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High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
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2009 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, Vol. 5, no 1, 35-41 p.Article in journal (Refereed) Published
Abstract [en]

Children with eczema and sensitization to foods are recommended skin care and, if food allergy is proven by challenge, an elimination diet. For most children the diet period is transient, but the process behind tolerance development and the influence of decreased allergen exposure is not fully known. The aim of the study was to investigate the effect of elimination diet on serum and salivary antibodies and to identify immunological parameters related to the ability to tolerate foods. Eighty-nine children, below 2 yr of age, with eczema and suspected food allergy were included. Recommended treatment was skin care to all children, and 60 children had a period of elimination diet. At 4½ yr of age, the children were divided into two groups, based on if they had been able to introduce the eliminated foods, or not. Serum and salivary antibodies were analyzed with enzyme-linked immunosorbent assay and UniCAP® before and after a 6-wk treatment period and at 4½ yr of age. Children sensitized to egg and/or milk that could eat and drink the offending foods at 4½ yr of age, had higher levels of Immunoglobulin G4 antibodies to ovalbumin and β-lactoglobulin and also higher IgG4/Immunoglobulin E ratios on inclusion in the study, than those who had to eliminate egg and/or milk from their diet, beyond 4½ yr of age. The highest IgG4/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative skin prick test on inclusion. The 6-wk treatment period did not significantly affect the levels of serum and salivary antibodies. In conclusion, eczematous, food sensitized infants with high levels of IgG4 and high ratios of IgG4/IgE antibodies to food allergens are more likely to consume these foods at 4½ yr than infants with low levels and ratios.

Place, publisher, year, edition, pages
2009. Vol. 5, no 1, 35-41 p.
Keyword [en]
food allergy, elimination diet, tolerance, immunoglobulin G4, eczema, children, immunoglobulin E
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13205DOI: 10.1111/j.1399-3038.2008.00738.xOAI: oai:DiVA.org:liu-13205DiVA: diva2:18031
Note
The fulltext of this work is available at Blackwell-Syergy: Sara Tomičić, Gunilla Norrman, Karin Fälth-Magnusson, Maria C. Jenmalm, Irene Devenney and Malin Fagerås Böttcher, High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life, 2008, Pediatric Allergy and Immunology, (5), 1, 35-41. http://dx.doi.org/10.1111/j.1399-3038.2008.00738.x Copyright: Blackwell-Synergy http://www.blackwellpublishing.com/ Available from: 2009-02-26 Created: 2009-02-26 Last updated: 2010-02-06Bibliographically approved
In thesis
1. Environmental and immunological factors associated with allergic disease in children
Open this publication in new window or tab >>Environmental and immunological factors associated with allergic disease in children
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Allergic diseases are characterised by dysregulated immune responses. The first manifestation of the atopic phenotype is often food allergy, with symptoms like eczema. Food allergy in children is generally outgrown before 3 years of age, but a temporary food elimination diet is often advocated. The prevalence of allergic diseases has increased in affluent countries during the last decades, possibly as a consequence of a changed lifestyle leading to decreased microbial load.

Aim: To investigate humoral, mucosal and cell-mediated immunity in association to allergy and allergy development in young children and relate this to environmental factors.

Subjects: Two cohorts of children were investigated; 1) Children from countries with high (Sweden) and low (Estonia) prevalence of allergy that were followed prospectively from birth to 5 years of age. 2) Infants with eczema and suspected food allergy that were followed prospectively to 4 ½ years of age.

Methods: Endotoxin levels were analysed in house dust samples. Antibodies were measured in serum and saliva samples with ELISA. Food allergen induced cytokine responses were analysed in mononuclear cells.

Results: The microbial load, delineated as endotoxin levels, was higher in house dust from Estonia than Sweden and was, in Swedish children, inversely associated with sensitisation and clinical symptoms of allergy. The decreased microbial load in Sweden may have an impact on mucosal immune responses as different IgA antibody patterns were observed in Sweden and Estonian children with much lower secretory (S)IgA antibody levels and high proportion of non-SIgA, i.e. IgA antibodies lacking the secretory component, in the Swedish children. Moreover, low levels of SIgA were associated with clinical symptoms in sensitised children.

High IgG4 antibody levels to food allergens during infancy were associated with faster tolerance development in food allergic children. Cytokine responses by mononuclear cells after allergen stimulation was upregulated with age in children with prolonged food allergy, but not in children who develop tolerance before 4 ½ years of age, possibly because of the prolonged elimination diet in the former group.

Summary: Reduced microbial exposure in affluent countries may affect the mucosal immune responses during infancy, possibly resulting in an increased risk of developing allergic disease. High levels of IgG4 antibodies during infancy are associated with faster achievement of tolerance in food allergic children. Allergen elimination during infancy may result in a dysfunctional cytokine response.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2008
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1061
Keyword
Allergic diseases, dysregulated immune responses, IgG4
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-11615 (URN)978-91-7393-913-3 (ISBN)
Public defence
2008-05-15, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2015-11-19
2. Eczema in young children: aspects of clinical investigation and treatment
Open this publication in new window or tab >>Eczema in young children: aspects of clinical investigation and treatment
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [sv]

Bakgrund: Eksem förekommer hos 10-20% av barn i hela världen. En tredjedel av barnen med eksem har födoämnesallergi. Hos de flesta växer födoämnesallergin bort innan skolåldern. Förbättrat kliniskt omhändertagande och bättre förståelse av hur klinisk tolerans uppkommer är viktiga mål för forskning inom barnmedicin.

Studieupplägg: Denna doktorsavhandling baseras på studier av två grupper av barn. Den första är en stor grupp med misstänkt allergi som undersökts med pricktest vid ett tillfälle. Den andra gruppen består av små barn med eksem och misstänkt födoämnesallergi. Barnen påbörjade studien innan två års ålder och har sedan följts över tid till fyra och ett halvt års ålder.

Säkerhet vid pricktest: 5908 barn med en medelålder på 6 år och 5 månader, undersöktes med pricktest (SPT). Sju barn (0,12 %) reagerade med generaliserad allergisk reaktion (GAR), och behövde antiallergisk medicinering. Sju barn reagerade vasovagalt (VVR) med svimning eller ”nära-svimning”. Riskfaktorer för GAR var ålder <1 år (RR 6,28) och aktivt eksem (RR 16,98). Risken för VVR var högst hos tonårsflickor och barn/ungdomar undersökta med många allergen (många prickar) samtidigt, oavsett om de var positiva eller inte.

Effekt av lokalbehandling och födoämneselimination hos spädbarn med eksem: 123 barn, 52 flickor och 71 pojkar deltog i studien. Åldern varierade mellan 1-24 månader, med en medelålder på 8,4 månader vid studiens början. Kraven för att få delta var eksem och/eller misstänkt födoämnesallergi. Diagnos av eksem gjordes med stöd av Hanifin och Rajkas kriterier. Eksemgrad bedömdes med instrumentet SCORAD. Barnen bedömdes vid två tillfällen med ca sex veckors mellanrum. 62 % av barnen hade positiv pricktest för födoämnen. SCORAD-värdena i gruppen med positiv pricktest var högre än i gruppen med negativ pricktest, barnen som var födoämnessensibiliserade hade alltså svårare eksem.

Efter sex veckors behandling; födoämneselimination+ lokalbehandling hos SPTpositiva barn; endast lokalbehandling hos SPT-negativa barn; var det ingen skillnad i eksemens svårighetsgrad mellan de två grupperna. Både födoämnessensibiliserade och icke födoämnessensibiliserade förbättrades signifikant av behandling. En grupp med negativ pricktest, men med påvisade antikroppar mot födoämnen i blodet (analyserade först i efterhand), som behandlades enbart med lokalbehandling förbättrade sina eksem lika mycket som de barn som också ställts på eliminationskost.

Antikroppar i blod och saliv i relation till toleransutveckling: Serumnivåer av total- samt ägg- och mjölkspecifika antikroppar av IgE, IgG1 och IgG4 analyserades. I saliv analyserades totalnivåer av sekretoriskt IgA samt specifikt IgA mot mjölk och ägg. Prover togs vid studiens början, efter sex veckor samt vid 4,5 års ålder. Barn som var sensibiliserade mot mjölk och/eller ägg, men som tålde dessa födoämnen vid 4,5 års ålder hade högre IgG4 nivåer och högre IgG4/IgE-kvot vid studiens början, än de barn som ej uppnått tolerans. De högsta IgG4/IgE-kvoterna sågs hos barnen med negativt pricktest men positivt specifikt IgE i blod. Under den första korta observationsperioden på sex veckor sågs ingen påverkan på barnens antikroppsnivåer.

Recept/metodutvecklande och resultat av öppna och dubbel-blinda placebokontrollerade födoämnesprovokationer: Efter recept och metodutveckling för födoämnesprovokationer med mjölk och ägg, utfördes 52 provokationer på 39 barn. Fyra barn, alla provocerade blint, reagerade på provokationen.

Generella slutsatser: Risken för generaliserade allergiska reaktioner vid pricktest är liten hos barn och tonåringar, men den finns. Riskfaktorer är låg ålder och aktivt eksem. Vasovagala reaktioner är lika vanliga som generaliserade allergiska reaktioner.

Lokalbehandling/smörjning ger signifikant förbättring av eksem. Elimination av födoämnen kanske inte är nödvändigt hos eksembarn med sensibilisering för mjölk och ägg under förutsättning att hudvården sköts noga. Höga IgG4/IgE-kvoter av specifika antikroppar mot födoämnen kan vara associerat med snabbare toleransutveckling, och kan stödja idén med fortsatt allergenexponering hos födoämnessensibiliserade barn.

Recept på beredningar som väl maskerar komjölk och ägg, vid öppna och blindade födoämnesprovokationer, är en god hjälp vid provokationer av små barn som ofta är misstänksamma mot nya smaker och konsistenser av mat.

Abstract [en]

Background: Eczema affects at least 20 % of children worldwide, and 1/3 of them also have food allergy. In most children, the food allergy is temporary. Improved clinical management and better understanding of etiological mechanisms underlying the tolerance development are target issues in paediatric research.

Study design: The thesis is based on two study groups. The first is a large group of children with suspected allergy investigated with skin prick test in a cross-sectional study. The second group is a cohort of infants with eczema and/or suspected food allergy before 2 years of age, investigated prospectively with follow-up to 4.5 years of age.

Safety of skin prick test (SPT): 5908 children with a mean age of 6.4 years (range: 1 month – 18 years) were investigated with SPT. Seven children, i.e. 0.12%, displayed a generalized allergic reaction (GAR), necessitating pharmacological treatment. Seven children showed a vasovagal reaction (VVR). Risk factors for GAR were age < 1 year (RR 6.28) and eczema (RR 16.98). The risk for VVR was highest among female adolescents, and children investigated with multiple skin pricks.

The effect of skin care and food elimination on eczema in infants: 123 children, 52 girls and 71 boys, with a mean age of 8.4 months (range: 1-24 months) were recruited due to eczema and/or suspected food allergy. For diagnosis of eczema, the Hanifin and Rajka criteria were used, and for scoring of eczema severity SCORAD. The infants were investigated twice with an interval of 6 weeks. 62% showed positive SPTs. The SCORAD was higher among the sensitized children before treatment compared to not sensitized children. After treatment, i.e. skin care for all and elimination diet for sensitized children, there was no difference regarding eczema severity. Both SPT-positive and SPT-negative children decreased their SCORAD values significantly after treatment. A SPT-negative subgroup, with circulating specific IgE to milk/egg, was only treated with skin care, but these children improved their eczema to the same extent as those also treated with an elimination diet.

Serum and salivary antibodies and achievement of tolerance Analyses were performed regarding: serum levels of total and egg- and milk-specific IgE antibodies, IgG1 and IgG4 antibodies to β-lactoglobulin (BLG) and ovalbumin (OVA); and salivary levels of total IgA, total SIgA and salivary IgA antibodies to OVA and BLG. Samples were drawn at inclusion, after 6 weeks of intervention (skin care, elimination diet), and at 4.5 years of age. Children sensitized to egg and/or milk who had developed tolerance at 4 ½ years of age had higher levels of IgG4 antibodies to OVA and BLG and also higher IgG4/IgE ratios on inclusion in the study, than those who remained non-tolerant. The highest IgG4/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative SPT on inclusion. The six-week treatment period did not significantly affect the levels of serum and salivary antibodies.

Recipes and outcomes of open and double-blinded food challenges in children: After development of recipes for open and blinded challenge with cow’s milk and egg, 52 challenges were performed in 39 children. 4 children, challenged blindly, had a positive outcome of the challenge.

General conclusions: The risk for generalized allergic reactions at SPT is low among children and teenagers, but allergic reactions do occur, and low age and eczema are risk factors. Vasovagal reactions occur as often as allergic reactions.

Skin care gives significant improvement of eczema severity. Elimination diet may not be needed in infants with sensitization to milk and/or egg, provided that the skin care is adequate.

High ratios of serum IgG4/IgE antibodies to food allergens may be associated with faster achievement of clinical tolerance, and may support the concept of benefit from continuing allergen exposure in sensitized children.

Recipes for masking of cow’s milk and egg in open or blinded food challenges may help to accomplish challenges in young children, often suspicious to unfamiliar tastes or textures.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2007. 66 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 999
Keyword
allergy, eczema, skin tests, food allergy, food challenge, IgG4, IgE, elimination diet, SCORAD, children, infants, adolescents
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-9048 (URN)978-91-85831-96-8 (ISBN)
Public defence
2007-05-31, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-06-19 Created: 2007-06-19 Last updated: 2012-01-30Bibliographically approved

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Tomičić, SaraNorrman, GunillaFälth-Magnusson, KarinJenmalm, Maria C.Devenney, IreneFagerås Böttcher, Malin

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