title: Distinguishing benign from pathologic TH2 immunity in atopic children.
abstract: BACKGROUND
  Although most children with asthma and rhinitis are sensitized to aeroallergens, only a minority of sensitized children are symptomatic, implying the underlying operation of efficient anti-inflammatory control mechanisms.
  
  
  OBJECTIVE
  We sought to identify endogenous control mechanisms that attenuate expression of IgE-associated responsiveness to aeroallergens in sensitized children.
  
  
  METHODS
  In 3 independent population samples we analyzed relationships between aeroallergen-specific IgE and corresponding allergen-specific IgG (sIgG) and associated immunophenotypes in atopic children and susceptibility to asthma and rhinitis, focusing on responses to house dust mite and grass.
  
  
  RESULTS
  Among mite-sensitized children across all populations and at different ages, house dust mite-specific IgG/IgE ratios (but not IgG4/IgE ratios) were significantly lower in children with asthma compared with ratios in those without asthma and lowest among the most severely symptomatic. This finding was mirrored by relationships between rhinitis and antibody responses to grass. Depending on age/allergen specificity, 20% to 40% of children with allergen-specific IgE (sIgE) of 0.35 kU/L or greater had negative skin test responses, and these children also expressed the high sIgG/sIgE immunophenotype. sIgG1 from these children inhibited allergen-induced IgE-dependent basophil activation in a dose-dependent fashion. Profiling of aeroallergen-specific CD4(+) TH memory responses revealed positive associations between sIgG/sIgE ratios and IL-10-dependent gene signatures and significantly higher IL-10/TH2 cytokine (protein) ratios among nonsymptomatic children.
  
  
  CONCLUSIONS
  In addition to its role in blocking TH2 effector activation in the late-phase allergic response, IL-10 is a known IgG1 switch factor. We posit that its production during allergen-induced memory responses contributes significantly to attenuation of inflammation through promoting IgG1-mediated damping of the FcεRI-dependent acute-phase reaction. sIgG1/sIgE balance might represent a readily accessible therapeutic target for asthma/rhinitis control.
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia; Queensland Children's Medical Research Institute, University of Queensland, Brisbane, Australia. Electronic address: patrick.holt@telethonkids.org.au.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Holt
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Deborah
authors.initials: D
authors.lastname: Strickland
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Bosco
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Danielle
authors.initials: D
authors.lastname: Belgrave
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Hales
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Simpson
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Elysia
authors.initials: E
authors.lastname: Hollams
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Holt
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Merci
authors.initials: M
authors.lastname: Kusel
authors.affiliation: Centre for Allergy Research, Karolinska Institute, Stockholm, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Ahlstedt
authors.affiliation: Queensland Children's Medical Research Institute, University of Queensland, Brisbane, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Sly
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Adnan
authors.initials: A
authors.lastname: Custovic
mesh_terms: D000293:Adolescent; D000485:Allergens / Q000276:immunology; D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D001249:Asthma / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001491:Basophils / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007109:Immunity; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007156:Immunologic Memory; D008297:Male; D010641:Phenotype; D006109:Poaceae / Q000009:adverse effects; D039981:Pyroglyphidae / Q000276:immunology; D012720:Severity of Illness Index; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D000485:Allergens; D016207:Cytokines; D007074:Immunoglobulin G; D007073:Immunoglobulin E
keywords: Asthma; IL-10; IgE; IgG(1); basophil activation; regulatory T cells; rhinitis; symptoms