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Reduced IL-2-induced IL-12 responsiveness in atopic children
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.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
2003 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 14, no 5, 351-357 p.Article in journal (Refereed) Published
Abstract [en]

Atopy may be associated with a reduced T-cell function particularly regarding maturation of T helper 1 (Th1) responses. We hypothesized that atopic children may have a reduced capacity to up-regulate the β2 subunit of the interleukin-12 (IL-12) receptor (IL-12Rβ2, the signal-transducing component). The study included 38 children followed from birth to the age of 7 years. Twenty one had a cumulative history of atopic disease, whereas 17 had none. Sixteen out of 21 children also had atopic symptoms within the past year (current), out of whom 10 children had atopic airway symptoms. The expression of IL-12Rβ2 mRNA was analyzed by quantitative real-time PCR and the secretion of interferon-γ (IFN-γ), IL-5 and IL-10 was assessed by enzyme-linked immunosorbent assay (ELISA). Children with current atopic airway symptoms and high levels of total IgE up-regulated IL-12Rβ2 mRNA expression less than non-atopic children with low IgE levels after IL-2 stimulation. This was accompanied by a low IL-2- and IL-12-induced IFN-γ production, possibly reflecting the reduced capacity of atopic children to up-regulate the IL-12 receptor. As IL-2 is needed to initiate and sustain immune responses and IL-12 promotes Th1 responses, this may contribute to the Th2-skewed pattern in atopic children.

Place, publisher, year, edition, pages
2003. Vol. 14, no 5, 351-357 p.
Keyword [en]
T-cells, IL-2, IL-12, IL-12Rβ2, childhood, atopic disease
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13845DOI: 10.1034/j.1399-3038.2003.00075.xOAI: oai:DiVA.org:liu-13845DiVA: diva2:21853
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Th1, Th2 and Treg associated factors in relation to allergy
Open this publication in new window or tab >>Th1, Th2 and Treg associated factors in relation to allergy
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Immune responses are often divided into T helper 1 (Th1), Th2 and Treg like immunity. Allergy is associated with Th2 like responses to allergens and possibly to reduced regulatory functions. Activation via the CD2 receptor increases the production of the Th1 associated cytokine IFN-g and enhances the responses of activated T cells to IL-12. This may be due to an up-regulation of the signal-transducing β2-chain of the IL-12 receptor. CD2 function may be impaired in allergic children. As IL-12 is a strong promoter of Th1 like responses, this may be one contributing factor to the Th2-skewed immune responses found in allergic children. IL-27 and its receptor component WSX-1 may also play a role in Th1 like responses. The transcription factors T-bet, GATA-3 and Foxp3 are associated with Th1, Th2 and Treg type of immune responses, respectively.

Aim: To investigate possible mechanisms behind the reduced Th1 and/or Treg associated immunity in relation to allergy by studying the CD2 induced regulation of IL-12Rβ2, WSX-1, T-bet, GATA-3 and Foxp3, as well as the production of different cytokines in children and adults. The aim was also to study the development of these factors during the first two years of life in relation to development of allergy in children from a country with high (Sweden) and low (Estonia) prevalence of allergy.

Material and methods: Four different study groups were included; 32 12-year-old children, 38 7-year-old children, 61 children followed from birth to two years of age and 20 adults. Peripheral blood mononuclear cells were cultured with PHA (which partly signals via CD2), IL-2 and IL-12 alone and in combination or with anti-CD2 alone or combined with anti-CD28 antibodies. mRNA expression of cytokine receptors and transcription factors was analysed with real-time PCR and production of Th1, Th2 and Treg associated cytokines with ELISA.

Results: We found lower PHA-induced IL-12Rβ2 and IFN-γ production in 12-year-old children with positive skin prick tests (SPT), compared with SPT negative children. We also found lower IL-2 induced IL-12Rβ2 in children with allergic airway symptoms and high IgE levels compared to children without a history of allergy and low IgE levels. This was accompanied with lower IL-2 and IL-12 induced IFN-γ. The spontaneous mRNA expression of IL-12Rβ2, WSX-1, T-bet, GATA-3 and Foxp3 was similar at birth and at 24 months. PHA induced up-regulation of all markers at all ages except for GATA-3, which was up-regulated in allergic children only at 6 and 12 months. PHA-induced T-bet and WSX-1 increased from birth to 24 months in non-allergic children. At a specific age, similar levels of all markers were found in allergic and non-allergic children, except for higher spontaneous IL-12Rβ2 at 24 months and higher PHA-induced WSX-1 at birth in allergic children. All cytokines increased with age. No clear differences were found between Swedish and Estonian children. CD2 stimulation induced Foxp3 and IL-10, while CD2 together with CD28 stimulation induced both Th1 and Th2 related transcription factors and cytokines. The combination also hampered the CD2 induced expression of Foxp3.

Conclusions: The CD2 pathway and the response to IL-2 may be impaired in allergic children as lower IL-12Rβ2 and IFN-g were found in allergic, compared to non-allergic children. This difference was not found in adults. CD2 may be involved in induction of regulatory T cell responses as stimulation via CD2 in the absence of other co-stimulatory molecules induced Foxp3 and IL-10. Different developmental patterns of Th1 and Th2 associated factors may influence the development of allergic diseases in childhood.

Place, publisher, year, edition, pages
Institutionen för molekylär och klinisk medicin, 2006
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 947
Keyword
Pediatrik, allergologi
National Category
Pediatrics
Identifiers
urn:nbn:se:liu:diva-6523 (URN)91-85497-83-5 (ISBN)
Public defence
2006-06-02, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2009-08-22
2. Maturation of T-lymphocytes and monocytes in children in relation to development of atopic disease
Open this publication in new window or tab >>Maturation of T-lymphocytes and monocytes in children in relation to development of atopic disease
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [sv]

Bakgrund: Atopiska sjukdomar har ökat i västvärlden under de senaste årtiondena. För att förstå den bakomliggande mekanismen vid sensibilisering mot allergen behöver vi förbättra vår kunskap av T-lymfocyters och monocyters utmognad hos små bam.

Mål: Att prospektivt studera utmognaden av T-lymfocyter och monocyter hos bam som senare utvecklade atopisk sjukdom.

Material och metoder: 170 barn med och utan atopisk sjukdom i familjen följdes från födelsen till 18 månaders ålder, och 38 av dessa följdes också upp vid sju års ålder. Förekomst av atopisk sjukdom under uppväxten(= kumulativ sjukhistoria) registrerades. En hudpricktest (SPT) utfördes vid 18 månader och vid sju års ålder. Markörer för ytreceptorer på T-celler (CD2, 3, 4, 8, 28) studerades med hjälp av flödescytometrisk teknik på alla bam vid födelsen och vid 18 månaders ålder. Dessa markörer studerades också vid 3, 6 och 12 månaders ålder i en undergrupp om 78 barn med stark familjär ärftlighet för atopisk sjukdom, eller avsaknad av sådan. Vid 18 månaders ålder deltog 54 barn, 29 icke-atopiska och 25 atopiska, i en funktionell T-cellsstudie. Proliferation av perifera mononukleära celler i blodet (PBMN celler) studerades med inmärkning av 3H-tymidin efter stimulering med anti-CD3 eller phytohemagglutinin (PHA). Anti-CD3 inducerad cytokin produktion (IL-4, IL-5, IL-6, IL-10, IL-13 och IFN-γ) rutalyserades med ELISA teknik (enzyme-linked immuno sorbent assay). Vid sju års ålder följdes 38/54 bam upp och IL-12 svaret hos PBMN celler studerades efter att stimulering med IL-2, IL-12 eller båda. Uttrycket av 1L-12Rß2 mRNA mättes med real-tids PCR (polymerase cltain reaction), medan cytokin-nivåer IL-5, IL-10 och IFN-γ mättes med ELISA. På 76 barn studerades monocyt-mru·kören CD14 med flödescytometrisk teknik, lösligt CD14 i serum (sCD14) med ELISA och total-nivåer av immunglobulin E (lgE) med UniCAP® vid födelsen, 3, 6, 12 och 18 månaders ålder. Vid sju års ålder rutalyserades också sCD14 och total-IgE hos 38 barn.

Resultat: Vid 18 månaders ålder var 118/170 barn icke-atopiska och 31/170 hade utvecklat atopisk sjukdom. CD4 FI på T-hjälpar (CD3+CD4+) celler var lägre vid födelsen och vid 3 månaders ålder hos barn med en atopisk kumulativ sjukhistoria vid 18 månaders än hos ickeatopiska. Atopi var också förenat med en låg andel av CD2+ lymfocyter vid 18 månaders ålder. Vid samma ålder hade barn med kumulativ sjukhistoria och en positiv SPT lägre CD2, liksom lägre CD3 FI på pan T (CD3+CD45+CD14-) celler och högre CD28 FI på CD2+CD8+CD28+ celler. Atopisk sjukdom vid 18 månader var förenat med högre nivåer av anti-CD3 inducerad IL-5 sekretion och SPT- barn med atopisk sjukdom producerade högre nivåer av IL-l O än SPT + barn. Kvoten av IL-4/ IL-l O och IL-4/ IFN-γ var högre hos barn med förhöjda nivåer av total IgE. Barn med atopisk sjukdom och atopiska luftvägssymptom uppreglerade uttrycket av IL-2 inducerad IL-I2Rß2 mRNA mindre än icke-atopiska brun vid sju års ålder. De hade också en lägre IL-2 och IL-12 inducerad IFN-y sekretion. Vidare var sCD14 lägre vid sju års ålder hos barn med en atopisk kumulativ sjukhistoria, än hos ickeatopiska barn. Detta mönster observerades också vid 3 och 18 månader hos SPT+ barn med kumulativ atopisk sjukhistoria vid 18 månaders ålder jämfört med SPT- icke-atopiska barn. Dessutom hade barn med mycket allergi i familjen lägre nivåer av sCDI4 vid 3, 12, och 18 månader och vid 7 års ålder än bam utan allergi i familjen.

Sammanfattning: Utmognaden av T celler och funktionen av dessa skiljer sig mellan atopiska och icke-atopiska barn. IL-12 svaret hos barn med atopiska luftvägssymptom och höga nivåer av total-IgE är reducerat. Sammantaget kan detta bidra till ett T-hjälpar 2 devierat humunsvar vid atopisk sjukdom. Atopiska barn har lägre nivåer av sCD14. De låga nivåerna kan möjligen vara en konsekvens av familjär atopisk ärftlighet/atopisk sjukdom och kan kanske också avspegla en minskad förmåga att svara på mikrobiella signaler hos atopiska individer.

Abstract [en]

Background: Atopic diseases have increased over the last decades in Westem countries. In order to understand the process underlying primary sensitisation to allergens we need to augment our knowledge of the maturation of T lymphocytes and monocytes in small children. The main aim was to prospectively study the development of T lymphocytes and monocytes in children who subsequently developed atopic disease.

Material and Methods: Children (n=170) with or without an atopic family history were followed from birth to 18 months of age, and a subgroup of 38 children were followed-up also at the age of seven. The cumulative history of atopic disease was recorded. A skin prick test (SPT) was performed at 18 months and at 7 years. T-cell surface markers (CD2, 3, 4, 8, 28) were studied in all children with flow cytometry at birth, and at 18 months. These markers were also studied at 3, 6, and 12 months in a subgroup of 78 children with either strong or no atopic family history. At 18 months 54 children, 29 non-atopic and 25 atopic, were included in a functional T-cell study. Phytohaemagglutinin (PHA) or antiCD3 induced proliferation in peripheral blood mononuclear cells (PBMC) was studied by analysing 3H-thymidine incorporation. Anti-CD3 induced cytokine production (IL-4, IL-5, IL-6, IL-10, IL-13 and IFN-γ) was analysed by enzyme-linked innnuno sorbent assay (ELISA). At the age of seven 38/54 children were followed-up and the responsiveness to IL-12 was studied after stimulation with IL-2, IL-12 or both. The expression of iL-12Rß2 mRNA PBMCs was measured with real time PCR, as well as the cytokines IL-5, IL-10 and IFN-γ (ELISA). The monocyte surface marker CD14 was studied with flow cytometty in a subgroup of 76 children at bitth, 3, 6, 12 and 18 months of age, as well as soluble CD14 in serum by ELISA, and total immunoglobulin E (IgE) by UniCAP®. Soluble CDI4 (sCD14) and total lgE were also analysed in the subgroup of 38 children at seven years of age.

Results: At 18 months 118/170 children were non-atopic and 31/170 had developed atopic disease. CD4 fluorescence intensity (Fl) on T-helper-(CD3+CD4+) cells was lower at birth and at 3 months in children with a cumulative history of atopy at 18 months than in nonatopics. Atopy was associated with a low proportion of CD2+ lymphocytes at 18 months. At this age children with a cumulative atopy and a positive SPT had lower CD2 FI, as well as lower CD3 Fl on pan T cells (CD3+CD45+CD14- cells) and higher CD28 Fl on CD2+CD8+CD28+ cells. Atopic disease at 18 months was associated with high levels of anti-CD3 induced IL-5 secretion and SPT-negative children with atopic disease produced higher levels of IL-l 0, than SPT -positive children. The IL-4/ IL-l 0 and IL-4/IFN-y ratios were higher in children with elevated total IgE levels. At age seven children with atopic aitway symptoms up-regulated the expression of IL-2 induced IL-12RP2 mRNA less than non-atopic children. This was accompanied by a low IL-2 and IL-12 induced IFN-y scretion. Fmther sCD 14 was lower at seven years in children with a cumulative histmy ofatopic disease, than in non-atopic children. This patte1n was also observed at 3 and 18 months in SPT-positive children with a cumulative histmy of atopy at 18 months compared to non-atopic SPT-negative children. In addition, children with a strong AFH had lower levels of sCD14 at 3, 12, and 18 months and at 7 years than children with no AFH.

Conclusions: The maturation of T cells and T-cell function differs between atopic and non-atopic children. IL-12 responsiveness is reduced in children with atopic ahway symptoms and high levels of total-IgE. Altogether this may contribute to a Th2 deviated immunity in atopic disease. Atopic children have reduced levels of sCD14. The low levels may be a consequence of the atopic disease/atopic family heredity and may also reflect a reduced capacity to respond to microbial signals in atopic individuals.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2002. 75 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 752
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26646 (URN)11211 (Local ID)91-7373-194-3 (ISBN)11211 (Archive number)11211 (OAI)
Public defence
2002-11-15, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-20Bibliographically approved

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Zdolsek, HelenaJanefjord, CamillaFälth-Magnusson, KarinJenmalm, Maria

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