| 1. |
- Badam, Tejaswi, et al.
(författare)
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CD4(+) T-cell DNA methylation changes during pregnancy significantly correlate with disease-associated methylation changes in autoimmune diseases
- 2022
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Ingår i: Epigenetics. - : Taylor & Francis Group. - 1559-2294 .- 1559-2308. ; 17:9, s. 1040-1055
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetics may play a central, yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy and could be involved in the pregnancy-induced modulation of several autoimmune diseases. We investigated changes in the methylome in isolated circulating CD4(+) T-cells in non-pregnant and pregnant women, during the 1(st) and 2(nd) trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with several hundreds of methylation differences, particularly during the 2(nd) trimester. A network-based modular approach identified several genes, e.g., CD28, FYN, VAV1 and pathways related to T-cell signalling and activation, highlighting T-cell regulation as a central component of the observed methylation alterations. The identified pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A negative correlation between pregnancy-associated methylation changes and disease-associated changes was found for multiple sclerosis and rheumatoid arthritis, diseases that are known to improve during pregnancy whereas a positive correlation was found for systemic lupus erythematosus, a disease that instead worsens during pregnancy. Thus, the directionality of the observed changes is in line with the previously observed effect of pregnancy on disease activity. Our systems medicine approach supports the importance of the methylome in immune regulation of T-cells during pregnancy. Our findings highlight the relevance of using pregnancy as a model for understanding and identifying disease-related mechanisms involved in the modulation of autoimmune diseases.
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| 2. |
- Ewerman, Lea, et al.
(författare)
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Immunomodulating Effects Depend on Prolactin Levels in Patients with Hyperprolactinemia
- 2020
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Ingår i: Hormone and Metabolic Research. - Stuttgart : Thieme Medical Publishers. - 0018-5043 .- 1439-4286. ; 52:04, s. 228-235
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Tidskriftsartikel (refereegranskat)abstract
- Prolactin is known to have immune modulatory effects acting through the prolactin receptor, which is present on a variety of immune cells. Certain chemokines contribute to form the type of T helper (Th) preponderance in the immune response. The objective of this work was to assess if hyperprolactinemia not related to pregnancy is associated with changes in circulating levels of chemokines and other immunological markers. In this cross sectional study, 35 patients with hyperprolactinemia (5 men), and 102 healthy blood donors (19 men) were included. Serum levels of Th1- Th2- and Th17-associated chemokines, C-reactive protein, immunoglobulins, and the B cell attracting chemokine CXCL13 were assessed. The hyperprolactinemic group had significantly higher levels of Th2 associated CCL22 (p=0.022), Th17 associated CXCL1 (p=0.001), B cell attracting CXCL13 (p=0.003), and C-reactive protein (p<0.001) compared to controls, and these proteins were also positively correlated with prolactin levels. While differences in CCL22, CXCL1, CXCL13, and C-reactive protein were present in patients with low or moderate hyperprolactinemia, no differences were observed at high (>3600 mU/l) prolactin levels. To evaluate a possible dose-associated response to prolactin, an in vitro model was used, showing prolactin-induced increase in T-helper cell activation at moderate levels, while activation decreased at higher levels. Hyperprolactinemia seems to have several immunomodulatory effects and was associated with increased levels of chemokines associated with Th2 and Th17 responses and B cell attraction. However, patients with greatly increased prolactin had normal levels of chemokines, and in vitro, high levels of prolactin decreased T-helper cell activation.
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| 3. |
- Gustafsson, Mika, et al.
(författare)
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A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases
- 2015
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 7:313
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Tidskriftsartikel (refereegranskat)abstract
- Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.
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| 4. |
- Hellberg, Jonas, 1973-
(författare)
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Skadestånd vid patentintrång
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Damages are generally considered to be the most central and important sanction for patent infringement, as they are the patent holder’s only opportunity to be financially compensated for losses suffered as a result of infringement. As patent has become increasingly important in line with rapid economic and technological development in society, the sanctions – including damages – have also received more attention, both nationally and internationally.The party seeking damages must, according to general rules of procedure and evidence, be fully able to “prove” that some sort of loss has occurred, that the loss extends to the amount being claimed in damages, and that the loss was caused by the patent infringement. In practice, this has proven very difficult for the patent holder.The aim of this dissertation is to examine the effectiveness of damages in patent infringement cases. In order to analyse damages as a sanction for patent infringement, what problems there are, and what solutions may be possible, the dissertation addresses both damages as a sanction and the patent litigation process with a special focus on evidence.What purpose imposed damages for patent infringement serve and whether it is possible to calculate if patent infringement is profitable are some of the questions answered. Other issues concerning alternative calculation methods and the possibility of punitive damages for deliberate infringement are also discussed. One section analyses the need for evidence relief rules with a relatively comprehensive de lege ferenda argument regarding the possibility of changing current evidence rules and which alternative solutions might then be considered. Concrete suggestions for change and improvement are presented. The dissertation also addresses problems with the current dispute resolution system within patent law. In particular, it analyses the efficiency of the litigation process, including potential changes intended to deal with the long, complex, and costly patent litigation processes.
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| 5. |
- Hellberg, Maria, et al.
(författare)
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Eradication of nasopharyngeal carriage of penicillin-non-susceptible Streptococcus pneumoniae-is it possible?
- 2012
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Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 44:12, s. 909-914
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Tidskriftsartikel (refereegranskat)abstract
- Background: The South Swedish Pneumococcal Intervention Project (SSPIP) was started in 1995 with the aim of limiting the spread of penicillin-non-susceptible pneumococci (PNSP) in Skåne County, Sweden. As part of the SSPIP, eradication therapy with rifampicin in combination with 1 more antibiotic was considered on a social indication after prolonged carriage of 2-3 months. Methods: In this retrospective study, 125 medical records were analyzed. Children aged 0-10 y referred for eradication therapy in Malmö and Lund, due to a prolonged nasopharyngeal carriage of PNSP with a penicillin G minimum inhibitory concentration of ≥ 0.5 mg/l, between the y 1997 and 2011 were included. Two consecutive negative cultures, with the second one no shorter than 7 days after treatment completion, were required for the carriage to be considered eradicated. Results: Out of 125 children, 71 received treatment with rifampicin in combination with amoxicillin (n = 44), erythromycin (n = 22), or clindamycin (n = 5) for 7 days. Eradication treatment was successful in 91.5% of the children. Six children (8.5%) had treatment failure with amoxicillin and rifampicin; 3 were found by late follow-up. There was a trend towards a better outcome with erythromycin and clindamycin combinations in comparison to amoxicillin. Conclusions: Eradication therapy was successful, but a proper follow-up is essential.
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| 6. |
- Hellberg, Sandra, et al.
(författare)
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Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis
- 2016
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 16:11, s. 2928-2939
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.
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| 7. |
- Hellberg, Sandra, 1986-
(författare)
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Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 8. |
- Hellberg, Sandra, et al.
(författare)
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Maintained thymic output of conventional and regulatory T cells during human pregnancy
- 2019
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Ingår i: 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
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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.
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| 9. |
- Hellberg, Sandra, et al.
(författare)
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Progesterone Dampens Immune Responses in In Vitro Activated CD4(+) T Cells and Affects Genes Associated With Autoimmune Diseases That Improve During Pregnancy
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The changes in progesterone (P4) levels during and after pregnancy coincide with the temporary improvement and worsening of several autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Most likely immune-endocrine interactions play a major role in these pregnancy-induced effects. In this study, we used next generation sequencing to investigate the direct effects of P4 on CD4(+) T cell activation, key event in pregnancy and disease. We report profound dampening effects of P4 on T cell activation, altering the gene and protein expression profile and reversing many of the changes induced during the activation. The transcriptomic changes induced by P4 were significantly enriched for genes associated with diseases known to be modulated during pregnancy such as MS, RA and psoriasis. STAT1 and STAT3 were significantly downregulated by P4 and their downstream targets were significantly enriched among the disease-associated genes. Several of these genes included well-known and disease-relevant cytokines, such as IL-12 beta, CXCL10 and OSM, which were further validated also at the protein level using proximity extension assay. Our results extend the previous knowledge of P4 as an immune regulatory hormone and support its importance during pregnancy for regulating potentially detrimental immune responses towards the semi-allogenic fetus. Further, our results also point toward a potential role for P4 in the pregnancy-induced disease immunomodulation and highlight the need for further studies evaluating P4 as a future treatment option.
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| 10. |
- Henningsson, Anna J., 1972-, et al.
(författare)
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Genome-wide DNA Methylation Profiling in Lyme Neuroborreliosis Reveals Altered Methylation Patterns of HLA Genes
- 2024
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Ingår i: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613. ; 229:4, s. 1209-1214
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Tidskriftsartikel (refereegranskat)abstract
- Lyme neuroborreliosis (LNB) is a complex neuroinflammatory disorder caused by Borrelia burgdorferi, which is transmitted through tick bites. Epigenetic alterations, specifically DNA methylation (DNAm), could play a role in the host immune response during infection. In this study, we present the first genome-wide analysis of DNAm in peripheral blood mononuclear cells from patients with LNB and those without LNB. Using a network-based approach, we highlighted HLA genes at the core of these DNAm changes, which were found to be enriched in immune-related pathways. These findings shed light on the role of epigenetic modifications in the LNB pathogenesis that should be confirmed and further expanded upon in future studies. We present the first genome-wide analysis of DNA methylation in peripheral blood mononuclear cells from patients with and those without the tick-borne infection Lyme neuroborreliosis (LNB). Our findings show that LNB is associated with immune-related DNA methylation changes.
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