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Environmental and immunological factors associated with allergic disease in children
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
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 [en]
Allergic diseases, dysregulated immune responses, IgG4
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-11615ISBN: 978-91-7393-913-3 (print)OAI: oai:DiVA.org:liu-11615DiVA: diva2:18034
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
List of papers
1. Endotoxin levels in Estonian and Swedish house dust and atopy in infancy
Open this publication in new window or tab >>Endotoxin levels in Estonian and Swedish house dust and atopy in infancy
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2003 (English)In: Clinical and Experimental Allergy, ISSN 1365-2222, Vol. 33, no 3, 295-300 p.Article in journal (Refereed) Published
Abstract [en]

Background Immune responses, including those to allergens, may be T helper (Th)2 skewed in newborns. In order to redress the fetal Th1/Th2 imbalance, Th1-stimulating factors, such as bacterial endotoxin, may be required. The increasing prevalence and severity of atopic diseases in industrialized countries, which are in marked contrast with the low prevalence of allergy among children in the formerly socialist countries of Europe, have been suggested to be caused by a reduced microbial stimulation.

Aim To relate the endotoxin levels in house dust from two countries with a low (Estonia) and a high (Sweden) prevalence of allergy to the development of atopic disease and sensitization in the children during the first 2 years of life.

Methods The study included 108 children from Tartu, Estonia and 111 children from Linköping, Sweden. Skin prick tests were performed at 3, 6, 12 and 24 months of age, and questionnaires were distributed to the families. At 24 months, a paediatrician examined the children. Dust samples were collected from mattresses and carpets and the endotoxin concentration was determined by a chromogenic Limulus assay.

Results The endotoxin levels were higher in Estonian than in Swedish house dust (median levels 29 (range 0.25–280) and 14 (range 0.25–99) EU/mg dust, respectively, P < 0.001). Furthermore, the levels were inversely related to the development of atopic disease and sensitization in the Swedish, but not in the Estonian, children.

Conclusions The low prevalence of atopic disease in Estonia may, at least in part, be related to the high endotoxin levels in this country. The findings support that high levels of endotoxin, or other bacterial products with Th1-stimulating properties, might protect children from developing atopic disease.

Keyword
atopy, childhood, endotoxin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13204 (URN)10.1046/j.1365-2222.2003.01562.x (DOI)000181330600006 ()12614441 (PubMedID)
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2013-05-14
2. High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life
Open this publication in new window or tab >>High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life
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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.

Keyword
food allergy, elimination diet, tolerance, immunoglobulin G4, eczema, children, immunoglobulin E
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13205 (URN)10.1111/j.1399-3038.2008.00738.x (DOI)
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
3. Slow salivary secretory IgA maturation may relate to low microbial pressure and allergic symptoms in sensitized children
Open this publication in new window or tab >>Slow salivary secretory IgA maturation may relate to low microbial pressure and allergic symptoms in sensitized children
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2011 (English)In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 70, no 6, 572-577 p.Article in journal (Refereed) Published
Abstract [en]

It is unknown why allergic symptoms do not develop in all sensitized children. We analyzed prospectively the postnatal secretory IgA (SIgA) development and whether high SIgA levels would protect sensitized infants from developing allergic symptoms. Salivary total IgA and SIgA levels were determined by ELISA, and allergy development was investigated at 3, 6, and 12 mo and at 2 and 5 y in two birth cohorts in Estonia (n = 110) and Sweden (n = 91), two geographically adjacent countries with different living conditions and allergy incidence. Total and SIgA levels increased with age, reaching adult levels at the age of 5. Virtually, all salivary IgA in Estonian children was in the secretory form, while a major part of IgA in Swedish saliva lacked the secretory component up to 2 y of age. In Sweden, high levels of salivary IgA without secretory component correlated inversely with house dust endotoxin levels. High SIgA levels were associated with less development of allergic symptoms in sensitized Swedish children. In conclusion, postnatal maturation of the salivary SIgA system proceeds markedly slower in Swedish than Estonian children, possibly as a consequence of low microbial pressure. SIgA may limit allergy-mediated tissue damage at mucosal surfaces in sensitized individuals.

Place, publisher, year, edition, pages
Nature Publishing Group, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73314 (URN)10.1203/PDR.0b013e318232169e (DOI)297433900005 ()21857384 (PubMedID)
Note

When submitted this article was titled "Slower maturation of the secretory IgA system in Swedish than Estonian children: possibly caused by low microbial pressure and related to expression of allergy in sensitised individuals".

Available from: 2012-01-03 Created: 2012-01-02 Last updated: 2017-12-08Bibliographically approved
4. Dysregulated Th1 and Th2 responses in food-allergic children: Does elimination diet contribute to the dysregulation?
Open this publication in new window or tab >>Dysregulated Th1 and Th2 responses in food-allergic children: Does elimination diet contribute to the dysregulation?
2010 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 21, no 4, 649-655 p.Article in journal (Refereed) Published
Abstract [en]

Infants with eczema and sensitization to foods are recommended skin care and, if food allergy is proven, an elimination diet. Although most of these children tolerate foods before 3 yr of age, some children experience prolonged food allergy. To our knowledge, no prospective study has investigated the cytokine profile in food-sensitized eczematous children with prolonged food intolerance. The aim of the study was to prospectively investigate the development of cytokine production induced by food allergen in food-sensitized eczematous children who, at 41/2 yr of age, were allergic or tolerant to egg or milk. Twenty-one eczematous infants, [age 5 (3-10) months; median and range], sensitized to egg and/or milk were included, put on elimination diet and followed prospectively. At 41/2 yr of age, the children were defined as tolerant or allergic to egg and/or milk based on open or double-blind placebo-controlled food challenges. Peripheral blood mononuclear cells (PBMC) were isolated from the children on inclusion, after 6 wk of elimination diet, and at 3 and 41/2 yr of age. Ovalbumin, beta-lactoglobulin and tetanus toxoid-induced IL-4, -5, -10, -13 and IFN-gamma production from PBMC were analyzed with enzyme-linked immunosorbent assay. The IFN-gamma and IL-5 secretion induced by food allergen at 41/2 yr was higher in cell cultures from children who were allergic to egg or milk than in tolerant children. In food-allergic children, the levels of IFN-gamma and IL-5 were higher at 41/2 yr compared with inclusion levels, but this increase was generally not observed in the tolerant children who consumed milk and egg. In conclusion, immune cells from food-allergic children on an elimination diet respond with up-regulated T helper 1 and T helper 2 cytokine secretion induced by food allergen. We hypothesize that allergen elimination may influence the regulatory mechanisms maintaining balanced immune responses to innocuous food antigens.

Place, publisher, year, edition, pages
Blackwell Publishing Ltd, 2010
Keyword
children; cytokines; elimination diet; food allergy; tolerance
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13207 (URN)10.1111/j.1399-3038.2009.00937.x (DOI)000278526100011 ()
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-13

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