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Combinations of type 1 diabetes, celiac disease and allergy: An immunological challenge
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The immune system is composed of a complex network of different cell types protecting the body against various possible threats. Among these cells are T-helper (Th) cells type 1 (Th1) and type 2 (Th2), as well as T regulatory (Treg) cells. Th1 and Th2 are supposed to be in balance with each other, while Tregs regulate the immune response, by halting it when the desired effect, i.e. destroying the threat, is acquired. However, sometimes this intricate interplay in the immune system is disturbed, leading to diseases as type 1 diabetes (T1D), celiac disease or allergic disease. According to the paradigm claiming that Th1- and Th2-cells inhibit each other a coexistence of a Th1-deviated disease and a Th2-deviated disease seems unlikely.

This thesis aimed to examine the immune response with focus on subsets of T-cells in children with T1D, celiac disease, allergy, or a combination of two of these diseases, in comparison to reference children (healthy).

In line with previous findings we observed that children with celiac disease showed a decreased spontaneous Th2-associated secretion, whereas children with allergic disease showed increased birch- and cat-induced Th2-associated response.

The most remarkable results in this thesis are those observed in children with combinations of diseases. The combination of T1D and celiac disease decreased the Th1-associated response against several antigens, but instead displayed a more pronounced Treg-associated response. Further, in children with combined T1D and allergy an increased Th1- and Th2-associated response was seen to a general stimulus, and an increased birch-induced Th1-, Th2-, Treg- and pro-inflammatory response. In contrast, the combination of allergy and celiac disease showed a decreased spontaneous Th1-, Th2-, Treg- and pro-inflammatory response.

In conclusion, we observed that two Th1-deviated diseases in combination suppress the immune response and increase the regulatory activity. Further it seems that allergy has the ability to shift the immune response in diverging directions depending on which disease it is combined with. The observed suppressive effect might be due to exhaustion of the immune system from the massive pressure of two immunological diseases in combination, while the pronounced Treg response might be caused by an attempt to compensate for the dysfunction. These results shed some light on the intriguing and challenging network that constitutes the immune system, and hopefully give clues regarding disease prevention and treatment.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 109 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1277
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71915ISBN: 978-91-7393-021-5 (print)OAI: oai:DiVA.org:liu-71915DiVA: diva2:455275
Public defence
2011-12-02, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2011-11-17Bibliographically approved
List of papers
1. Combinations of common chronic paediatric diseases deviate the immune response in diverging directions
Open this publication in new window or tab >>Combinations of common chronic paediatric diseases deviate the immune response in diverging directions
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2006 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 146, no 3, 433-442 p.Article in journal (Refereed) Published
Abstract [en]

The cytokine pattern of T lymphocytes has not been characterized in children with combinations of paediatric immunological disorders. We describe cytokine secretion in children with type 1 diabetes, coeliac disease and allergy and combinations of two of these diseases after stimulation with 'disease-specific' antigens. Peripheral blood mononuclear cells (PBMC) were collected from 68 children with type 1 diabetes, allergy or coeliac disease, two of these diseases in combination or none of these diseases. Using the enzyme-linked immunospot (ELISPOT) technique, interferon (IFN)-γ and interleukin (IL)-4 were analysed from fresh PBMC spontaneously and after in vitro stimulation with antigens associated with one or more of these diseases (insulin, gluten, birch and cat extract, β-lactoglobulin, ovalbumin and phytohaemagglutinin) in order to divide T helper (Th)1- from Th2-like lymphocytes. Stimulation with birch and cat extract caused increased IL-4 secretion in allergic children. A low IFN-γ response to insulin was found in type 1 diabetic children, whereas allergic children responded to insulin by increased IL-4 secretion. Children suffering from both type 1 diabetes (Th1-prone) and allergy (Th2-prone) reacted distinctly to general mitogen stimulation. Children suffering from two Th1-dominated diseases (type 1 diabetes and coeliac disease) showed hardly any response to either food or inhalation allergens. Our results indicate an important interplay between common immunological diseases in children. The combination of two Th1-deviated diseases is associated with a suppressed immune response, whereas a combination of Th1- and Th2-dominated diseases appears to increase the general immune response. © 2006 The Author(s).

Keyword
type 1 diabetes, allergy, clinical immunology, coeliac disease, cytokines
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-36067 (URN)10.1111/j.1365-2249.2006.03228.x (DOI)29686 (Local ID)29686 (Archive number)29686 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
2. Diverging immune responses when allergy, type 1 diabetes and celiac disease coexist
Open this publication in new window or tab >>Diverging immune responses when allergy, type 1 diabetes and celiac disease coexist
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

An imbalance between different immune cells, among them T-cells and inflammatory cells, has been proposed to be part of the disease process in type 1 diabetes (T1D), celiac disease and allergy. T-cells and inflammatory cells exert their actions through cytokines and chemokines, and the secretion of those can be used to describe the cell milieu during an immune response.

This study included seventy-two children, diagnosed with T1D, celiac disease, allergy, or a combination of two of these diseases and compared to reference children. The study aimed to evaluate the secretion of 27 different cytokines and chemokines in cell culture supernatant after in vitro stimulation with disease-associated antigens (birch, gluten, insulin) detected by Luminex technique.

Combination of allergy with either T1D or celiac disease gave diverging results. Children with combination of T1D and allergy showed an increased secretion of several cytokines (IL-2, IL-4, IL-5, IL-7, IL-9, IL-10, IL-12, IL-15, IL-17 and CCL11), in comparison to almost all groups from birch stimulation. In contrast, when allergy was combined with celiac disease, the spontaneous secretion of IL-1β, IL-5, IL-6, IL-9, IL-10, IL-12 and CCL3 was decreased compared to children with T1D or allergy, as well as children with celiac disease alone, children with combination of T1D and allergy and reference children.

In conclusion, our results shed some light on the immune responses in children with common immunological diseases. Our study indicates diverging immune responses when allergy, type 1 diabetes and celiac disease coexist.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71911 (URN)
Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2011-11-09Bibliographically approved
3. How and when to pick up the best signals from markers associated with T-regulatory cells?
Open this publication in new window or tab >>How and when to pick up the best signals from markers associated with T-regulatory cells?
2009 (English)In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 345, no 1-2, 29-39 p.Article in journal (Refereed) Published
Abstract [en]

Regulatory T (Treg) cells are important tools with the purpose to control and regulate the immune system. These cells use FOXP3, TGF-beta, CTLA-4 and sCTLA-4 to regulate other T-cells. Since cryopreservation of peripheral blood mononuclear cells (PBMC) is a convenient way to handle samples, we investigated whether these cells will change their mRNA expression of Treg associated markers, as well as secretion of TGF-beta1, after cryopreservation. Additionally, we aimed to investigate the mRNA expression after two different time intervals of in vitro antigen stimulation. PBMC from healthy adults were stimulated either fresh (48/96 h) or after cryopreservation (48 h), with PHA, tetanus toxoid, beta-lactoglobulin, ovalbumin or in culture medium exclusively (spontaneous). The mRNA expression of FOXP3, TGF-beta, CTLA-4 and sCTLA-4 were studied with multiplex real-time RT-PCR and TGF-beta1 with ELISA. Cryopreserved PBMC were appropriate for detection of the Treg associated markers FOXP3, TGF-beta, CTLA-4 and sCTLA-4 expressed spontaneously. Also antigen-induced mRNA expression of CTLA-4, sCTLA-4 and TGF-beta and secreted TGF-beta1, with the exception of FOXP3, preserved a stable transcription activity after cryopreservation. Further, a stimulation period of 48 h in general revealed the highest mRNA expression of the markers studied. In conclusion, cryopreserved cells are in general suitable for studying Treg associated markers.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18986 (URN)10.1016/j.jim.2009.03.010 (DOI)19341742 (PubMedID)
Available from: 2009-06-07 Created: 2009-06-07 Last updated: 2017-12-13Bibliographically approved
4. Diverse FOXP3 Expression in Children with Type 1 Diabetes and Celiac Disease
Open this publication in new window or tab >>Diverse FOXP3 Expression in Children with Type 1 Diabetes and Celiac Disease
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2008 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1150, 273-277 p.Article in journal (Refereed) Published
Abstract [en]

Imbalance between different types of T lymphocytes, such as T helper (Th) and regulatory T cells (Tregs), has been reported to play a part in the pathogenesis behind such autoimmune diseases as type 1 diabetes (T1D) and celiac disease (CD). Defects in Tregs are proposed to at least partly explain the imbalance of Th cells found in children with immunologic diseases. Peripheral blood mononuclear cells from 24 children with T1D and/or CD, and reference children (that is, those without any of these diseases) were stimulated with disease-associated antigens (insulin, gluten, transglutaminase [tTG]), and phytohemagglutinin (PHA). The mRNA expression of the Treg-associated marker FOXP3 was analyzed with multiplex real-time RT-PCR. Children with T1D showed both a low spontaneous (P < 0.05) and PHA-induced (P < 0.01) expression of FOXP3 mRNA compared to children with CD. Children with T1D also had a low PHA-induced FOXP3 mRNA expression compared to the group of children diagnosed with both T1D and CD (P < 0.05). Spontaneous (P < 0.05) and PHA-induced (P < 0.05) FOXP3 mRNA expression was high in children with CD compared to reference children. In contrast, stimulation with insulin tended to induce high FOXP3 mRNA expression in T1D children compared to reference children (P = 0.057). In conclusion, children with only T1D generally showed a lower FOXP3 mRNA expression than did children with CD, or with T1D in combination with CD, which suggests impaired regulation of the immune system in children with T1D.

Keyword
type 1 diabetes, celiac disease, immune regulation, FOXP3
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16622 (URN)10.1196/annals.1447.018 (DOI)
Note
Volume 1150 Issue: Immunology of Diabetes V From Bench to Bedside.Available from: 2009-02-08 Created: 2009-02-06 Last updated: 2017-12-14
5. Combined type 1 diabetes and celiac disease in children give raise to a pronounced Treg population
Open this publication in new window or tab >>Combined type 1 diabetes and celiac disease in children give raise to a pronounced Treg population
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Regulatory T-cells (Treg) suppress the immune response in order to avoid harmful effects. A wide range of highly expressed markers are associated to Treg, among them are CD4, CD25, CD39 and forkhead box p3 (FOXP3). Others are expressed in a low number on Tregs, for example CD45RA and CD127. Type 1 diabetes (T1D) and celiac disease are both autoimmune diseases, caused by an unwanted immune response, and Treg cells have been associated to both diseases. As T1D and celiac disease share same risk genes, patients have the risk of developing the other disease subsequently. Treg cells have been implicated to be associated with development of T1D combined with celiac disease.

This pilot study aimed to investigate the expression of Treg associated markers in both CD4+CD25+ and CD4+CD25high cells by flow cytometry. In order to evaluate the involvement of Treg cells, CD39, CD45RA, CD127 and FOXP3 were studied in children with combination of T1D and celiac disease, in comparison to children with either T1D or celiac disease, and healthy children.

Our data point out that children with combination of T1D and celiac disease have higher expression of FOXP3 as well as CD39, together with a decreased expression of both CD127 and CD45RA, in comparison to children with exclusively T1D or celiac disease. Even though none of the groups differed from the reference group, our data indicates that children with combination of T1D and celiac disease have a more pronounced Treg population, both in frequency and MFI, compared to children with either T1D or celiac disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71912 (URN)
Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2011-11-09Bibliographically approved

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