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Bergh, Ann-Charlotte
Publications (8 of 8) Show all publications
Ingelsson, B., Söderberg, D., Strid, T., Söderberg, A., Bergh, A.-C., Loitto, V.-M., . . . Rosén, A. (2018). Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C. Proceedings of the National Academy of Sciences of the United States of America, 115(3), E478-E487
Open this publication in new window or tab >>Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed) Published
Abstract [en]

Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

Place, publisher, year, edition, pages
Washington, DC, United States: National Academy of Sciences, 2018
Keywords
CpG-C, DAMP, immune DNA sensing, lymphocyte signaling, mitochondrial DNA release
National Category
Basic Medicine Immunology in the medical area
Research subject
Economic Information Systems
Identifiers
urn:nbn:se:liu:diva-144187 (URN)10.1073/pnas.1711950115 (DOI)000423091400018 ()29295921 (PubMedID)2-s2.0-85042104216 (Scopus ID)
Funder
Swedish Cancer Society
Note

Funding agencies: Linkoping Medical Society; Linkoping University; ALF grants; Region Ostergotland, Sweden; Linkoping University Cancer; Ingrid Asp Foundation; Swedish Cancer Society

Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2018-09-07Bibliographically approved
Bergh, A.-C. (2016). Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic lymphocytic leukemia (CLL) cells rapidly die when put in culture implying that microenvironmental signals delivered by accessory cells confer CLL cells with a growth advantage. Recent findings show that CLL cells are antigen experienced and antigen binding play a critical role in the pathogenesis of the disease. The overall aim of this thesis was to study the influence of the microenvironment and antigen binding in CLL.

In paper I, we studied the influence of the small redox-regulatory molecule thioredoxin (Trx) on CLL cell survival and proliferation. We found Trx to be highly expressed in CLL lymph nodes (LNs), secreted from stromal cells surrounding proliferating CLL cells in proliferation centers, indicating growth promoting properties. Secreted Trx was also shown to protect CLL cells from apoptosis.

In paper II, oxidized LDL was added to subset #1 CLL cells. However, in contrast to our hypothesis, we could not observe activation and proliferation of CLL cells. Instead subset #1 CLL cells were unresponsive/anergic through the B cell receptor (BcR). This anergic state could however be overcome by “wash out” of bound antigen or addition of toll-like receptor 9 stimulation in some patients.

Gene expression profiles differ between groups of CLL patients and in peripheral blood (PB) and LN compartment, due to different microenvironments. However, it is not known whether these differences also apply for DNA methylation. In paper III, we identified various genes that were alternatively methylated between IGHV mutated (M) and unmutated (UM) groups. For example prognostic genes, CLLU1 and LPL, genes involved in B cell signaling, IBTK, as well as numerous TGF-β and NF-κB/TNF pathway genes.

The intensity and duration of BcR signals are fine-tuned by enhancing or inhibitory coreceptors. SHP-1 inhibits BcR-signals by dephosphorylation. In paper IV, we compared the expression and activity of SHP-1 in CLL cells from LN with matched PB samples. However, in contrast to our hypothesis, SHP-1 activity/phosphorylation status in PB and LN, did not differ significantly.

This thesis, add another piece to the puzzle, on how the microenvironment and antigens influence CLL pathogenesis. Since great variations among individuals are seen, further studies in different groups of patients are necessary to elucidate the importance of antigen for the development of CLL.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. p. 83
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1501
National Category
Cell and Molecular Biology Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124576 (URN)10.3384/diss.diva-124576 (DOI)978-91-7685-867-7 (ISBN)
Public defence
2016-02-26, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2018-01-10Bibliographically approved
Bergh, A.-C., Evaldsson, C., Pedersen, L. B., Geisler, C., Stamatopoulos, K., Rosenquist, R. & Rosén, A. (2014). Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia. Haematologica, 99(11), 1722-1730
Open this publication in new window or tab >>Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia
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2014 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 11, p. 1722-1730Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia B-cells express auto/xeno-antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde present on low-density lipoprotein, apoptotic blebs, and on certain microbes. The poor-prognostic stereotyped subset #1 (Clan I IGHV genes-IGKV1(D)-39) express IgM B-cell receptors that bind oxidized low-density lipoprotein. In this study, we have used for the first time this authentic cognate antigen, since it is more faithful to B-cell physiology than anti-IgM, for analysis of downstream B-cell receptor-signal transduction events. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen-binding induced prompt receptor-clustering, followed by internalization. However, the receptor-signal transduction was silenced, revealing no Ca2+ mobilization or cell-cycle entry, while phosphorylated extracellular-regulated kinase1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein. Interestingly, B-cell receptor responsiveness was recovered after 48 hours culture in the absence of antigen in half of the cases. Toll-like receptor 9-ligand was found to breach the B-cell receptor-signaling incompetence in 5 of 12 cases pointing to intra-subset heterogeneity. Altogether, this study supports B-cell receptor-unresponsiveness to cognate self-antigen on its own in poor-prognostic subset #1 chronic lymphocytic leukemia indicating that these cells proliferate by other mechanisms that may override B-cell receptor-silencing brought about in a context of self-tolerance/anergy. These novel findings have implications for the understanding of chronic lymphocytic leukemia pathobiology and therapy.

Place, publisher, year, edition, pages
Ferrata Storti Foundation, 2014
Keywords
Anergy; B-cell Receptor Signaling; Chronic Lymphocytic Leukemia; Oxidized LDL; Stereotyped subsets
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-109020 (URN)10.3324/haematol.2014.106054 (DOI)000347016300013 ()25085355 (PubMedID)
Available from: 2014-07-28 Created: 2014-07-28 Last updated: 2017-12-05
Cahill, N., Bergh, A.-C., Kanduri, M., Göransson-Kultima, H., Mansouri, L., Isaksson, A., . . . Rosenquist, R. (2013). 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments. Leukemia, 27(1), 150-158
Open this publication in new window or tab >>450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
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2013 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 1, p. 150-158Article in journal (Refereed) Published
Abstract [en]

In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K-arrays, we provide the most comprehensive DNA methylation study of CLL to date, analysing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (e.g. CLLU1, LPL, ZAP70, NOTCH1), epigenetic regulator (e.g. HDAC9, HDAC4, DNMT3B), B-cell signaling (e.g. IBTK) and numerous TGF-ß and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.Leukemia accepted article preview online, 27 August 2012; doi:10.1038/leu.2012.245.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80705 (URN)10.1038/leu.2012.245 (DOI)000313511400021 ()22922567 (PubMedID)
Available from: 2012-08-29 Created: 2012-08-29 Last updated: 2017-12-07
Rosén, A., Bergh, A.-C., Gogok, P., Evaldsson, C., Lanemo Myhrinder, A., Hellqvist, E., . . . Klein, E. (2012). Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection. OncoImmunology, 1(1), 18-27
Open this publication in new window or tab >>Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection
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2012 (English)In: OncoImmunology, ISSN 2162-402X, Vol. 1, no 1, p. 18-27Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) cells express the receptor for Epstein-Barr virus (EBV) and can be infected in vitro. Infected cells do not express the growth-promoting set of EBV-encoded genes and therefore they do not yield LCLs, in most experiments. With exceptional clones, lines were obtained however. We describe a new line, HG3, established by in vitro EBV-infection from an IGHV1–2 unmutated CLL patient clone. All cells expressed EBNA-2 and LMP-1, the EBV-encoded genes pivotal for transformation. The karyotype, FISH cytogenetics and SNP-array profile of the line and the patient's ex vivo clone showed biallelic 13q14 deletions with genomic loss of DLEU7, miR15a/miR16–1, the two micro-RNAs that are deleted in 50% of CLL cases. Further features of CLL cells were: expression of CD5/CD20/CD27/CD43 and release of IgM natural antibodies reacting with oxLDL-like epitopes on apoptotic cells (cf. stereotyped subset-1). Comparison with two LCLs established from normal B cells showed 32 genes expressed at higher levels (> 2-fold). Among these were LHX2 and LILRA. These genes may play a role in the development of the disease. LHX2 expression was shown in self-renewing multipotent hematopoietic stem cells, and LILRA4 codes for a receptor for bone marrow stromal cell antigen-2 that contributes to B cell development. Twenty-four genes were expressed at lower levels, among these PARD3 that is essential for asymmetric cell division. These genes may contribute to establish precursors of CLL clones by regulation of cellular phenotype in the hematopoietic compartment. Expression of CD5/CD20/CD27/CD43 and spontaneous production of natural antibodies may identify the CLL cell as a self-renewing B1 lymphocyte.

Place, publisher, year, edition, pages
Landes Biosciences, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79040 (URN)10.4161/onci.1.1.18400 (DOI)000316257500004 ()
Available from: 2012-06-28 Created: 2012-06-28 Last updated: 2017-09-22
Evaldsson, C., Morad, V., Bergh, A.-C., Horkko, S. & Rosén, A. (2012). Peripheral blood B-cells bind epitopes on oxidized low-density lipoprotein (oxLDL) in FEBS JOURNAL, vol 279, issue SI, pp 207-207. In: FEBS JOURNAL (pp. 207-207). Wiley-Blackwell, 279(SI)
Open this publication in new window or tab >>Peripheral blood B-cells bind epitopes on oxidized low-density lipoprotein (oxLDL) in FEBS JOURNAL, vol 279, issue SI, pp 207-207
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2012 (English)In: FEBS JOURNAL, Wiley-Blackwell , 2012, Vol. 279, no SI, p. 207-207Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Series
FEBS JOURNAL, ISSN 1742-464X
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-82055 (URN)000308128601500 ()
Available from: 2012-10-01 Created: 2012-09-28 Last updated: 2017-09-22
Bäckman, E., Bergh, A.-C., Lagerdahl, I., Rydberg, B., Sundström, C., Tobin, G., . . . Rosén, A. (2007). Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro. Haematologica, 92(11), 1495-1504
Open this publication in new window or tab >>Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro
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2007 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 92, no 11, p. 1495-1504Article in journal (Refereed) Published
Abstract [en]

Background and Objectives: The redox-regulatory protein thioredoxin has several functions including transcriptional regulation, and antioxidant, cytokine, and chemokine activities. We have previously shown that extracellular thioredoxin protects B-cell chronic lymphocytic leukemia (CLL) cells from apoptosis in vitro. In this study we were interested to determine whether thioredoxin is produced by cells surrounding the CLL cells in the in vivo microenvironment and whether this cell-derived thioredoxin has any leukemia growth-promoting effect in vitro. Design and Methods: Lymph nodes from CLL patients (n=25) were analyzed for thioredoxin expression by immunohistology. Stromal cells purified from the lymph nodes were analyzed for thioredoxin secretion at the single cell level using an ELIspot assay. The survival effect of the stromal-derived thioredoxin was tested by co-culturing stromal- and CLL cells with and without Fab-fragments of an anti-thioredoxin antibody. Results: The results indicated that the thioredoxin production correlated with the amount of proliferating cells and was mainly localized to the proliferation centers (pseudofollicles) in the CLL lymph nodes. The leukemia cells per se showed minimal thioredoxin levels, in contrast, stromal cells strongly expressed thioredoxin. Purified primary stromal cells, which secreted extracellular thioredoxin, significantly protected the CLL cells from undergoing apoptosis in 72 h co-cultures. Interestingly, this anti-apoptotic effect could be abrogated by addition of Fab-fragments of an anti- thioredoxin antibody. Interpretation and Conclusions: In conclusion, we have shown that stromal cells in the lymph node microenvironment produce thioredoxin and that the thioredoxin production is localized to the proliferation centers of the CLL lymph nodes. In addition, thioredoxin produced by purified stromal cells rescued CLL cells from apoptosis in vitro. ©2007 Ferrata Storti Foundation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-40728 (URN)10.3324/haematol.11448 (DOI)54003 (Local ID)54003 (Archive number)54003 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
Bergh, A.-C., El-Schich, Z., Delfani, P., Ohlsson, L., Rosén, A. & Gjörloff Wingren, A.B cell receptor signaling suppressor SHP-1 is active in CLL lymph node and peripheral blood.
Open this publication in new window or tab >>B cell receptor signaling suppressor SHP-1 is active in CLL lymph node and peripheral blood
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Protein tyrosine phosphatase SHP-1 expression and activity is downregulated or lost in several leukemias and lymphomas due to DNA promotor hypermethylation, catalytic site mutation or oxidation, or phosphorylation at inhibitory sites, implying a negative role of SHP-1 in development of leukemias/lymphomas. In chronic lymphocytic leukemia (CLL), B cell receptor (BcR) and microenvironment signal levels are important in the pathogenesis. Considering that SHP-1 is a BcR signaling suppressor, we hypothesized that SHP-1 would be down-regulated and/or inactivated in the proliferative center lymph node (LN) cells. We analyzed PTPN6 (SHP-1) gene expression, SHP-1 protein expression and phosphorylation status in matched CD5+/CD19+ peripheral blood (PB) and LN cells from 6 CLL patients, and in comparison, BcR (anti-IgM) in vitro triggered CLL PB cells from 10 patients. Gene expression of PTPN6 was significantly higher in PB compared to LN CLL cells in 50% of the cases. SHP-1 protein expression level and phosphorylation at SHP-1Y536 and SHP-1S591 were, however, equal in PB and LN samples. SHP-1 phosphorylation at Y536 and S591, in PB CLL cells cultured ex vivo was significantly reduced upon BcR engagement in all patient samples. These results indicate that in vivo BcR signaling in CLL is paralyzed.

Keywords
B cell, chronic lymphocytic leukemia, SHP-1, suppressor, tyrosine phosphorylation
National Category
Cell and Molecular Biology Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124575 (URN)
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2018-01-10Bibliographically approved
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