| 1. |
- Bengnér, Malin, et al.
(author)
-
Independent skewing of the T cell and NK cell compartments associated with cytomegalovirus infection suggests division of labor between innate and adaptive immunity.
- 2014
-
In: Age (Omaha). - : Springer Science and Business Media LLC. - 0161-9152 .- 1574-4647. ; 36:2, s. 571-582
-
Journal article (peer-reviewed)abstract
- Cytomegalovirus (CMV) infection induces profound changes in different subsets of the cellular immune system. We have previously identified an immune risk profile (IRP) where CMV-associated changes in the T cell compartment, defined as a CD4/CD8 ratio < 1, are associated with increased mortality in elderly people. Since natural killer (NK) cells have an important role in the defense against viral infections, we examined whether the expansion of CD8 + T cells seen in individuals with CD4/CD8 ratio < 1 is coupled to a parallel skewing of the NK cell compartment. A number of 151 subjects were examined with CMV serology and a flow cytometry panel for assessment of T cell and NK cell subsets. CMV-seropositive individuals had higher frequencies of CD57 + and NKG2C + NK cells and lower frequencies of NKG2A + NK cells, in line with a more differentiated NK cell compartment. Intriguingly, however, there was no correlation between CD4/CD8 ratio and NK cell repertoires among CMV-seropositive donors, despite the profound skewing of the T cell compartment in the group with CD4/CD8 ratio < 1. Conversely, donors with profound expansion of NK cells, defined as NKG2C + NK cells with high expression of CD57 and ILT-2, did not display more common changes in their T cell repertoire, suggesting that NK cell expansion is independent of the T cell-defined IRP. Altogether, these results indicate that the effect of CMV on CD8 T cells and NK cells is largely nonoverlapping and independent.
|
|
| 2. |
- Buse, Eberhard, et al.
(author)
-
The placenta in toxicology. Part I : Animal models in toxicology
- 2014
-
In: Toxicologic pathology (Print). - : Sage Publications. - 0192-6233 .- 1533-1601. ; 42:2, s. 314-326
-
Research review (peer-reviewed)abstract
- The immune system represents a key defense mechanism against potential pathogens and adverse non-self materials. During pregnancy, the placenta is the point of contact between the maternal organism and non-self proteins of the fetal allograft and hence undoubtedly fulfils immune functions. In the placenta bacteria, foreign (non-self) proteins and proteins that might be introduced in toxicological studies or by medication are barred from reaching the progeny, and the maternal immune system is primed for acceptance of non-maternal fetal protein. Both immunologic protection of the fetus and acceptance of the fetus by the mother require effective mechanisms to prevent an immunologic fetomaternal conflict and to keep both organisms in balance. This is why the placenta requires toxicological consideration in view of its immune organ function. The following articles deal with placenta immune-, control-, and tolerance mechanisms in view of both fetal and maternal aspects. Furthermore, models for experimental access to placental immune function are addressed and the pathological evaluation is elucidated. "The Placenta as an Immune Organ and Its Relevance in Toxicological Studies" was subject of a continuing education course at the 2012 Society of Toxicologic Pathology meeting held in Boston, MA.
|
|
| 3. |
- Cline, J Mark, et al.
(author)
-
The placenta in toxicology. Part III : Pathologic assessment of the placenta
- 2014
-
In: Toxicologic pathology (Print). - : Sage Publications. - 0192-6233 .- 1533-1601. ; 42:2, s. 339-344
-
Journal article (peer-reviewed)abstract
- This short review is derived from the peer-reviewed literature and the experience and case materials of the authors. Brief illustrated summaries are presented on the gross and histologic normal anatomy of rodent and macaque placentas, including typical organ weights, with comments on differences from the human placenta. Common incidental findings, background lesions, and induced toxic lesions are addressed, and a recommended strategy for pathologic evaluation of placentas is provided.
|
|
| 4. |
- Edvardsson, Maria, et al.
(author)
-
Classification of ≥80-year-old individuals into healthy, moderately healthy, and frail based on different frailty scores affects the interpretation of laboratory results
- 2022
-
In: Asian Journal of Medical Sciences. - : Nepal Journals Online (NepJOL). - 2467-9100 .- 2091-0576. ; 13:9, s. 63-71
-
Journal article (peer-reviewed)abstract
- Background: Interpretation laboratory analyses are crucial when assessing the patient’s condition. Reference intervals from apparently healthy and disease-free individuals may cause problems when outcomes from elderly patients with chronic diseases and on medications are being interpreted. Elderly individuals are a heterogeneous group ranging from individuals managing their daily life independently to individuals with diseases and impairment, in need of nursing care around the clock, that is, frail; a term widely used although there is no consensus on the definition.Aims and Objectives: The aim of the study was to study the effect of classification of elderly into healthy, moderately healthy, and frail, based on activities of daily living (ADL) and Mini-Mental State Examination (MMSE) or frailty index (FI), on the interpretation of outcomes regarding: Albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and gamma-glutamyltransferase (γ-GT) levels.Materials and Methods: Individuals ≥80 years (n=568) were classified either on ADL and MMSE or number of deficits, (FI).Results: Individuals classified as frail based on FI had lower mean levels for ALT, creatinine and γ-GT than individuals classified based on ADL and MMSE (P<0.05).Conclusion: The model to define health status to some extent affected laboratory analyte levels in ≥80 years old, classified as healthy, moderately healthy, and frail based on ADL and MMSE versus FI.
|
|
| 5. |
|
|
| 6. |
- Gawel, Danuta, et al.
(author)
-
A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases
- 2019
-
In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 11
-
Journal article (peer-reviewed)abstract
- Background: Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. Methods: The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. Results: We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Conclusions: Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.
|
|
| 7. |
|
|
| 8. |
- Gustafsson (Lidström), Charlotte, et al.
(author)
-
Gene expression profiling of human decidual macrophages : Evidence for immunosuppressive phenotype
- 2008
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:4, s. e2078-
-
Journal article (peer-reviewed)abstract
- Background: Although uterine macrophages are thought to play an important regulatory role at the maternal-fetal interface, their global gene expression profile is not known. Methodology/Principal Findings: Using micro-array comprising approximately 14,000 genes, the gene expression pattern of human first trimester decidual CD14+ monocytes/macrophages was characterized and compared with the expression profile of the corresponding cells in blood. Some of the key findings were confirmed by real time PCR or by secreted protein. A unique gene expression pattern intrinsic of first trimester decidual CD14+ cells was demonstrated. A large number of regulated genes were functionally related to immunomodulation and tissue remodelling, corroborating polarization patterns of differentiated macrophages mainly of the alternatively activated M2 phenotype. These include known M2 markers such as CCL-18, CD209, insulin-like growth factor (IGF)-1, mannose receptor c type (MRC)-1 and fibronectin-1. Further, the selective up-regulation of triggering receptor expressed on myeloid cells (TREM)-2, alpha-2-macroglobulin (A2M) and prostaglandin D2 synthase (PGDS) provides new insights into the regulatory function of decidual macrophages in pregnancy that may have implications in pregnancy complications. Conclusions/Significance: The molecular characterization of decidual macrophages presents a unique transcriptional profile replete with important components for fetal immunoprotection and provides several clues for further studies of these cells.
|
|
| 9. |
- Göhner, Claudia, et al.
(author)
-
The placenta in toxicology. Part IV : Battery of toxicological test systems based on human placenta
- 2014
-
In: Toxicologic pathology (Print). - : Sage Publications. - 0192-6233 .- 1533-1601. ; 42:2, s. 345-351
-
Journal article (peer-reviewed)abstract
- This review summarizes the potential and also some limitations of using human placentas, or placental cells and structures for toxicology testing. The placenta contains a wide spectrum of cell types and tissues, such as trophoblast cells, immune cells, fibroblasts, stem cells, endothelial cells, vessels, glands, membranes, and many others. It may be expected that in many cases the relevance of results obtained from human placenta will be higher than those from animal models due to species specificity of metabolism and placental structure. For practical and economical reasons, we propose to apply a battery of sequential experiments for analysis of potential toxicants. This should start with using cell lines, followed by testing placenta tissue explants and isolated placenta cells, and finally by application of single and dual side ex vivo placenta perfusion. With each of these steps, the relative workload increases while the number of feasible repeats decreases. Simultaneously, the predictive power enhances by increasing similarity with in vivo human conditions. Toxic effects may be detected by performing proliferation, vitality and cell death assays, analysis of protein and hormone expression, immunohistochemistry or testing functionality of signaling pathways, gene expression, transport mechanisms, and so on. When toxic effects appear at any step, the subsequent assays may be cancelled. Such a system may be useful to reduce costs and increase specificity in testing questionable toxicants. Nonetheless, it requires further standardization and end point definitions for better comparability of results from different toxicants and to estimate the respective in vivo translatability and predictive value.
|
|
| 10. |
- Hellberg, Sandra, 1986-
(author)
-
Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis
- 2019
-
Doctoral thesis (other academic/artistic)abstract
- Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a pre-requisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement.The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4+ T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4+ T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment.The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4+ T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAKSTAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31 expression and TREC content, were used and showed that thymic output of T cells is maintained during human pregnancy, or even possibly increased in terms of regulatory T cells.This thesis further supports a pivotal role for CD4+ T cells and T cell activation in the MS pathogenesis and adds to the knowledge of how they could be involved in driving disease. We identified a novel strategy for capturing central aspects of the deviating response to T cell activation that could be translated into potentially clinically relevant biomarkers. Further, P4 is emerging as a promising candidate for the pregnancy-induced immunomodulation that could be of importance as a future treatment option. Lastly, maintained thymic output of T cells during human pregnancy challenges the rodent-based dogma of an inactive thymus during pregnancy. Thymic dysfunction has been reported not only in MS but also in rheumatoid arthritis, another inflammatory disease that improves during pregnancy, which highlights a potential role for thymus in immune regulation that could be involved in the pregnancy-induced amelioration.
|
|
| 11. |
- Hellberg, Sandra, et al.
(author)
-
Maintained thymic output of conventional and regulatory T cells during human pregnancy
- 2019
-
In: Journal of Allergy and Clinical Immunology. - Philadelphia, United States : American Academy of Allergy, Asthma and Immunology. - 0091-6749 .- 1097-6825. ; 143:2, s. 771-775.e7
-
Journal article (other academic/artistic)abstract
- During pregnancy, immunological tolerance toward the semiallogeneic fetus needs to be established while at the same time an effective immune defense must be maintained.1 The pregnancy-associated thymic involution reported in rodents2 has been suggested to support maternal immune regulation by reducing the output of potentially harmful TH cells. However, the functional importance of this thymic involution remains unclear and it is not known whether it even occurs in humans.3 In fact, the role of thymus during human pregnancy and in pregnancy-associated tolerance remains largely unknown,4 albeit a role for thymic-derived regulatory T (Treg) cells in pregnancy complications has been suggested,4 supporting a role for thymus in immune regulation during human pregnancy. The aim of this study was to assess the role of thymus in TH-cell regulation during human pregnancy by analyzing the output of different TH-cell populations.
|
|
| 12. |
- Håkansson, Irene, 1976-
(author)
-
Biomarkers and Disease Activity in Multiple Sclerosis : A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis
- 2019
-
Doctoral thesis (other academic/artistic)abstract
- This thesis focuses on disease activity in clinically isolated syndrome (CIS) and newly diagnosed relapsing remitting multiple sclerosis (RRMS). The papers are based on data from 41 patients in a prospective longitudinal cohort study. All patients were untreated at baseline. Age- and sex-matched healthy controls (n=22) for blood and cerebrospinal fluid (CSF) samples were recruited from blood donors.Paper I evaluated the prognostic value of baseline levels of CXCL1, CXCL8, CXCL10, CXCL13, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9) and osteopontin in CSF in relation to disease activity during the first two years of follow-up. Disease activity was defined as clinical relapses, new T2 lesions in brain magnetic resonance imaging (MRI) and/or sustained Expanded Disability Status Scale (EDSS) progression. Absence of these three signs of disease activity was called no evidence of disease activity (NEDA-3). Logistic regression analysis showed that NFL in CSF was the best predictive marker of disease activity and correctly classified 93% of the patients with evidence of disease activity during two years of follow-up and 67% of those without.Paper II presented four year follow-up data from the cohort and also included brain volume data as well as serum levels of NFL. The correlation between NFL in CSF and serum was fairly strong (r=0.74, p<0.001). NFL in CSF was associated with new T2 lesions as well as with brain volume loss, whereas CHI3L1 in CSF was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22 and MMP-9 in CSF were mainly associated with new T2 lesions. Taken together, paper I and II confirm and extend the knowledge of NFL as a useful biomarker in CIS and RRMS and suggests that NFL, rather than total brain volume loss, could be included in an expanded NEDA concept and used in clinical monitoring of disease activity/treatment effect. Although serum levels of NFL were correlated with the corresponding CSF levels, CSF-NFL showed a stronger association to subsequent disease activity (NEDA-3).Paper III addressed the patients´ self-reported Modified Fatigue Impact Scale (MFIS) scores in relation to other cohort study data. MFIS scores correlated with other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36) scores (Spearman´s rho 0.45-0.78, all p≤0.01)) but not with EDSS ratings, number of T2 lesions, total brain volume or NFL levels, indicating that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters.Paper IV focused on the complement factors C1q, C3, C3a and sC5b-9 in CSF and plasma. CSFC1q was significantly higher in patients than in controls at baseline. The subgroup of patients with ongoing relapse at baseline also had higher levels of CSF-C3a than controls. Baseline levels of CSF-C1q and CSF-C3a correlated significantly with several pro-inflammatory chemokines as well as with MMP-9, CHI3L1 and NFL in CSF. Baseline CSF-C3a also correlated significantly with the number of T2 lesions and Gadolinium enhancing lesions in brain MRI at baseline, as well as with the number of new T2 lesions during follow-up. This study indicates that the complement system is involved already at early stages of MS. It also suggests that especially CSF-C1q and CSF-C3a levels are associated with other neuroinflammatory and neurodegenerative markers and that CSF-C3a levels may carry some prognostic information.
|
|
| 13. |
- Kempe, Per, et al.
(author)
-
Immune profile in relation to sex steroid cyclicity in healthy women and women with multiple sclerosis
- 2018
-
In: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 1:26, s. 53-59
-
Journal article (peer-reviewed)abstract
- To prospectively study systemic in vivo immunological effects of sex hormones, using different phases of oral combined hormonal contraceptives (CHC), and the natural menstrual cycles in both healthy women and in women with multiple sclerosis (MS), blood samples from sixty female MS patients and healthy controls with and without CHC were drawn in high and low estrogenic/progestogenic phases. Expression of Th-associated genes in blood cells was determined by qPCR and a panel of cytokines and chemokines was measured in plasma. High hormone level phases were associated with increases in Th1 (TBX21) and Th2 (GATA3) associated markers, as well as the B cell-associated chemokine CXCL13, while the inhibitory regulator CTLA-4 was decreased. These changes were not observed in MS patients, of whom most were treated with immunomodulatory drugs. Our data indicate immune activating properties in vivo of high steroid sex hormone levels during both CHC and normal menstrual cyclicity.
|
|
| 14. |
- Kempe, Per, et al.
(author)
-
T cell subset-associated transcription factors, cytokines and chemokines in relation to the menstrual cycle and use of combined hormonal contraceptives in women with multiple sclerosis and healthy controls
- 2014
-
Other publication (other academic/artistic)abstract
- Study question: Do peripheral blood levels of cytokines, chemokines, and transcription factors for different T helper (Th) cell subsets change in relation to high and low estrogen/progestogen states in women with multiple sclerosis (MS) and healthy controls with and without combined hormonal contraceptives (CHC)?Summary answer: Our findings indicate a general activation of peripheral blood T cells and B cells during high estrogen/progestogen phases with higher levels of transcription factors associated with both Th1 (TBX21) and Th2 (GATA3) subsets of T cells and the B cell-associated chemokine CXCL13.What is known already: There are some indications that sex steroids may positively affect MS clinically and immunologically.Study design, size, duration: A total of 60 women were included. Paired blood samples were drawn in high and low estrogen/progestogen phases during the same cycle in women using or not using CHC.Participants/materials, setting, methods: Participants were female MS patients and healthy controls with and without CHC. Concentrations of cytokines and chemokines were measured using multiplex bead technology and expression of transcription factors in blood cells was determined by qPCR. Owing to possible differences in cell composition, expression of Th-associated transcription factors were normalized to the T cell-specific transcription factor CD3E.Main results and the role of chance: Sixty women were included but 13 women dropped out, leaving 47 women to the statistical analyses. In healthy controls using CHC, both TBX21, and GATA3 expression was higher in the high estrogen/progestogen phase than in the low estrogen/progestogen phase. TBX21 expression in high estrogen/progestogen phase differed significantly between groups with the highest levels in healthy controls without CHC. In all MS patients as well as in healthy controls using CHC, the concentrations of CXCL13 was significantly higher in the high estrogen/progestogen phase compared to the low estrogen/progestogen phase.Limitations, reasons for caution: The low number of participants. A majority of the MS patients were using immunomodulatory drugs which may have interfered with the results. The study design makes it impossible to differ between estrogenic and progestogenic effects.Wider implications of the findings: Our findings show that high and low levels of estrogens and/or progestogens differently affect immune parameters related to Th cell subsets as well as B cells. The differences between high- and low estrogen/progestogen phases were most obvious in women using CHC indicating that CHC is more potent than 17β-Estradiol/progesterone in inducing immune changes in both MS patients and healthy women.Study funding/competing interest(s): This study was funded by the County Councils of Östergötland and Västernorrland, Sweden. No author have any conflicts of interest to declare.
|
|
| 15. |
- Mjösberg, Jenny, et al.
(author)
-
Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ T-regs in human second trimester pregnancy is induced by progesterone and 17 beta-estradiol
- 2009
-
In: Journal of Reproductive Immunology(ISSN 0165-0378), vol 81, issue 2. - : Elsevier BV. ; , s. 160-161
-
Conference paper (peer-reviewed)abstract
- CD4+CD25high regulatory T cells (Tregs) are implicated in maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim was to determine the frequency, phenotype and function of circulating Tregs in second trimester human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expression of Foxp3, CD127 and HLA-DR, as determined by multi-color flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from non-pregnant women. By co-culturing FACS-sorted Tregs and autologous CD4+CD25- responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as non-pregnant women in terms of suppressing IL-2, TNF-α and IFN-γ secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Further, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need re-evaluation.
|
|
| 16. |
- Mjösberg, Jenny, et al.
(author)
-
Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17θ-estradiol
- 2009
-
In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 183:1, s. 759-769
-
Journal article (peer-reviewed)abstract
- CD4+CD25high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4+CD25– responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-, and IFN- secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|
|
| 17. |
- Nestor, Colm E, et al.
(author)
-
Sublingual immunotherapy alters expression of IL-4 and its soluble and membrane-bound receptors
- 2014
-
In: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 69:11, s. 1564-1566
-
Journal article (peer-reviewed)abstract
- Seasonal allergic rhinitis (SAR) is a disease of increasing prevalence, which results from an inappropriate T-helper cell, type 2 (Th2) response to pollen. Specific immunotherapy (SIT) involves repeated treatment with small doses of pollen and can result in complete and lasting reversal of SAR. Here, we assayed the key Th2 cytokine, IL-4, and its soluble and membrane-bound receptor in SAR patients before and after SIT. Using allergen-challenge assays, we found that SIT treatment decreased IL-4 cytokine levels, as previously reported. We also observed a significant decrease in the IL-4 membrane-bound receptor (mIL4R) at both the level of mRNA and protein. SIT treatment resulted in a significant increase in the inhibitory soluble IL-4 receptor (sIL4R). Reciprocal changes in mIL4R and sIL4R were also observed in patient serum. Altered mIL4R and sIL4R is a novel explanation for the positive effects of immunotherapy with potential basic and clinical research implications.
|
|
| 18. |
- Nilsson, Bengt-Olof, 1954-, et al.
(author)
-
The Immune Risk Phenotype and IL-6 among Nonagenarians and Associations with Morbidity and Mortality : Findings from the Swedish NONA Immune Longitudinal Study
-
Other publication (other academic/artistic)abstract
- In this NONA immune longitudinal study, we examine 4-year mortality in relation to a set of laboratory parameters, morbidity and cause of death in a population-based sample of oldest-old individuals (n=138). Four groups were constructed based on levels for the CD4/CD8 ratio (above or below one = IRP, immune risk phenotype group) and levels for IL-6 (below or above the median 3.15 pg/mL). 4-year mortality was higher in the “IRP” group (73 %), the “IL-6” group (64 %), and the “Double risk group” (82 %) compared with the “No risk” group (29 %; p-values between .005 and .000). Cognitive dysfunction and dementia were more common in the two groups with elevated IL-6 levels (p-values between .014 and .001), whereas cardiovascular disease tended (p = .081) to be associated with both “IRP” and “IL-6” groups. The most common cause of death was related to cardio- and cerebrovascular disease (59 %,), followed by infection in 15 % of the cases and cancer in 7 %. Despite their strong associations with 4-year mortality, neither IRP nor IL-6 could be linked to any specific cause of death, possibly because both IRP and IL-6 are multi-factorial risk factors, being associated with several different diseases and mechanisms which cause death.
|
|
| 19. |
- Papapavlou, Georgia, et al.
(author)
-
Differential effects of estradiol and progesterone on human T cell activation in vitro
- 2021
-
In: European Journal of Immunology. - : Wiley-VCH Verlagsgesellschaft. - 0014-2980 .- 1521-4141. ; 51:10, s. 2430-2440
-
Journal article (peer-reviewed)abstract
- Estradiol (E2) and progesterone (P4) are steroid hormones important for the regulation of immune responses during pregnancy. Their increasing levels coincide with an improvement of T cell-mediated diseases such as multiple sclerosis (MS). Although immune-endocrine interactions are involved in this phenomenon, the relative contribution of hormones is not known. We here report a direct comparison of E2- and P4-mediated effects on human CD4+ T cells, key cells in immune regulation. T cells were stimulated to obtain different activation levels and exposed to a broad range of hormone concentrations. Activation level was assessed by CD69/CD25 expression by flow cytometry, and secreted proteins (n = 196) were measured in culture supernatants using proximity extension assay and electrochemiluminescence immunoassay. We found that in low activated cells, pregnancy-relevant E2 concentrations increased activation and the secretion of several immune- and inflammation-related proteins. P4, on the other hand, showed a biphasic pattern, where serum-related concentrations upregulated activation and protein secretion while placenta-relevant concentrations induced a prominent dampening irrespective of the initial activation level. Our results demonstrate the importance of P4 as a major hormone in the immune modulation of T cells during pregnancy and emphasize the need to further evaluate its potency in the treatment of diseases like MS.
|
|
| 20. |
- Rüdhmer-Dahle, Charlotte, 1956-
(author)
-
Studies on T cells and cytokines in Guillain-Barré syndrome and experimental allergic neuritis
- 2001
-
Doctoral thesis (other academic/artistic)abstract
- Guillain-Barrésyndrome (GBS) is an inflammatory disease of peripheral nerves, characterised by muscle weakness. The nerves are attacked and destroyed by the immune system. The symptoms usually progress over a few weeks and many patients become severely disabled. However, in contrast to many other organspecific autoimmune diseases, GBS is self-limiting and most patients recover. Individuals of all ages can be affected. The incidence is about 1/100 000 per year. An infection often precedes the onset of neurological symptoms and probably triggers the immune-mediated attack.Activation of T cells and the resulting release of cytokines are decisive for the regulation of antigen-specific inflammation. Different cytokine patterns promote different types of responses. Interferon-y (lFN-γ) has a key role in Th type 1 responses, and is thought to be a driving force in many organ-specific autoimmune diseases. Interleukin-4 (IL-4) promotes Th type 2 responses, characterised by the production of certain antibodies and activation of mastcells and eosinophils. Th type 1 and Th type 2 responses down-regulate one another and the balance between them is important for the immune homeostasis. TGF-ß is an important cytokine with strong down-regulatory properties.Flow cytometry studies showed that circulating T cells were activated in patients with GBS as determined by expression of HLA-DR on T cells, increased proportion of activated memory phenotype (CD4+CD29+), and decreased proportion of naive phenotype (CD4+CD45RA+). A sensitive Ell-spot method was used to determine cytokine secretion from circulating mononuclear cells with or without stimulation with immunogenic peptides from myelin proteins P2 and PO. Both spontaneous and myelin-specific cytokine secretion were increased in patients compared with controls. Increased numbers of myelin-specific cells secreting IL-4 and TGF-ß were found in the majority of the patients, indicating a Th2 type and down-regulatory cytokine profile, in line with the self-limiting character of the disease.An animal model of GBS, experimental allergic neuritis (EAN), is known to be inducible by myelin-specific T cells, supporting the pathogenetic role of T cells. A Th1 deviated, IFN-y-producing cell population from EAN, was in vitro stimulated with autoantigen and IL-4, thereby obtaining a Th2 cytokine profile. These myelin-specific cells were subsequently transferred to rats with EAN, and were found to ameliorate the disease course.In conclusion, Circulating T cells are activated in patients with GBS. Most patients have myelin-specific T cells that mainly secrete down-regulatory cytokines such as IL-4 and TGF-ß, which probably have a beneficial role in regulating the disease process. In vitro deviation of myelin-specific T cells into Th2 phenotype and subsequent transfer of these cells ameliorated the disease course in EAN.
|
|
| 21. |
|
|
| 22. |
- Strindhall, Jan, et al.
(author)
-
Humoral response to influenza vaccination in relation to pre-vaccination antibody titres, vaccination history, cytomegalovirus serostatus and CD4/CD8 ratio
- 2016
-
In: INFECTIOUS DISEASES. - : TAYLOR & FRANCIS LTD. - 2374-4235 .- 2374-4243. ; 48:6, s. 436-442
-
Journal article (peer-reviewed)abstract
- Background Annual vaccination against influenza virus is generally recommended to elderly and chronically ill, but the relative importance of factors influencing the outcome is not fully understood. Methods In this study of 88 individuals all aged 69 years, the increase in haemagglutinin-inhibiting (HI) antibodies to trivalent inactivated influenza vaccine was correlated with HI titres before vaccination, prior vaccinations against influenza, cytomegalovirus serostatus and, as an estimate of immune risk profile, the ratio between CD4 + and CD8 + T cells. Results Vaccine responses were impaired by high pre-existing HI antibody titres. For influenza B repeated vaccinations and an inverse CD4/CD8 ratio had a negative impact on the vaccine response. Cytomegalovirus seropositivity had no apparent effect on HI titres before or after vaccination. Conclusions It is concluded that both pre-existing HI antibodies and previous vaccinations to influenza may influence the humoral response to influenza vaccination and that a CD4/CD8 ratio < 1 may indicate an impaired ability to respond to repeated antigenic stimulation.
|
|
| 23. |
|
|
| 24. |
- Strindhall, Jan, et al.
(author)
-
The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals : the Swedish HEXA immune study
- 2013
-
In: Age (Omaha). - : Springer Netherlands. - 0161-9152 .- 1574-4647. ; 35:3, s. 985-991
-
Journal article (peer-reviewed)abstract
- The Swedish OCTO and NONA immune longitudinal studies were able to identify and confirm an immune risk profile (IRP) predictive of an increased 2-year mortality in very old individuals, 86–94 years of age. The IRP, was associated with persistent cytomegalovirus infection and characterized by inverted CD4/CD8 ratio and related to expansion of terminally differentiated effector memory T cells (TEMRA phenotype). In the present HEXA immune longitudinal study, we have examined a younger group of elderly individuals (n = 424, 66 years of age) in a population-based sample in the community of Jönköping, Sweden, to examine the relevance of findings previously demonstrated in the very old. Immunological monitoring that was conducted included T cell subsets and CMV-IgG and CMV-IgM serology. The result showed a prevalence of 15 % of individuals with an inverted CD4/CD8 ratio, which was associated with seropositivity to cytomegalovirus and increases in the level of TEMRA cells. The proportion of individuals with an inverted CD4/CD8 ratio was significantly higher in men whereas the numbers of CD3+CD4+ cells were significantly higher in women. In conclusion, these findings are very similar to those previously found by us in the Swedish longitudinal studies, suggesting that an immune profile previously identified in the very old also exists in the present sample of hexagenerians. Therefore, it will be important to examine clinical parameters, including morbidity and mortality, to assess whether the immune profile also is a risk profile associated with higher mortality in this sample of hexagenerians.
|
|
| 25. |
- Svensson-Arvelund, Judit, 1982-, et al.
(author)
-
The placenta in toxicology. Part II : Systemic and local immune adaptations in pregnancy
- 2014
-
In: Toxicologic pathology (Print). - : Sage Publications. - 0192-6233 .- 1533-1601. ; 42:2, s. 327-338
-
Journal article (peer-reviewed)abstract
- During pregnancy, the maternal immune system is challenged by the semiallogeneic fetus, which must be tolerated without compromising fetal or maternal health. This review updates the systemic and local immune changes taking place during human pregnancy, including some examples in rodents. Systemic changes are induced by contact of maternal blood with placental factors and include enhanced innate immunity with increased activation of granulocytes and nonclassical monocytes. Although a bias toward T helper (Th2) and regulatory T cell (Treg) immunity has been associated with healthy pregnancy, the relationship between different circulating Th cell subsets is not straightforward. Instead, these adaptations appear most evidently at the fetal-maternal interface, where for instance Tregs are enriched and promote fetal tolerance. Also innate immune cells, that is, natural killer cells and macrophages, are enriched, constituting the majority of decidual leukocytes. These cells not only contribute to immune regulation but also aid in establishing the placenta by promoting trophoblast recruitment and angiogenesis. Thus, proper interaction between leukocytes and placental trophoblasts is necessary for normal placentation and immune adaptation. Consequently, spontaneous maladaptation or interference of the immune system with toxic substances may be important contributing factors for the development of pregnancy complications such as preeclampsia, preterm labor, and recurrent miscarriages.
|
|
