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Th1, Th2 and Treg associated factors in relation to allergy
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
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 [sv]
Pediatrik, allergologi
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:liu:diva-6523ISBN: 91-85497-83-5 (print)OAI: oai:DiVA.org:liu-6523DiVA: diva2:21856
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
List of papers
1. PHA-induced IL-12Rb2 mRNA expression in atopic and non-atopic children
Open this publication in new window or tab >>PHA-induced IL-12Rb2 mRNA expression in atopic and non-atopic children
2001 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, Vol. 31, no 10, 1493-1500 p.Article in journal (Refereed) Published
Abstract [en]

Background

IL-12 is a strong inducer of Th1 responses. Stimulation via the CD2 receptor increases IFN-γ production and enhances the responsiveness of activated T-cells to IL-12, possibly due to an up-regulation of the signal transducing β2 chain of the IL-12 receptor (IL-12Rβ2). Atopic children have a reduced Th1-like immunity and a reduced CD2 expression. Our hypothesis is that atopic individuals have a reduced function of the CD2 pathway, causing reduced responsiveness to IL-12 and decreased IFN-γ production.

Objective

The aim was to study the mRNA expression of the IL-12Rβ2 chain, after stimulation via the CD2 pathway in peripheral blood mononuclear cells (PBMC), of atopic and non-atopic children, and to investigate correlations to the production of Th1 and Th2 cytokines.

Materials and methods

The study included 23 skin prick test positive, and 9 non-sensitized, 12-year-old children. PBMC were stimulated for 24 h with phytohemagglutinin (PHA) (2 µg/mL), which stimulates T cells through the CD2 pathway. Expression of IL-12Rβ2 mRNA was analysed by quantitative real time PCR and the cytokine production was detected with ELISA.

Results

Atopic and non-atopic children had similar baseline expression of IL-12Rβ2 mRNA, whereas PHA-induced IL-12Rβ2 mRNA expression was lower in atopic than in non-atopic children. The PHA-induced IL-12Rβ2 mRNA expression correlated well with the PHA-induced IFN-γ production and with the IFN-γ/IL-4 ratio.

Conclusion

PBMC from atopic children expressed less IL-12Rβ2 mRNA than non-atopic children after stimulation via the CD2 pathway (PHA). This may indicate a reduced capacity to respond to Th1-inducing stimuli in atopic children.

Keyword
CD2, PHA, IL-12Rβ2, Quantitative Real Time PCR, ELISA, cytokine, atopic children
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13844 (URN)10.1046/j.1365-2222.2001.01206.x (DOI)
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2009-05-20
2. 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
3. Development of Th1, Th2 and Treg associated immunity during the first two years of life in relation to allergy
Open this publication in new window or tab >>Development of Th1, Th2 and Treg associated immunity during the first two years of life in relation to allergy
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(English)Manuscript (Other (popular science, discussion, etc.))
Identifiers
urn:nbn:se:liu:diva-13846 (URN)
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2010-01-14
4. CD2 controlled expression of regulatory T cell associated Foxp3 and IL-10 in humans
Open this publication in new window or tab >>CD2 controlled expression of regulatory T cell associated Foxp3 and IL-10 in humans
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(English)Manuscript (Other (popular science, discussion, etc.))
Identifiers
urn:nbn:se:liu:diva-13847 (URN)
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2010-01-14

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