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Low expression of CD39+/CD45RA+ on regulatory T cells (Treg) cells in type 1 diabetic children in contrast to high expression of CD101+/CD129+ on Treg cells in children with coeliac disease
Jönköping University, School of Health and Welfare, The Jönköping Academy for Improvement of Health and Welfare. Department of Pediatrics, Ryhov County Hospital; Futurum – the Academy for Health and Care in Jönköping County Council.
Jönköping University, School of Health and Welfare, HHJ, Dep. of Natural Science and Biomedicine. Jönköping University, School of Health and Welfare, HHJ. Biomedical Platform. Futurum – the Academy for Health and Care in Jönköping County Council; Division of Medical Diagnostics, Ryhov County Hospital.ORCID iD: 0000-0002-7995-3546
Jönköping University, School of Health and Welfare, HHJ, Dep. of Natural Science and Biomedicine. Jönköping University, School of Health and Welfare, HHJ. Biomedical Platform. Futurum – the Academy for Health and Care in Jönköping County Council; Division of Medical Diagnostics, Ryhov County Hospital.ORCID iD: 0000-0002-9819-0468
2015 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 180, no 1, p. 70-82Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes (T1D) and coeliac disease are both characterized by an autoimmune feature. As T1D and coeliac disease share the same risk genes, patients risk subsequently developing the other disease. This study aimed to investigate the expression of T helper (Th), T cytotoxic (Tc) and regulatory T cells (Treg) in T1D and/or coeliac disease children in comparison to healthy children. Subgroups of T cells (Th:CD4+ or Tc:CD8+); naive (CD27+CD28+CD45RA+CCR7+), central memory (CD27+CD28+CD45RA-CCR7+), effector memory (early differentiated; CD27+CD28+CD45RA-CCR7- and late differentiated; CD27-CD28-CD45RA-CCR7-), terminally differentiated effector cells (TEMRA; CD27-CD28-CD45RA+CCR7-) and Treg (CD4+CD25+FOXP3+CD127-) cells, and their expression of CD39, CD45RA, CD101 and CD129, were studied by flow cytometry in T1D and/or coeliac disease children or without any of these diseases (reference group). Children diagnosed with both T1D and coeliac disease showed a higher percentage of TEMRA CD4+ cells (P<0·05), but lower percentages of both early and late effector memory CD8+ cells (P<0·05) compared to references. Children with exclusively T1D had lower median fluorescence intensity (MFI) of forkhead box protein 3 (FoxP3) (P<0·05) and also a lower percentage of CD39+ and CD45RA+ within the Treg population (CD4+CD25+FOXP3+CD127-) (P<0·05). Children with exclusively coeliac disease had a higher MFI of CD101 (P<0·01), as well as a higher percentage of CD129+ (P<0·05), in the CD4+CD25hi lymphocyte population, compared to references. In conclusion, children with combined T1D and coeliac disease have a higher percentage of differentiated CD4+ cells compared to CD8+ cells. T1D children show signs of low CD39+/CD45RA+ Treg cells that may indicate loss of suppressive function. Conversely, children with coeliac disease show signs of CD101+/CD129+ Treg cells that may indicate suppressor activity.

Place, publisher, year, edition, pages
John Wiley & Sons, 2015. Vol. 180, no 1, p. 70-82
Keywords [en]
Coeliac disease; T cytotoxic cells; T helper cells; T regulatory cells; Type 1 diabetes
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:hj:diva-26373DOI: 10.1111/cei.12559ISI: 000351245800008PubMedID: 25421756Scopus ID: 2-s2.0-84924326222OAI: oai:DiVA.org:hj-26373DiVA, id: diva2:807790
Available from: 2015-04-24 Created: 2015-04-24 Last updated: 2021-09-07Bibliographically approved
In thesis
1. Pinpointing biomarkers of importance for children with combined type 1 diabetes and celiac disease
Open this publication in new window or tab >>Pinpointing biomarkers of importance for children with combined type 1 diabetes and celiac disease
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) and celiac disease are both characterized by an autoimmune feature. The diseases also share the same risk genes, and thereby patients have an increased risk of developing the other disease subsequently. The pattern of peripheral T and B cell subsets and soluble immune markers (cytokines, chemokines, acute phase proteins, adipocytokines and matrix metalloproteinases) are not yet well characterized in children with a combination of the common pediatric immunological disorders, T1D and celiac disease. To better understand the complex pathophysiology, it is important to gain a deeper knowledge of alterations present in the peripheral immune profile in children with these autoimmune diseases. Pinpointing biomarkers, e.g. peripheral immune markers, can hopefully contribute to the improvement of prognosis, diagnosis, and disease management. Flow cytometry is useful for studying different immune cells, but several pre-analytical factors may affect the outcome. In order to generate reliable results, it is important to evaluate the impact of different pre-analytical factors that possibly can lead to in vitro alterations of the immune cells.

Aim: The overall aim of this thesis was to increase our knowledge of peripheral immune marker patterns in children with a combined diagnosis of T1D and celiac disease, with a focus on T and B cell subsets and soluble immune markers; by immunological methods evaluated and adapted for this purpose.

Methods: This thesis comprises methodological and cross-sectional studies. The methodological studies are based on whole blood collected from sixty blood donors to examine the impact of pre-analytical factors (anticoagulant, sample handling time, isolation and cryopreservation) that may affect the immune cells (Study I, II). The cross-sectional studies include blood samples collected from a total of 103 participants (children with T1D and/or celiac disease or no diagnosis at all). The pattern of peripheral B (Study II) and T (Study III) cell subsets were examined by flow cytometry. Nearly thirty soluble immune markers were quantified in serum by Luminex technology (Study IV).

Results: Peripheral lymphocytes were stable in whole blood samples up to 24 hours, regardless of the anticoagulant. Generally, T and B cell subsets were not affected by isolation and cryopreservation. Children with combined T1D and celiac disease had higher percentages of terminally differentiated memory T helper cells, lower percentages of effector memory T cytotoxic cells and lower expression of suppressive immune markers on regulatory T cells compared with the other study groups. Further, children with combined T1D and celiac disease had a higher percentage of memory B and lower percentages of naive B cells than children with either T1D or celiac disease. Contrary, children with single diagnoses had an inverted naive/memory B cell pattern compared to children with combined diagnoses. Several of the "classical" (cytokines, chemokines), as well as "non-classical" (acute phase proteins, adipocytokines, matrix metalloproteinases) immune markers, were lower in children with combined diagnoses compared to the other study groups.

Conclusions: Based on our results, we conclude that whole blood samples stored up to 24 hours are feasible for flow cytometric analysis of lymphocyte subsets, regardless of the type of anticoagulant. Further, isolated and cryopreserved immune cells are feasible for flow cytometric analysis of T and B cell subsets. Impairment in the T and B cells mediated immune regulation in children with combined T1D and celiac disease seems to be clearly divergent from those seen in children with exclusively one of these two autoimmune diseases. Children with combined T1D and celiac disease appear to have a suppressed immune profile, including "classical" and "non-classical" immune markers. The methodological studies provide deeper knowledge of how reliable results can be obtained in studies of peripheral immune cells, e.g., in children with autoimmune diseases. The knowledge obtained by this thesis also brings a better understanding of the pattern of peripheral immune markers in T1D and/or celiac disease. This could potentially contribute to promoting the improvement of prognosis, diagnosis, and disease management.

Place, publisher, year, edition, pages
Jönköping: Jönköping University, School of Health and Welfare, 2021. p. 151
Series
Hälsohögskolans avhandlingsserie, ISSN 1654-3602 ; 107
Keywords
Type 1 diabetes, celiac disease, children, biomarkers, immune markers, flow cytometry, cryopreservation, T cells, T-regulatory cells, B cells, B-regulatory cells, cytokines, chemokines, acute phase proteins, adipocytokines, matrix metalloproteinases
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:hj:diva-54578 (URN)978-91-88669-06-3 (ISBN)
Public defence
2021-10-14, Forum Humanum, School of Health and Welfare, Jönköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2021-09-07 Created: 2021-09-07 Last updated: 2021-09-07Bibliographically approved

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Åkesson, KarinTompa, AndreaFaresjö, Maria

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