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- Lingman Framme, Jenny, 1977, et al.
(author)
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Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs
- 2022
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In: Journal of Clinical Immunology. - : Springer. - 0271-9142 .- 1573-2592. ; 42, s. 618-633
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Journal article (peer-reviewed)abstract
- Background: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS).Purpose: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS.Methods: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed.Results: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells.Conclusions: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring.Clinical Implications: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.
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- Lundberg, Vanja
(author)
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Thymic exosomes - effects on selection and maturation of thymocytes
- 2022
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Doctoral thesis (other academic/artistic)abstract
- T cell tolerance is primarily shaped in the thymus, through direct and indirect presentation of self-antigens to developing T cells. Medullary thymic epithelial cells (mTECs), producing and expressing self-antigens, together with dendritic cells (DCs) are the key antigen presenting cells in the thymus. In addition to direct presentation of self-antigens by mTECs, antigens are transferred to DCs followed by presentation to developing thymocytes. The underlying mechanism of this antigen transfer is not understood. Extracellular vesicles (EVs), and more specifically exosomes, are known to carry antigens and genomic material with a biological function to target cells. This thesis report thymic exosomes as mediators of antigen transfer important for T cell maturation, negative selection and Treg development. Furthermore, we show that thymic exosomes carry co-stimulatory molecules and MHC II. In the first paper, we report that exosomes derived from primary human thymic epithelial cell cultures carry self-antigens associated with autoimmune diseases. The second paper demonstrates how exosomes from mouse thymic tissue induce the final maturation of thymocytes, independently of antigen presenting cells (APCs), before they egress the thymus as T cells, in vitro. In order to study the impact of thymic exosomes on central tolerance in vivo, we used the transgenic mouse model insHEL-3A9 TCR, which is well described in studies of central tolerance. We report that thymic exosomes from HEL-mice carry the dominant HEL-peptide in complex with MHC II on their surface. Injection of thymic exosomes from HEL-mice into 3A9 TCR mice resulted in a reduction of HEL-specific thymocytes and expansion of peripheral Tregs, suggesting that thymic exosomes are important for tolerance induction. In conclusion, this thesis reports that thymic exosomes carry self-antigens and are mediators for the induction of central and peripheral tolerance.
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- Lundberg, Vanja, et al.
(author)
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Thymic exosomes promote the final maturation of thymocytes
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- Extensive knowledge has been gained the last years concerning mechanisms underlying the selection of single positive thymocytes in the thymic medulla. Less is known regarding other important processes in the thymic medulla such as the regulation of late stage thymocyte maturation. We have previously reported that exosomes are abundant in the thymus with a phenotype that indicates an epithelial cell origin and immunoregulatory properties. In this study we use an in vitro system to investigate the effects of thymic exosomes on the maturation of single positive thymocytes as well as effects on nTreg formation. We show that thymic exosomes promote the maturation of single positive CD4(+)CD25(-) cells into mature thymocytes with S1P(1)(+)Qa2(+) and CCR7(+)Qa2(+) phenotypes. Furthermore, we show that thymic exosomes reduce the formation of CD4(+)CD25(+)FoxP3(+) thymocytes and that these exosome effects are independent of dendritic cell co-stimulation but require intact exosomal RNA content and surface proteins. An efficient direct uptake of exosomes by both thymocytes and thymic DC's is also demonstrated. In conclusion, this study demonstrates that exosomes may represent a new route of communication within the thymus.
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- Oikonomou, Vasileios, et al.
(author)
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The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.
- 2024
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In: The New England journal of medicine. - 1533-4406. ; 390:20, s. 1873-1884
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Journal article (peer-reviewed)abstract
- Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses.Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients.Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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- Proletov, Ian, et al.
(author)
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Primary and secondary glomerulonephritides 1.
- 2014
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In: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 29 Suppl 3:May, s. 186-200
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Journal article (peer-reviewed)
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| 8. |
- Rentzos, Georgios K., et al.
(author)
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Intestinal allergic inflammation in birch pollen allergic patients in relation to pollen season, IgE sensitization profile and gastrointestinal symptoms
- 2014
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In: Clinical and Translational Allergy. - : Wiley. - 2045-7022. ; 4:19
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Journal article (peer-reviewed)abstract
- Background: Birch pollen allergic patients frequently experience gastrointestinal upset accompanied by a local allergic inflammation in the small intestine especially during the pollen season. However, it is not known if the GI pathology is connected to the subjective symptoms of the patient. The objective of this study was to evaluate the immune pathology of the duodenal mucosa and the serum IgE antibody profiles in birch pollen allergic patients in relation to their gastrointestinal symptoms, during and outside the birch pollen season. Methods: Thirty-two patients with birch pollen allergy and sixteen healthy controls were enrolled in the study. Twenty allergic patients had gastrointestinal symptoms and twelve did not. All participants underwent an allergy investigation and gastroscopy with duodenal biopsy. The duodenal biopsies were retrieved during the pollen season (May-June) and off-season (November-March). The biopsies were immunostained for mast cells (IgE and tryptase), eosinophils, T cells (CD3), and dendritic cells (CD11c). Pollen-specific IgE antibodies were determined by ImmunoCAP and component microarray (ISAC). Results: Patients in both pollen allergic groups showed similar degree of intestinal allergic inflammation during the pollen season regardless of gastrointestinal symptoms. The eosinophils, mast cells and dendritic cells were increased in the mucosa. Patients with gastrointestinal symptoms had significantly elevated IgE antibodies to birch (rBet v 1), hazelnut (rCor a 1), and apple (rMal d1) during the pollen season. Conclusions: Patients allergic to birch pollen have clear signs of an ongoing allergic inflammation in their intestinal mucosa, which is aggravated during the pollen season. The magnitude of the allergic intestinal inflammation is not associated with subjective gastrointestinal symptoms of the individual patient. © 2014 Rentzos et al.; licensee BioMed Central Ltd.
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| 9. |
- Rentzos, Georgios K., et al.
(author)
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Use of a basophil activation test as a complementary diagnostic tool in the diagnosis of severe peanut allergy in adults
- 2015
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In: Clinical and Translational Allergy. - : Wiley. - 2045-7022. ; 5
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Journal article (peer-reviewed)abstract
- Background: Diagnosis of severe peanut allergy is difficult and delays in making an accurate diagnosis may place the patient at risk. Adults with a history of anaphylaxis must strictly avoid any contact with peanuts or products that may contain traces of peanuts. For these persons, conventional evaluations with skin prick testing (SPT) and IgE tests may not be sufficient to assess the risk of anaphylaxis. Therefore, we investigated whether the basophil activation test (BAT) could be used for the diagnosis of severe peanut allergy in adults. We compared the non-invasive BAT with conventional laboratory diagnostic tests, including SPT and specific IgE to allergen extracts and components, for the diagnosis of severe peanut allergy. Methods: Forty-seven persons with severe allergy to peanuts and a clinical diagnosis of anaphylaxis (PA-group), 22 subjects with peanut sensitization (PS-group) and 22 control (C-group) subjects, all in the age range of 18-60 years, were recruited retrospectively and prospectively into the study. Thirty-four patients with peanut allergy and 11 peanut-sensitized patients were sensitized to soy, while 36 patients in the PA-group and 20 patients in the PS-group were sensitized to birch pollen. All the patients and control subjects were investigated with BAT and SPT for responses to peanut, soy and birch extracts and their serum samples were assayed for the presence of specific IgE to peanut, soy and birch extracts, as well as IgE to allergen components (ISAC). Results: In a multivariate factor analysis, severe peanut allergy (PA) was positively associated with SPT to peanut, IgE to peanut, BAT to peanut and IgE to rAra h 1, 2, 3 and 6 peanut components, as well as to soy components (nGly m 5 and nGly m 6). In contrast, peanut sensitization was positively associated with increased levels of IgE to rAra h 8, birch and birch-related components. BAT-detected reactivity to peanut was significantly higher in patients who had a history of severe allergy to peanuts, as compared with patients who were sensitized to peanuts (p < 0.001), and the receiver operating curve (ROC) analysis showed that BAT had high sensitivity and specificity for predicting severe peanut allergy, with a ROC area under the curve of 0.862. However, in the PA-group, the BAT results for peanut correlated only weakly with the levels of IgE to rAra h 1, 2 and 3 and nAra h 6. Study limitations: oral provocation in the patients with a history of severe peanut allergy could not be performed to compare clinical reactivity with the BAT result due to ethical constraints. Neither was it possible to perform BAT with peanut recombinant allergens which were not available at the time the study commenced Conclusions: BAT is useful in determining the severity of peanut allergy and may be used as a complementary diagnostic tool to ensure accurate diagnosis of severe peanut allergy in adults. Thus, it may reduce the need to subject these patients to further tests, including an open challenge with peanuts. © 2015 Rentzos et al.; licensee BioMed Central.
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| 10. |
- Skogberg, Gabriel, et al.
(author)
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Altered expression of autoimmune regulator in infant down syndrome thymus, a possible contributor to an autoimmune phenotype.
- 2014
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In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 193:5, s. 2187-95
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Journal article (peer-reviewed)abstract
- Down syndrome (DS), caused by trisomy of chromosome 21, is associated with immunological dysfunctions such as increased frequency of infections and autoimmune diseases. Patients with DS share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients affected by autoimmune polyendocrine syndrome type 1. Autoimmune polyendocrine syndrome type 1 is caused by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates the expression of tissue-restricted Ags (TRAs) in thymic epithelial cells. We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quantitative PCR. AIRE mRNA levels were elevated in thymic tissue from DS patients, and trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found. Immunohistochemical stainings showed altered cell composition and architecture of the thymic medulla in DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-positive dendritic cells as well as enlarged Hassall's corpuscles. In addition, we evaluated the proteomic profile of thymic exosomes in DS individuals and controls. DS exosomes carried a broader protein pool and also a larger pool of unique TRAs compared with control exosomes. In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thymic epithelial cells that affect thymic selection processes.
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