermatitis lesions contain pharmacologic amounts of lipoteichoic acid

Vaccinia virus–specific molecular signature in atopic dermatitis skin

Murine atopic dermatitis responds to peroxisome proliferator-activated receptors α and β/δ (but not γ) and liver X receptor activators

Chromosome 11q13.5 variant associated with childhood eczema: An effect supplementary to filaggrin mutations

Glycation of a food allergen by the Maillard reaction enhances its T-cell immunogenicity: Role of macrophage scavenger receptor class A type I and II

Reassessing the role of hyaluronidase in yellow jacket venom allergy

Allergy or tolerance in children sensitized to peanut: Prevalence and differentiation using component-resolved diagnostics

Hepatitis A virus antibodies in immunoglobulin preparations

Lymphocyte subsets in healthy Malawians: Implications for immunologic assessment of HIV infection in Africa

Defect of regulatory T cells in patients with Omenn syndrome

Increased risk of serious pneumococcal disease in patients with atopic conditions other than asthma

Identification of a novel subset of human circulating memory CD4+ T cells that produce both IL-17A and IL-4

Host-microbial interactions in childhood atopy: Toll-like receptor 4 (TLR4), CD14, and fecal Escherichia coli

Gap junctions between regulatory T cells and dendritic cells prevent sensitization of CD8+ T cells

Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor

Counterregulation of β2-adrenoceptor function in human mast cells by stem cell factor

Atypical presentation of IL-12 receptor β1 deficiency with pneumococcal sepsis and disseminated nontuberculous mycobacterial infection in a 19-month-old girl born to nonconsanguineous US residents

Cross-linking IgE augments human conventional dendritic cell production of CC chemokine ligand 28

Sustained response to mepolizumab in refractory Churg-Strauss syndrome

Persistent rotavirus vaccine shedding in a new case of severe combined immunodeficiency: A reason to screen

Cardiorespiratory fitness, adiposity, and incident asthma in adults

Fetal origin of atopic dermatitis

How allergic are “allergic shiners”?

Reply

Do indications to sublingual immunotherapy need to be revised?

Case reports by Cochard and Eigenmann

Reply

Correction