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Maturation of T-lymphocytes and monocytes in children in relation to development of atopic disease
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-26646Local ID: 11211ISBN: 91-7373-194-3 (print)OAI: oai:DiVA.org:liu-26646DiVA: diva2:247195
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
List of papers
1. Expression of the T–cell markers CD3, CD4 and CD8 in healthy and atopic Children during the first 18 months of life
Open this publication in new window or tab >>Expression of the T–cell markers CD3, CD4 and CD8 in healthy and atopic Children during the first 18 months of life
Show others...
1999 (English)In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 119, no 1, 6-12 p.Article in journal (Refereed) Published
Abstract [en]

Background: There is little information available about the development of T–cell immunity in healthy and atopic children. We have studied prospectively the mean fluorescence intensity of the T–cell receptor complex–associated CD3, CD4 and CD8 in relation to atopic family history (AFH) and the development of atopic disease.

Methods: Children with a defined AFH (n = 172) were followed from birth to 18 months and the cumulative history of atopic disease was recorded. Blood samples were obtained at birth and at 18 months, and in a subgroup of 78 children also at 3, 6 and 12 months. Multicolour flow cytometry was used to analyse pan T–cells (CD3+CD45+CD14–), T–helper–(CD3+CD4+) and T–cytotoxic–(CD3+CD8+) cells.

Results: At 18 months, 31 children were atopic and 118 non–atopic. Children who developed atopic disease had a higher CD4 expression (mean fluorescence intensity, MFI) on CD4+CD3+ lymphocytes at birth and at 3 months, particularly as compared with non–atopic children without AFH. Furthermore, the CD3 expression on CD3+CD45+CD14– lymphocytes increased more slowly with age in children with double atopic heredity, as compared with children with no or only one atopic family member.

Conclusions: The higher expression of the CD4 receptor in early infancy in children who developed atopic disease compared with non–atopics suggests a delayed expression in T–helper cells. Children with a strong AFH had a slower increase in the expression of CD3, indicating a delayed T–cell maturation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25286 (URN)10.1159/000024169 (DOI)10341315 (PubMedID)9726 (Local ID)9726 (Archive number)9726 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
2. Expression of and responses to CD2 and CD3 in 18-month-old children with and without atopic dermatitis
Open this publication in new window or tab >>Expression of and responses to CD2 and CD3 in 18-month-old children with and without atopic dermatitis
2000 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 11, no 3, 175-182 p.Article in journal (Refereed) Published
Abstract [en]

We hypothesize that atopy is associated with a reduced T-cell function early in life and an imbalance in cytokine production. The purpose of this study was to investigate the expression of and responses to CD2 and CD3 in children who did or did not develop atopic dermatitis early in life. The expression of CD2 and CD3 was analyzed by flow cytometry, and proliferation of CD2 and CD3 was studied by 3H-thymidine incorporation in phytohaemagglutinin (PHA)- and anti-CD3-stimulated peripheral blood mononuclear cells (PBMC) of 18-month-old children, 25 with and 29 without atopic dermatitis. Exogenous interleukin (IL)-2 was added to compensate for possible functional differences in accessory cells. Anti-CD3-induced secretion of IL-4, IL-5, IL-6, IL-10, IL-13, and interferon-γ (IFN-γ) was analyzed by enzyme-linked immunosorbent assay (ELISA). Atopy was associated with a low proportion of CD2+ lymphocytes. Responsiveness to PHA, which activates lymphocytes partly via the sheep erythrocyte receptor, CD2, was reduced in the allergic children. The anti-CD3-induced proliferation declined more rapidly with antibody dilution in the allergic than in the non-allergic children. Atopic dermatitis was associated with high levels of anti-CD3-stimulated IL-5 secretion. The IL-4/IL-10 and IL-4/IFN-γ ratios were higher in children with elevated total immunoglobulin E (IgE) levels. Skin prick test-negative children with eczema produced higher levels of IL-10 than skin prick test-positive children. In conclusion, atopic children have a reduced T-cell function. Atopic dermatitis is associated with increased IL-5 production, while high total IgE levels are associated with high IL-4/IFN-γ and IL-4/IL-10 ratios.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25768 (URN)10.1034/j.1399-3038.2000.00083.x (DOI)10202 (Local ID)10202 (Archive number)10202 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Expression of the T-cell markers CD2 and CD28 in healthy and atopic children during the first 18 months of life
Open this publication in new window or tab >>Expression of the T-cell markers CD2 and CD28 in healthy and atopic children during the first 18 months of life
2003 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 14, no 3, 169-177 p.Article in journal (Refereed) Published
Abstract [en]

Atopy may be associated with a reduced T-cell function early in life, particularly regarding maturation of Th1 responses. The T-cell surface molecules CD2 and CD28 are involved in important T-cell activation pathways. Stimulation via the CD2 receptor increases the responsiveness to interleukin (IL)-12, which is a potent inducer of Th1 responses, whereas CD28 stimulation is critical for Th2 differentiation. Our aim was to prospectively study the expression of the cell-surface markers CD2 and CD28 on T-cells in relation to development of atopic disease. Children (n = 172) were followed from birth to 18 months and the cumulative history of atopic disease was recorded. Blood samples were obtained at birth and at 18 months, and in a subgroup of 78 infants also at 3, 6 and 12 months. Flow cytometry was used to analyze the T-cell markers CD2 and CD28, the latter also within the subsets of T-helper (CD4+) and T-cytotoxic (CD8+) cells. At 18 months, 31 children had and 118 did not have atopic symptoms. At this age, skin prick test (SPT) positive children with atopic symptoms with or without an atopic family history (AFH) showed a lower expression of CD2 mode fluorescence intensity (FI) as well as a lower proportion of CD2+ cells, as compared with non-sensitized children with neither atopic symptoms nor AFH. This was accompanied by a higher expression of CD28 FI on CD2+CD8+CD28+ cells. No significant differences were seen at time points before 18 months, although the proportion of CD2+ tended to be low also earlier in life. In conclusion, the observed reduced expression of CD2 in atopic infants may support previous findings that atopy is associated with a reduced CD2 function. The high CD28 FI in SPT positive children with atopic symptoms may possibly be a consequence of a TH2-skewed immune system.

Keyword
Atopic disease, CD2, CD28, Childhood, T lymphocyte
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-46607 (URN)10.1034/j.1399-3038.2003.00016.x (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
4. Reduced IL-2-induced IL-12 responsiveness in atopic children
Open this publication in new window or tab >>Reduced IL-2-induced IL-12 responsiveness in atopic children
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.

Keyword
T-cells, IL-2, IL-12, IL-12Rβ2, childhood, atopic disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13845 (URN)10.1034/j.1399-3038.2003.00075.x (DOI)
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2017-12-13Bibliographically approved
5. Reduced levels of soluble CD14 in atopic children
Open this publication in new window or tab >>Reduced levels of soluble CD14 in atopic children
2004 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 34, no 4, 532-539 p.Article in journal (Refereed) Published
Abstract [en]

Background A reduced microbial stimulation has been reported as a reason for the increasing prevalence of atopic diseases in industrialized countries. Antigen-presenting cells (APC), responding to microbial signals by pattern recognition receptors such as CD14, have an important role in the development of the Th1/Th2 balance.

Objective We hypothesized that atopic children have a lower expression of CD14 on monocytes and lower soluble CD14 levels (sCD14).

Methods Seventy-six children were followed prospectively from birth and signs of atopic disease were evaluated. The expression of CD14 on monocytes was analysed with flow cytometry at 0, 3, 6, 12 and 18 months. Circulating levels of sCD14 were analysed by ELISA and total IgE was analysed by fluoroenzymo immunoassay at these ages, and in a subgroup, followed up at 7 years.

Results Levels of sCD14 were reduced at 7 years both in children with a current or a cumulative history of atopy compared to non-atopic children with P=0.002 and 0.001, respectively. Sensitized children with atopic symptoms had lower sCD14 at 3 and 18 months and at 7 years of age than non-atopic non-sensitized children with P=0.023, 0.039 and 0.008, respectively.

Conclusion The lower levels of sCD14 observed in atopic children may be a consequence of an atopic family heredity and/or atopic disease, but it may also reflect a reduced capacity to respond to microbial signals.

Keyword
antigen-presenting cells, atopic disease, CD14(m), childhood, Soluble CD14
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22339 (URN)10.1111/j.1365-2222.2004.1921.x (DOI)1540 (Local ID)1540 (Archive number)1540 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

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Aniansson Zdolsek, Helena

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