| 1. |
- Ekebergh, Andreas, 1984, et al.
(författare)
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Exploring a cascade Heck-Suzuki reaction based route to kinase inhibitors using design of experiments
- 2015
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 13:11, s. 3382-3392
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Tidskriftsartikel (refereegranskat)abstract
- Design of Experiments (DoE) has been used to optimize a diversity oriented palladium catalyzed cascade Heck-Suzuki reaction for the construction of 3-alkenyl substituted cyclopenta[b]indole compounds. The obtained DoE model revealed a reaction highly dependent on the ligand. Guided by the model, an optimal ligand was chosen that selectively delivered the desired products in high yields. The conditions were applicable with a variety of boronic acids and were used to synthesize a library of 3-alkenyl derivatized compounds. Focusing on inhibition of kinases relevant for combating melanoma, the library was used in an initial structure-activity survey. In line with the observed kinase inhibition, cellular studies revealed one of the more promising derivatives to inhibit cell proliferation via an apoptotic mechanism.
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| 2. |
- Albinsson, Sofie, et al.
(författare)
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Distinct populations of eosinophils in the human thymus with capacity to modulate thymocyte maturation.
- 2023
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 169:1, s. 57-68
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Tidskriftsartikel (refereegranskat)abstract
- Local differentiation of eosinophil precursors occurs in the human thymus. Thymic eosinophils are often positioned in the corticomedullary junction between the CD4+ CD8+ double-positive (DP) thymocytes and the CD4+ or CD8+ single-positive (SP) thymocytes. The aims of this study were to (1) determine if there are distinct thymic eosinophil populations that differ from the blood eosinophil populations and (2) evaluate the capacity of thymic eosinophils to promote the development of SP thymocytes from DP thymocytes. Thymic and blood eosinophils from thymectomized infants (n=7) were compared regarding the expression of 34 molecules using cytometry by time-of-flight (CyTOF). In addition, FACS-sorted thymic eosinophils were co-cultured with autologous CD3/CD28-stimulated DP, CD4 SP, and CD8 SP thymocytes and analysed by flow cytometry and CyTOF. X-shift clustering analysis and viSNE dimensionality reduction were performed. Seven eosinophil populations were identified within the blood and thymus, respectively, five of which were specific for either tissue. Whereas the blood eosinophil populations varied between individuals, the thymic eosinophil populations were more uniform. The eosinophil-thymocyte co-cultures resulted in (1) an increase in CD4 SP thymocytes when eosinophils were cultured with DP thymocytes, (2) decreased frequency of CD8 SP thymocytes when these were cultured with eosinophils, and (3) a more mature thymic phenotype when eosinophils were cultured with CD4 SP thymocytes. Thymic eosinophils are a specialized population of eosinophils with a distinct phenotype that separates them from their blood counterparts, and in vitro they appear to favour CD4 SP thymocyte development to the detriment of CD8 SP thymocytes.
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| 3. |
- Albinsson, Sofie, 1992, et al.
(författare)
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Eosinophils interact with thymocytes and proliferate in the human thymus
- 2021
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Ingår i: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 51:6, s. 1539-1541
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophils differentiate and mature in the thymus, outside of the bone marrow, in healthy individuals. Locally developed thymic eosinophils may contribute to the maturation and selection of human thymocytes.
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| 4. |
- Albinsson, Sofie, 1992, et al.
(författare)
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Extracellular distribution of galectin-10 in the esophageal mucosa of patients with eosinophilic esophagitis
- 2023
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Ingår i: CLINICAL AND EXPERIMENTAL IMMUNOLOGY. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 212:2, s. 147-155
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Tidskriftsartikel (refereegranskat)abstract
- CD16+ eosinophils and large amounts of extracellular vesicles containing galectin-10, a T-cell suppressive eosinophil protein, were found in the esophageal mucosa of patients with active eosinophilic esophagitis. Both the CD16+ eosinophils and the released galectin-10-containing extracellular vesicles disappeared in successfully treated patients but remained in the mucosa of the non-responders to treatment. Eosinophilic esophagitis is a T-cell-driven allergic condition hallmarked by eosinophil infiltration of the esophagus. Eosinophils exposed to proliferating T cells release galectin-10 and have T-cell suppressive function in vitro. The aims of this study were to evaluate if eosinophils co-localize with T cells and release galectin-10 in the esophagus of patients with eosinophilic esophagitis. Esophageal biopsies from 20 patients with eosinophilic esophagitis were stained for major basic protein, galectin-10, CD4, CD8, CD16, and CD81 and analyzed by immunofluorescence confocal microscopy before and after topical corticosteroid treatment. CD4+ T-cell numbers decreased in the esophageal mucosa of responders to treatment but not in the non-responders. Suppressive (CD16+) eosinophils were present in the esophageal mucosa of patients with active disease and decreased after successful treatment. Unexpectedly, eosinophils and T cells were not in direct contact with each other. Instead, the esophageal eosinophils released large amounts of galectin-10-containing extracellular vesicles and featured cytoplasmic projections that contained galectin-10, both of which disappeared from the esophagus of the responders but remained in the non-responders. To conclude, the presence of CD16+ eosinophils together with the massive release of galectin-10-containing extracellular vesicles in the esophageal mucosa might indicate that eosinophils exert T-cell suppression in eosinophilic esophagitis.
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| 5. |
- Andersson, Jennie, 1978, et al.
(författare)
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Eosinophils from hematopoietic stem cell recipients suppress allogeneic T cell proliferation.
- 2014
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Ingår i: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. - : Elsevier BV. - 1523-6536. ; 20:12, s. 1891-8
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophilia has been associated with less severe graft-versus-host disease (GVHD), but the underlying mechanism is unknown. We hypothesized that eosinophils diminish allogeneic T cell activation in patients with chronic GVHD. The capacity of eosinophils derived from healthy subjects and hematopoietic stem cell (HSC) transplant recipients, with or without chronic GVHD, to reduce allogeneic T cell proliferation was evaluated using a mixed leukocyte reaction. Eosinophil-mediated inhibition of proliferation was observed for the eosinophils of both healthy subjects and patients who underwent HSC transplantation. Eosinophils from patients with and without chronic GVHD were equally suppressive. Healthy eosinophils required cell-to-cell contact for their suppressive capacity, which was directed against CD4(+) T cells and CD8(+) T cells. Neither eosinophilic cationic protein, eosinophil-derived neurotoxin, indoleamine 2,3-dioxygenase, or increased numbers of regulatory T cells could account for the suppressive effect of healthy eosinophils. Real-time quantitative PCR analysis revealed significantly increased mRNA levels of the immunoregulatory protein galectin-10 in the eosinophils of both chronic GVHD patients and patients without GVHD, as compared with those from healthy subjects. The upregulation of galectin-10 expression in eosinophils from patients suggests a stimulatory effect of HSC transplantation in itself on eosinophilic galectin-10 expression, regardless of chronic GVHD status. To conclude, eosinophils from HSC transplant recipients and healthy subjects have a T cell suppressive capacity.
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| 6. |
- Käppi, Timo, 1975, et al.
(författare)
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Collagenous Gastritis in Children: Incidence, Disease Course, and Associations With Autoimmunity and Inflammatory Markers.
- 2020
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Ingår i: Clinical and translational gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 2155-384X. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Collagenous gastritis (CG), a rare disorder of unknown etiology, has been postulated to have immune-mediated mechanisms. We investigated (i) the incidence and prevalence of CG in a pediatric population; (ii) the clinical, endoscopic, and histologic characteristics of childhood-onset CG; and (iii) the evidence for autoimmunity and/or inflammatory activity in these patients.Clinical, endoscopic, and histologic data were reviewed longitudinally in a population-based Swedish cohort of 15 patients with childhood-onset CG diagnosed in the period 2008-2019. A set of 11 autoantibodies, 4 blood inflammatory biomarkers, and the human leukocyte antigen DQ2/DQ8 genotype was analyzed cross-sectionally.The incidence rate of childhood-onset CG was 0.25/100,000 person-years, with an incidence rate ratio of girls to boys of 4.2 (95% confidence interval, 1.2-15). The prevalence of CG was 2.1/100,000 in children aged younger than 18 years. The endoscopic and histologic findings remained pathologic in all the examined patients during a median follow-up of 4.4 years. Many patients had heredity for autoimmune disorders (47%) and/or tested positive for autoantibodies (40%) or human leukocyte antigen DQ2/DQ8 (53%). No associated autoimmune comorbidities were observed. The serum levels of calprotectin and amyloid A were increased in 10/15 (67%) and 5/15 (33%) of the patients, respectively, whereas plasma C-reactive protein levels were normal in all, but 1 patient.The results indicate that childhood-onset CG is rare and has a chronic disease course. Although signs of autoimmune predisposition are frequent, early development of autoimmune comorbidities seems seldom. Serum calprotectin and amyloid A represent novel candidate biomarkers of inflammatory activity in CG (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A349).
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| 7. |
- Käppi, Timo, 1975, et al.
(författare)
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High frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation
- 2019
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Ingår i: Transplantation. - 1534-6080. ; 103:11, s. 2338-2346
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Tidskriftsartikel (refereegranskat)abstract
- Allergy and other immune-mediated diseases are more frequently reported in children who have undergone liver transplantation. Furthermore, autoantibodies are also prevalent, suggesting a state of immune dysregulation in these patients. Whether or not these processes occur simultaneously in the same individual has not been studied previously.A cohort of 43 children who had undergone liver transplantation for nonautoimmune liver disease at median age of 1.3 years was investigated for allergy and autoimmune disease. Sensitization to food and inhalant allergens was assessed and autoantibodies were measured.The prevalence of food allergy was 26% and that of respiratory allergy was 23%, while 33% and 26% of the subjects were sensitized to food and inhalant allergens, respectively. Autoimmune disease (i.e., autoimmune hepatitis) occurred in a single individual (2%), whereas autoantibodies were present in 44% of the children. Food allergy and autoantibodies occurred concomitantly in 19% of the children, which was almost twice the frequency expected by chance (11%, p=0.04). Respiratory allergy and the presence of autoantibodies were unrelated (12% concurrence vs the expected 10%, p = 0.73). In the logistic regression analysis, autoantibody formation was associated with discontinued immunosuppression and food allergy, with odds ratios of 13 (p=0.01) and 7.1 (p=0.03), respectively.In contrast to respiratory allergy, food allergy and autoantibody formation occurred together in the same children who underwent liver transplantation at a frequency higher than would be expected by chance. This may reflect an underlying immune dysregulation that impairs immune tolerance to both food allergens and autoantigens.
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| 8. |
- Lingblom, Christine, 1984, et al.
(författare)
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Differences in eosinophil molecular profiles between children and adults with eosinophilic esophagitis.
- 2017
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 72:9, s. 1406-1414
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophilic esophagitis (EoE) afflicts both children and adults. It has been debated whether pediatric and adult EoE represent different disease entities. The objectives of this study were to determine if the blood eosinophil molecular pattern of children with EoE is: 1) distinct from that of healthy children; and 2) different from that of adults with EoE.Blood eosinophils from children and adults with EoE, and healthy controls, were analyzed with flow cytometry regarding levels of CD23, CD44, CD54, CRTH2, FOXP3 and galectin-10. Eosinophil FOXP3 and galectin-10 mRNA levels were determined by qPCR. The data was analyzed by using a multivariate method of pattern recognition.An eosinophil molecular pattern capable of distinguishing children with EoE from control children was identified. A smaller fraction of eosinophils from children with EoE expressed CD44 and a larger fraction expressed CRTH2 than the controls. Eosinophils from children with EoE also had higher levels of galectin-10 mRNA and lower levels of FOXP3 mRNA. The eosinophils from children with EoE had lower levels of surface CD54 and of FOXP3 mRNA compared with the eosinophils from the adult patients. A key finding was the detection in healthy individuals of age-related differences in the levels of several eosinophil markers.Children with EoE can be distinguished from healthy children based on the molecular patterns of their blood eosinophils. Age-related physiologic differences in eosinophil molecular patterns may partly explain the different blood eosinophil phenotypes in children versus adults with EoE. This article is protected by copyright. All rights reserved.
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| 9. |
- Lingblom, Christine, 1984, et al.
(författare)
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Eosinophils from eosinophilic oesophagitis patients have T cell suppressive capacity and express FOXP3.
- 2017
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 1365-2249 .- 0009-9104. ; 187:3, s. 455-465
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophilic esophagitis (EoE) is an antigen-driven T cell-mediated chronic inflammatory disease where food and environmental antigens are thought to have a role. Human eosinophils express the immunoregulatory protein galectin-10 and have T cell suppressive capacity similar to regulatory T cells (Tregs ). We hypothesized that one function of eosinophils in EoE might be to regulate the T cell-driven inflammation in the oesophagus. This was tested by evaluating the suppressive capacity of eosinophils isolated from the blood of adult EoE patients in a mixed lymphocyte reaction. In addition, eosinophilic expression of forkhead box protein 3 (FOXP3), the canonical transcription factor of Tregs , was determined by conventional and imaging flow cytometry, quantitative polymerase chain reaction (qPCR), confocal microscopy and immunoblotting. It was found that blood eosinophils from EoE patients had T cell suppressive capacity, and that a fraction of the eosinophils expressed FOXP3. A comparison of EoE eosinophils with healthy control eosinophils indicated that the patients' eosinophils had inferior suppressive capacity. Furthermore, a higher percentage of the EoE eosinophils expressed FOXP3 protein compared with the healthy eosinophils, and they also had higher FOXP3 protein and mRNA levels. FOXP3 was found in the cytosol and nucleus of the eosinophils from both the patients and healthy individuals, contrasting with the strict nuclear localization of FOXP3 in Tregs . To conclude, these findings suggest that the immunoregulatory function of eosinophils may be impaired in EoE.
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| 10. |
- Lingblom, Christine, 1984, et al.
(författare)
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Kinetic studies of galectin-10 release from eosinophils exposed to proliferating T cells
- 2021
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 203:2, s. 230-234
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-10 is involved in the T cell suppressive activity of regulatory T cells and eosinophils alike. We have identified a subpopulation of T cell suppressive eosinophils that express CD16 on the surface and contain more galectin-10 compared with conventional CD16-negative eosinophils. Our main goal was to determine how the intracellular protein galectin-10 is released from eosinophils when exposed to proliferating T cells and if such release could be inhibited. Confocal microscopy and imaging flow cytometry were used to study the release of galectin-10 from eosinophils incubated with polyclonally activated T cells. T cell proliferation was monitored by measurement of the incorporation of [H-3]-thymidine. Initially, galectin-10-containing synapses formed between eosinophils and T cells. Subsequently, the plasma membrane of eosinophils began to disintegrate and cap-like accumulations of galectin-10 budded on the eosinophil cell surface. Lastly, eosinophil extracellular traps composed of nuclear DNA and galectin-10 were freed. It was solely the CD16-expressing suppressive eosinophils that formed synapses and eosinophil extracellular traps containing galectin-10. Dissolution of the extracellular traps by DNase I partly abrogated the T cell suppression exerted by eosinophils. Extracellular trap formation has mainly been associated with anti-bacterial defense, but we show a new putative function of these cellular formations, as mediators of T cell suppression by enabling the release of galectin-10 from eosinophils.
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| 11. |
- Lingblom, Christine, 1984, et al.
(författare)
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Patient-Reported Outcomes and Blood-Based Parameters Identify Response to Treatment in Eosinophilic Esophagitis
- 2021
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Ingår i: Digestive Diseases and Sciences. - : Springer Science and Business Media LLC. - 0163-2116 .- 1573-2568. ; 66, s. 1556-1564
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Tidskriftsartikel (refereegranskat)abstract
- Background Noninvasive methods to assess treatment response in eosinophilic esophagitis are needed. Aims Our aim was to determine whether a blood-based biomarker panel centered on immune parameters could identify histologic response to treatment in eosinophilic esophagitis patients. Methods A pilot study involving adult patients with active eosinophilic esophagitis recruited at two Ear, Nose, Throat clinics in Sweden was designed. The patients (n = 20) donated blood and esophageal biopsies and filled in three questionnaires before and after a 2-month course of topical corticosteroids. Blood samples were analyzed for absolute levels of granulocytes and T cells and the fractions of eosinophils expressing 10 different surface markers by flow cytometry. All data were analyzed by multivariate methods of pattern recognition. Results Multivariate modeling revealed that a combination of 13 immune parameters and 10 patient-reported outcome scores were required to create a model capable of separating responders (n = 15) from non-responders (n = 5). Questions regarding symptoms of esophageal dysfunction and capacity to eat certain foods from two of the questionnaires were discriminatory in the multivariate model, as were absolute counts of T cells, eosinophils, and eosinophil expression of activation markers and cell adhesion molecules. Conclusions A combination of blood-based immune parameters and directed questions may prove helpful to monitor response to treatment, perhaps reducing the need for repeat endoscopies in eosinophilic esophagitis patients in the future.
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| 12. |
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| 13. |
- Lingblom, Christine, 1984, et al.
(författare)
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Regulatory Eosinophils Suppress T Cells Partly through Galectin-10
- 2017
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 198:12, s. 4672-4681
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophils have the capacity to regulate the function of T cell subsets. Our aim was to test the hypothesis of the existence of a regulatory subset of eosinophils. Human eosinophils were incubated with T cells that were stimulated with allogeneic leukocytes or CD3/ CD28 cross-linking. After 2 d of coculture, 11% of the eosinophils gained CD16 expression. A CD16(hi) subset of eosinophils, encompassing 1-5% of all eosinophils, was also identified in the blood of healthy subjects. FACS sorting showed that these CD16(hi) eosinophils were significantly stronger suppressors of T cell proliferation than were conventional CD16 neg eosinophils. Human eosinophils contain stores of the immunoregulatory protein galectin-10. We found that Ab-mediated neutralization of galectin-10 partially abrogated the suppressive function of the eosinophils. Moreover, recombinant galectin-10 by itself was able to suppress T cell proliferation. Finally, we detected galectin-10-containing immune synapses between eosinophils and lymphocytes. To conclude, we describe a subset of suppressive eosinophils expressing CD16 that may escape detection because CD16-based negative selection is the standard procedure for the isolation of human eosinophils. Moreover, we show that galectin-10 functions as a T cell-suppressive molecule in eosinophils.
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| 14. |
- Lingblom, Christine, 1984, et al.
(författare)
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Topical Corticosteroids Do Not Revert the Activated Phenotype of Eosinophils in Eosinophilic Esophagitis but Decrease Surface Levels of CD18 Resulting in Diminished Adherence to ICAM-1, ICAM-2, and Endothelial Cells.
- 2014
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Ingår i: Inflammation. - : Springer Science and Business Media LLC. - 1573-2576 .- 0360-3997. ; 37:6, s. 1932-1944
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Tidskriftsartikel (refereegranskat)abstract
- Swallowed topical corticosteroids are the standard therapy for eosinophilic esophagitis (EoE) in adults. Eosinophils in the blood of untreated EoE patients have an activated phenotype. Our aim was to determine if corticosteroids restore the phenotype of eosinophils to a healthy phenotype and if certain cell-surface molecules on blood eosinophils correlate with eosinophilic infiltration of the esophagus. Levels of eight surface markers on eosinophils from treated and untreated EoE patients were determined by flow cytometry and analyzed using multivariate methods of pattern recognition. Corticosteroid-treated EoE patients' eosinophils had decreased levels of CD18 compared to both untreated patients and healthy controls, but maintained their activated phenotype. CD18 expression correlated positively with eosinophil numbers in the esophagus and promoted the adherence of eosinophils to ICAM-1, ICAM-2, and to endothelial cells. The diminished expression of CD18 may be one mechanism behind the reduced entry of eosinophils into the esophagus in corticosteroid-treated EoE patients.
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| 15. |
- Wass, Linda, et al.
(författare)
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Cultivation of the causative agent of human neoehrlichiosis from clinical isolates identifies vascular endothelium as a target of infection.
- 2019
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Ingår i: Emerging microbes & infections. - : Informa UK Limited. - 2222-1751. ; 8:1, s. 413-425
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Tidskriftsartikel (refereegranskat)abstract
- Candidatus (Ca.) Neoehrlichia mikurensis is the cause of neoehrlichiosis, an emerging tick-borne infectious disease characterized by fever and vascular events. The bacterium belongs to the Anaplasmataceae, a family of obligate intracellular pathogens, but has not previously been cultivated, and it is uncertain which cell types it infects. The goals of this study were to cultivate Ca. N. mikurensis in cell lines and to identify possible target cells for human infection. Blood components derived from infected patients were inoculated into cell lines of both tick and human origin. Bacterial growth in the cell cultures was monitored by real-time PCR and imaging flow cytometry. Ca. N. mikurensis was successfully propagated from the blood of immunocompromised neoehrlichiosis patients in two Ixodes spp. tick cell lines following incubation periods of 7-20 weeks. Human primary endothelial cells derived from skin microvasculature as well as pulmonary artery were also susceptible to infection with tick cell-derived bacteria. Finally, Ca. N. mikurensis was visualized within circulating endothelial cells of two neoehrlichiosis patients. To conclude, we report the first successful isolation and propagation of Ca. N. mikurensis from clinical isolates and identify human vascular endothelial cells as a target of infection.
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| 16. |
- Ekebergh, Andreas, 1984, et al.
(författare)
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Cyclopenta[ b]indole Derivative Inhibits Aurora B in Primary Cells
- 2020
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 5:51, s. 33455-33460
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Tidskriftsartikel (refereegranskat)abstract
- The Aurora family of kinases is closely involved in regulating cell division. Inhibition of Aurora A and B with small molecules is currently being investigated in clinical trials for the treatment of different cancers. It has also been evaluated as a treatment option against different autoimmune diseases in preclinical studies. Here, we present a cyclopenta[b]indole derivative capable of inhibiting Aurora B selectively in kinase assays. To evaluate the Aurora B inhibition capacity of the compound, we used a kinase IC50 assay as well as a suppression assay of proliferating primary cells. In addition, we examined if the cells had gained a phenotype characteristic for Aurora B inhibition after treatment with the compound. We found that the compound selectively inhibited Aurora B (IC50 = 1.4 μM) over Aurora A (IC50 > 30 μM). Moreover, the compound inhibited proliferating PBMCs with an IC50 = 4.2 μM, and the cells displayed reduced phosphorylation of histone H3 as well as tetraploidy, consistent with Aurora B inhibition.
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| 17. |
- Larsson, Helene, et al.
(författare)
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Investigating immune profile by CyTOF in individuals with long-standing type 1 diabetes
- 2023
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Ingår i: Scientific Reports. - : Nature Research. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D) is an autoimmune disease caused by T-cell mediated destruction of pancreatic beta cells. Eosinophils are found in pancreatic tissue from individuals with T1D. Eosinophilic suppression of T cells is dependent of the protein galectin-10. Little is known when it comes to the role of eosinophil granulocytes in type 1 diabetes. Here we show that individuals with long-standing T1D had lower levels of galectin-10hi eosinophils and a subgroup of galectin-10hi eosinophils were entirely absent in all T1D patients. In addition, 7% immature eosinophils were present in the circulation of T1D patients whereas 0.8% in healthy individuals. Furthermore, higher levels of CD4+CD8+ T cells and Th17 cells were observed in patients with T1D. Blood samples from 12 adult individuals with long-standing T1D and 12 healthy individuals were compared using cytometry by time-of-flight. Lower levels of galectin-10hi eosinophils, which are potent T cell suppressors, in individuals with T1D could indicate that activated T cells are enabled to unrestrictedly kill the insulin producing beta cells. This is the first study showing absence of galectin-10hi eosinophilic subgroup in individuals with T1D compared with healthy controls. This study is a first important step toward unraveling the role of the eosinophils in patients with T1D.
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| 18. |
- Lingblom, Christine, 1984
(författare)
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Functional and Phenotypic Studies of Eosinophilic Granulocytes in Patients with Eosinophilic Esophagitis
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Eosinophilic Esophagitis (EoE) is a chronic inflammatory disorder of unknown etiology, in which the esophagus is infiltrated by eosinophils and T cells. Topical corticosteroids are one of the treatment options for patients with EoE. The function of eosinophils in EoE is unknown, here we hypothesize that eosinophils serve as immunoregulatory cells. The eosinophils in the blood of untreated adult patients with EoE have a distinct phenotype. The aims of this thesis were to explore whether the eosinophilic phenotype of untreated patients with EoE can be reverted to the healthy phenotype by topical corticosteroid treatment, and to examine whether blood eosinophils from children with EoE have a distinct phenotype, different from that of healthy children. Moreover, we tested the hypothesis that eosinophils, similar to regulatory T cells, can diminish T cell proliferation and express FOXP3. The role of the eosinophilic protein galectin-10 in mediating immunosuppression was also investigated. This thesis demonstrates that the EoE phenotype of blood eosinophils is not restored by topical corticosteroid treatment, except with respect to CD18. We also show that eosinophils from patients with EoE have an immunoregulatory phenotype, i.e., increased levels of FOXP3 and galectin-10. Moreover, eosinophils from healthy subjects and patients with EoE are able to suppress T cell proliferation in vitro, in part via galectin-10. We show that eosinophils exposed to activated T cells release galectin-10 via DNA nets and appear to transfer this protein to T cells through synapses. Two subsets of eosinophils emerge after co-culturing. Finally, we demonstrate that the blood eosinophils of children with EoE have a distinct phenotype, different from that of healthy children and that of adults with EoE. Importantly, we reveal marked age-related differences regarding the molecular patterns displayed by the blood eosinophils of healthy donors. Our finding that eosinophils from patients with EoE have upregulated immunoregulatory molecules could indicate that the function of eosinophils in EoE is to reduce a T cell-mediated inflammation in the esophagus.
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