19657
2016
eng
141-154
2
171
article
1
--
2016-12-01
--
Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis
Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.
International Archives of Allergy and Immunology
1018-2438
1423-0097
10.1159/000450949
27902985
urn:nbn:de:bvb:20-opus-196577
This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
swordwue
2020-01-14T14:18:46+00:00
attachment; filename=deposit.zip
c83b8f6f2bd0a0207069c72555c5d60e
International Archives of Allergy and Immunology 2016;171(2):141–154 DOI: 10.1159/000450949
false
true
Deutsches Urheberrecht
Giovanni Almanzar
Matthias Klein
Marc Schmalzing
Deborah Hilligardt
Nady El Hajj
Hermann Kneitz
Vanessa Wild
Andreas Rosenwald
Sandrine Benoit
Henning Hamm
Hans-Peter Tony
Thomas Haaf
Matthias Goebeler
Martina Prelog
eng
uncontrolled
methylation
eng
uncontrolled
systemic sclerosis
eng
uncontrolled
suppression
eng
uncontrolled
Tregs
eng
uncontrolled
Th17
Medizin und Gesundheit
open_access
Kinderklinik und Poliklinik
Pathologisches Institut
Institut für Humangenetik
Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
Medizinische Klinik und Poliklinik II
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/19657/IAA450949.pdf
14649
2016
eng
3
13
article
1
2017-03-31
--
--
Efforts of the human immune system to maintain the peripheral CD8+ T cell compartment after childhood thymectomy
Background
Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system.
The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls.
Results
Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV.
Conclusions
After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans.
Immunity & Ageing
10.1186/s12979-016-0058-z
urn:nbn:de:bvb:20-opus-146497
Immunity & Ageing (2016) 13:3 DOI 10.1186/s12979-016-0058-z
Manuela Zlamy
Giovanni Almanzar
Walther Parson
Christian Schmidt
Johannes Leierer
Birgit Weinberger
Verena Jeller
Karin Unsinn
Matthias Eyrich
Reinhard Würzner
Martina Prelog
eng
uncontrolled
thymectomy
eng
uncontrolled
naive T cells
eng
uncontrolled
TRECs
eng
uncontrolled
TCR diversity
eng
uncontrolled
CMV
eng
uncontrolled
CD8
eng
uncontrolled
telomeres
Medizin und Gesundheit
open_access
Kinderklinik und Poliklinik
Förderzeitraum 2016
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14649/Zlamy_10.1186_s12979-016-0058-z.pdf
9643
2013
eng
article
1
--
--
--
Maternal cigarette smoking and its effect on neonatal lymphocyte subpopulations and replication
Background
Significant immunomodulatory effects have been described as result of cigarette smoking in adults and pregnant women. However, the effect of cigarette smoking during pregnancy on the lymphocyte subpopulations in newborns has been discussed, controversially.
Methods
In a prospective birth cohort, we analyzed the peripheral lymphocyte subpopulations of smoking (SM) and non-smoking mothers (NSM) and their newborns and the replicative history of neonatal, mostly naive CD4 + CD45RA + T cells by measurements of T-cell-receptor-excision-circles (TRECs), relative telomere lengths (RTL) and the serum cytokine concentrations.
Results
SM had higher lymphocyte counts than NSM. Comparing SM and NSM and SM newborns with NSM newborns, no significant differences in proportions of lymphocyte subpopulations were seen. Regardless of their smoking habits, mothers had significantly lower naive T cells and higher memory and effector T cells than newborns. NSM had significantly lower percentages of CD4 + CD25++ T cells compared to their newborns, which was not significant in SM. There were no differences regarding cytokine concentrations in newborns of SM and NSM. However, NSM had significantly higher Interleukin-7 concentrations than their newborns. Regardless of smoking habits of mothers, newborns had significantly longer telomeres and higher TRECs than their mothers. Newborns of SM had significantly longer telomeres than newborns of NSM.
Conclusions
Apart from higher lymphocyte counts in SM, our results did not reveal differences between lymphocyte subpopulations of SM and NSM and their newborns, respectively. Our finding of significantly longer RTL in newborns of SM may reflect potential harm on lymphocytes, such as cytogenetic damage induced by smoking.
BMC Pediatrics
10.1186/1471-2431-13-57
http://www.biomedcentral.com/1471-2431/13/57
urn:nbn:de:bvb:20-opus-96435
In: BMC Pediatrics (2013) 13: 57, doi:10.1186/1471-2431-13-57
Martina Prelog
Giovanni Almanzar
Gernot Eberle
Andrea Lassacher
Christian Specht
Christian Koppelstaetter
Peter Heinz-Erian
Rudolf Trawöger
David Bernhard
eng
uncontrolled
Cigarette smoking
eng
uncontrolled
Lymphocytes
eng
uncontrolled
T cell receptor excision circles
eng
uncontrolled
Telomeres
Medizin und Gesundheit
open_access
Kinderklinik und Poliklinik
Förderzeitraum 2013
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/9643/Prelog_1471-2431-13-57.pdf
9632
2013
eng
article
1
--
--
--
Increased replication of CD4+ naive T cells and changes in T cell homeostasis in a case of acute exacerbation of juvenile idiopathic arthritis: a case comparison study
Introduction
Juvenile idiopathic arthritis is a heterogeneous T cell-mediated autoimmune disease with symptoms of premature aging of the immune system (immunosenescence). The present work is an investigation of immunosenescence parameters, such as quantity of naive and CD28- T cells, T cell receptor excision circles, relative telomere length and alterations of peripheral T cell replication, and was performed via comparison of a case of acute exacerbation of juvenile idiopathic arthritis against six patients with juvenile idiopathic arthritis with disease remission and six age-matched healthy donors over a follow-up course of 12 months.
Case presentation
Phenotypical T cell characterization and intracellular interferon γ, tumor necrosis factor α, and interleukin 2 production were studied in peripheral blood mononuclear cells from seven patients with juvenile idiopathic arthritis and six healthy control donors, with findings determined by flow cytometry. T cell receptor excision circles and relative telomere length quantification were performed on deoxyribonucleic acid isolated from naive (CD4+CD28+CD45RA+) T cells and investigated via reverse transcription polymerase chain reaction. Ki67 expression was studied by immunohistochemistry on naive T cells. The non-parametric Mann-Whitney U test and Wilcoxon test for two independent groups of variables were used to compare healthy donors with patients with juvenile idiopathic arthritis. During follow-up, patients with juvenile idiopathic arthritis showed lower total counts of naive and CD28-expressing T cells compared to healthy donors. Acute exacerbation led to low naive and CD28+ T cell populations and elevated proportions of Ki67-expressing CD4+ naive T cells. In conditions of exacerbation, T cell receptor excision circle numbers were in the lower range in patients with juvenile idiopathic arthritis and increased after follow-up. Healthy donors showed significantly higher relative telomere lengths compared to patients with juvenile idiopathic arthritis.
Conclusions
This investigation illustrates that the changes in T cell homeostasis in patients with juvenile idiopathic arthritis may be the result of several mechanisms, such as diminished thymus function and peripheral exertions to maintain the peripheral T cell pool. The results also demonstrate that hallmarks of immunosenescence such as decreased naive T cell levels and lower T cell receptor excision circle numbers can only be interpreted together with replication markers such as relative telomere length or Ki67 expression.
Journal of Medical Case Reports
10.1186/1752-1947-7-135
http://www.jmedicalcasereports.com/content/7/1/135
urn:nbn:de:bvb:20-opus-96325
In: Journal of Medical Case Reports (2013) 7: 135, doi:10.1186/1752-1947-7-135
Giovanni Almanzar
Manuela Zlamy
Christian Koppelstaetter
Andrea Brunner
Verena Jeller
Christina Duftner
Christian Dejaco
Juergen Brunner
Martina Prelog
eng
uncontrolled
Exacerbation
eng
uncontrolled
Juvenile idiopathic arthritis
eng
uncontrolled
Naive T cells
eng
uncontrolled
T cell receptor excision circles
Medizin und Gesundheit
open_access
Kinderklinik und Poliklinik
Förderzeitraum 2013
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/9632/Almanzar_1752-1947-7-135.pdf
9635
2013
eng
article
1
--
--
--
Lower CD28+ T cell proportions were associated with CMV-seropositivity in patients with Hashimoto’s thyroiditis
Background
Alterations in the naive T cell subpopulations have been demonstrated in patients with T cell mediated autoimmune disorders, reminiscent of immunological changes found in the elderly during immunosenescence, including the switch from CD45RA + to CD45RO + T cells and decreased thymic function with increased compensatory proliferative mechanisms, partly associated with latent Cytomegalovirus (CMV) infection. The present study was aimed to investigate proportions of lymphocytes, their relation to CMV-seropositivity and the replicative history of CD45RA + expressing T cells in Hashimoto’s thyroiditis (HT, n = 18) and healthy controls (HC, n = 70).
Methods
Proportions of peripheral T cells were investigated by flow cytometry. The replicative history was assessed by T cell receptor excision circles (TRECs) and relative telomere length (RTL). Expression of CD62L was analyzed by immunohistochemistry in thyroid sections. The role of CMV was assessed by serology, ELISPOT assay and in situ hybridization.
Results
Our results demonstrated a significant increase of CD28-negative T cells, associated with CMV-seropositivity in HT patients. HT showed abundant CD45RO + T cells with peripheral loss of CD62L-expressing CD8 + CD45RA + T cells, the latter mainly depending on disease duration. CD62L was expressed in thyroid lymphocyte infiltrations. The diagnosis of HT and within the HT group CMV-seropositivity were the main determinants for the loss of CD28 expression. RTL was not different between HC and HT. HT showed significantly lower TRECs in CD4 + CD45RA + T cells compared to HC.
Conclusions
Patients with HT display a peripheral T cell phenotype reminiscent of findings in elderly persons or other autoimmune disorders. Whether these mechanisms are primary or secondary to the immunological alterations of autoimmune conditions should be investigated in longitudinal studies which may open research on new therapeutic regimes for treatment of HT and associated autoimmune diseases.
BMC Endocrine Disorders
10.1186/1472-6823-13-34
http://www.biomedcentral.com/1472-6823/13/34
urn:nbn:de:bvb:20-opus-96352
In: BMC Endocrine Disorders (2013) 13: 34, doi:10.1186/1472-6823-13-34
Martina Prelog
Jörn Schönlaub
Reinhard Würzner
Christian Koppelstaetter
Giovanni Almanzar
Andrea Brunner
Martin Gasser
Rupert Prommegger
Gabriele Häusler
Klaus Kapelari
Wolfgang Högler
eng
uncontrolled
Immunosenescence
eng
uncontrolled
CD62L
eng
uncontrolled
Regulatory T cells
eng
uncontrolled
TREC
eng
uncontrolled
Telomere
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
Kinderklinik und Poliklinik
Förderzeitraum 2013
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/9635/Prelog_1472-6823-13-34.pdf
23783
2021
eng
12
article
1
--
2021-04-29
--
Induction of IL-9 in Peripheral Lymphocytes of Rheumatoid Arthritis Patients and Healthy Donors by Th17-Inducing Cytokine Conditions
IL-9-producing Th9 cells display a group of helper T cells with similarities to Th17 and Th2 T cells and have been shown to be involved in synovial inflammation in rheumatoid arthritis (RA) patients. So far, it is unclear which parameters drive Th9 differentiation in lymphocytes derived from RA patients compared to immunologically healthy individuals and whether autocrine mechanisms are able to enhance Th9 polarization. Further, parallel pathways of induction of IL-17-producing cells with Th9 phenotype have to be distinguished from exclusively Th9-inductive mechanisms. Thus, the present study aimed to determine the parameters of Th9 induction by simulation in a standardized inflammatory cytokine milieu.Peripheral naive and non-naive T cells of RA patients and healthy donors (HD) were cultured under Th9 and Th17-driving conditions and phenotypically analyzed by flow cytometry and molecular analysis.Our findings indicate a similar differentiation pathway of Th9 and Th17 cells and similar distributions of IL-9+ T cells in RA and HD regardless of Th9- or Th17-promoting cytokine milieus. Whereas the magnitude and direction of Th9- or Th17-polarization was about the same in RA and HD, IL-17+ CD4+ T cells were significantly stimulated by Th17-inducing conditions in HD. In conclusion, the results indicate that Th9- and Th17-inducing cytokine conditions mimicking autoimmune inflammation in RA may have similar stimulatory effects regarding polarization of peripheral naive and non-naive T cells into Th9 or Th17 cells. The results suggest that the differentiation of Th9 cells may be also induced by Th17-driving conditions.
Frontiers in Immunology
1664-3224
10.3389/fimmu.2021.668095
urn:nbn:de:bvb:20-opus-237838
2021-05-13T14:26:43+00:00
sword
swordwue
attachment; filename=deposit.zip
a03bd39ee3d17136388d6e73f6351cbc
Frontiers in Immunology (2021) 12:668095. doi: 10.3389/fimmu.2021.668095
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Jana Heim
Giovanni Almanzar
Marc Schmalzing
Michael Gernert
Hans-Peter Tony
Martina Prelog
eng
uncontrolled
Th9
eng
uncontrolled
Th17
eng
uncontrolled
interleukin-9
eng
uncontrolled
rheumatoid arthritis
eng
uncontrolled
PU.1
Medizin und Gesundheit
open_access
Kinderklinik und Poliklinik
Medizinische Klinik und Poliklinik II
Import
Förderzeitraum 2021
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/23783/fimmu-12-668095.pdf
30045
2022
eng
1
20
article
1
--
--
--
Mitigated suppressive function of regulatory T cells (Treg) upon Th17-inducing cytokines in oligo- and polyarticular Juvenile Idiopathic Arthritis (JIA) patients
Background
The plasticity of T helper-17 (Th17) and regulatory T (Treg) cells may be a clue to pathogenesis of Juvenile Idiopathic Arthritis (JIA). It is still unclear, whether targeted suppression of Interleukin (IL)-17 is able to influence regulatory function of Treg to control pro-inflammatory effectors in JIA. This study aimed to assess the effect of a Th17-stimulating cytokine environment and of IL-17A-inhibition on phenotype plasticity and suppressive function of Treg derived from JIA patients.
Methods
Th17 and Treg characteristics of CD4\(^{+}\) helper T cells were investigated in blood samples of JIA patients with oligo- and polyarticular pattern and healthy controls (HC). Isolated CD4\(^{+}\)CD25\(^{+}\)CD127\(^{-}\) cells defined as Treg were cultivated with Th17-inducing cytokine environment as well as with IL-17A-inhibitors and analyzed for plasticity of phenotype by flow cytometry. Furthermore, inhibitory function of Treg on autologous effectors after cultivation with these stimuli was determined by suppression assays.
Results
Our findings demonstrated significantly elevated proportions of Th17 and Th17-like Treg in JIA compared to HC. After incubation with Th17-inducing stimuli, increased FoxP3 expression in separated Treg in JIA and an impaired suppressive capacity in JIA and HC were found. Blockade of IL-17A resulted in adjustment of FoxP3-expression in JIA to proportions found in controls and in regular suppressive function.
Conclusions
Our results demonstrate an induction of FoxP3 expressing Treg by Th17-inducing cytokines with concomitant mitigated suppressive function. In contrast, specific IL-17A blockade maintains suppressive Treg function and adjusted FoxP3-expression in JIA to levels found in controls. These findings may help to provide experimental evidence for the successful clinical use of IL-17A inhibition in JIA patients.
Pediatric Rheumatology
10.1186/s12969-022-00680-z
urn:nbn:de:bvb:20-opus-300453
@articleHolzer.2022, author = Holzer, Marie-Therese and Almanzar, Giovanni and Woidich, Robert and Hügle, Boris and Haas, Johannes-Peter and Prelog, Martina, year = 2022, title = Mitigated suppressive function of regulatory T cells (Treg) upon Th17-inducing cytokines in oligo- and polyarticular Juvenile Idiopathic Arthritis (JIA) patients, pages = 26, volume = 20, number = 1, journal = Pediatric rheumatology online journal, doi = 10.1186/s12969-022-00680-z,
md5:291ea6057acdf3c995eb6bda85acc2e6
2023-01-20T07:10:16+00:00
/tmp/php59R9XA
bibtex
63ca3e583d24e2.38442621
Pediatric Rheumatology 2022, 20(1):26. DOI: 10.1186/s12969-022-00680-z
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Marie-Therese Holzer
Giovanni Almanzar
Robert Woidich
Boris Hügle
Johannes-Peter Haas
Martina Prelog
eng
uncontrolled
IL-17A-inhibition
eng
uncontrolled
T cell plasticity
eng
uncontrolled
suppressive function
eng
uncontrolled
JIA
eng
uncontrolled
Th17
eng
uncontrolled
Treg
Gynäkologie, Geburtsmedizin, Pädiatrie, Geriatrie
open_access
Kinderklinik und Poliklinik
Förderzeitraum 2022
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/30045/Pediatric_Holzer.pdf
17968
2016
eng
6
11
article
1
2019-04-24
--
--
Hypermethylation of FOXP3 Promoter and Premature Aging of the Immune System in Female Patients with Panic Disorder?
Immunological abnormalities associated with pathological conditions, such as higher infection rates, inflammatory diseases, cancer or cardiovascular events are common in patients with panic disorder. In the present study, T cell receptor excision circles (TRECs), Forkhead-Box-Protein P3 gene (FOXP3) methylation of regulatory T cells (Tregs) and relative telomere lengths (RTLs) were investigated in a total and subsamples of 131 patients with panic disorder as compared to 131 age- and sex-matched healthy controls in order to test for a potential dysfunction and premature aging of the immune system in anxiety disorders. Significantly lower TRECs (p = 0.004) as well as significant hypermethylation of the FOXP3 promoter region (p = 0.005) were observed in female (but not in male) patients with panic disorder as compared to healthy controls. No difference in relative telomere length was discerned between patients and controls, but significantly shorter telomeres in females, smokers and older persons within the patient group. The presently observed reduced TRECs in panic disorder patients and FOXP3 hypermethylation in female patients with panic disorder potentially reflect impaired thymus and immunosuppressive Treg function, which might partly account for the known increased morbidity and mortality of anxiety disorders conferred by e.g. cancer and cardiovascular disorders.
PLoS ONE
10.1371/journal.pone.0157930
urn:nbn:de:bvb:20-opus-179684
PLoS ONE 2016, 11(6):e0157930. DOI:10.1371/journal.pone.0157930
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Martina Prelog
Deborah Hilligardt
Christian A. Schmidt
Grzegorz K. Przybylski
Johannes Leierer
Giovanni Almanzar
Nady El Hajj
Klaus-Peter Lesch
Volker Arolt
Peter Zwanzger
Thomas Haaf
Katharina Domschke
eng
uncontrolled
DNA methylation
eng
uncontrolled
antidepressants
eng
uncontrolled
regulatory T cells
eng
uncontrolled
panic disorder
eng
uncontrolled
treatment guidelines
eng
uncontrolled
telomere length
eng
uncontrolled
inflammatory diseases
eng
uncontrolled
anxiety disorders
Medizin und Gesundheit
open_access
Kinderklinik und Poliklinik
Institut für Humangenetik
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17968/Prelog_Plos_One.PDF