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Gustafsson, Mika
Publications (10 of 31) Show all publications
Das, J., Verma, D., Gustafsson, M. & Lerm, M. (2019). Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naive subjects. Epigenetics, 14(6), 589-601
Open this publication in new window or tab >>Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naive subjects
2019 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 6, p. 589-601Article in journal (Refereed) Published
Abstract [en]

The protection against tuberculosis induced by the Bacille Calmette Guerin (BCG) vaccine is unpredictable. In our previous study, altered DNA methylation pattern in peripheral blood mononuclear cells (PBMCs) in response to BCG was observed in a subgroup of individuals, whose macrophages killed mycobacteria effectively (responders). These macrophages also showed production of Interleukin-1 beta (IL-1 beta) in response to mycobacterial stimuli before vaccination. Here, we hypothesized that the propensity to respond to the BCG vaccine is reflected in the DNA methylome. We mapped the differentially methylated genes (DMGs) in PBMCs isolated from responders/non-responders at the time point before vaccination aiming to identify possible predictors of BCG responsiveness. We identified 43 DMGs and subsequent bioinformatic analyses showed that these were enriched for actin-modulating pathways, predicting differences in phagocytosis. This could be validated by experiments showing that phagocytosis of mycobacteria, which is an event preceding mycobacteria-induced IL-1 beta production, was strongly correlated with the DMG pattern.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2019
Keywords
DNA methylation; BCG-vaccination; phagocytosis; actin regulation; Mycobacterium tuberculosis; Tuberculosis
National Category
Medical Genetics
Identifiers
urn:nbn:se:liu:diva-158857 (URN)10.1080/15592294.2019.1603963 (DOI)000471388000001 ()31010371 (PubMedID)
Note

Funding Agencies|Hjart-Lungfonden [20150709]; Vetenskapsradet [2012-3349]

Available from: 2019-07-15 Created: 2019-07-15 Last updated: 2019-07-25
Schleicher, J., Conrad, T., Gustafsson, M., Cedersund, G., Guthke, R. & Linde, J. (2017). Facing the challenges of multiscale modelling of bacterial and fungal pathogen-host interactions. Briefings in Functional Genomics & Proteomics, 16(2), 57-69
Open this publication in new window or tab >>Facing the challenges of multiscale modelling of bacterial and fungal pathogen-host interactions
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2017 (English)In: Briefings in Functional Genomics & Proteomics, ISSN 2041-2649, E-ISSN 2041-2657, Vol. 16, no 2, p. 57-69Article in journal (Refereed) Published
Abstract [en]

Recent and rapidly evolving progress on high-throughput measurement techniques and computational performance has led to the emergence of new disciplines, such as systems medicine and translational systems biology. At the core of these disciplines lies the desire to produce multiscale models: mathematical models that integrate multiple scales of biological organization, ranging from molecular, cellular and tissue models to organ, whole-organism and population scale models. Using such models, hypotheses can systematically be tested. In this review, we present state-of-the-art multiscale modelling of bacterial and fungal infections, considering both the pathogen and host as well as their interaction. Multiscale modelling of the interactions of bacteria, especially Mycobacterium tuberculosis, with the human host is quite advanced. In contrast, models for fungal infections are still in their infancy, in particular regarding infections with the most important human pathogenic fungi, Candida albicans and Aspergillus fumigatus. We reflect on the current availability of computational approaches for multiscale modelling of host-pathogen interactions and point out current challenges. Finally, we provide an outlook for future requirements of multiscale modelling.

Place, publisher, year, edition, pages
Oxford University Press, 2017
Keywords
host–pathogen interaction; infection; mathematical modelling; multiscale modelling
National Category
Genetics
Identifiers
urn:nbn:se:liu:diva-126449 (URN)10.1093/bfgp/elv064 (DOI)000397205400001 ()26857943 (PubMedID)
Available from: 2016-03-24 Created: 2016-03-24 Last updated: 2018-11-26Bibliographically approved
Gustafsson, M., Gawel, D., Alfredsson, L., Baranzini, S., Bjorkander, J., Blomgran, R., . . . Benson, M. (2015). A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases. Science Translational Medicine, 7(313), Article ID 313ra178.
Open this publication in new window or tab >>A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases
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2015 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 313, article id 313ra178Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2015
National Category
Biological Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-123522 (URN)10.1126/scitranslmed.aad2722 (DOI)000365237400003 ()26560356 (PubMedID)
Note

Funding Agencies|Cancer fund, Swedish Medical Research Council [K2013-61X-22310-01-04, 2012-3168]; Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research [250114]; Sigrid Juselius Foundation; Generalitat de Catalunya AGAUR [2014-SGR364]; Spanish Association Against Cancer; Spanish Ministry of Health ISCIII FIS [PI12/01528]; RTICC [RD12/0036/0008]

Available from: 2015-12-22 Created: 2015-12-21 Last updated: 2018-04-10Bibliographically approved
Bruhn, S., Fang, Y., Barrenäs, F., Gustafsson, M., Zhang, H., Konstantinell, A., . . . Benson, M. (2014). A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy. Science Translational Medicine, 6(218)
Open this publication in new window or tab >>A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy
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2014 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 6, no 218Article in journal (Refereed) Published
Abstract [en]

The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (T(H)2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2014
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-104118 (URN)10.1126/scitranslmed.3007410 (DOI)000329789600003 ()
Available from: 2014-02-07 Created: 2014-02-07 Last updated: 2018-01-11
Nestor, C., Barrenäs, F., Wang, H., Lentini, A., Zhang, H., Bruhn, S., . . . Benson, M. (2014). DNA Methylation Changes Separate Allergic Patients from Healthy Controls and May Reflect Altered CD4(+) T-Cell Population Structure. PLoS Genetics, 10(1), e1004059
Open this publication in new window or tab >>DNA Methylation Changes Separate Allergic Patients from Healthy Controls and May Reflect Altered CD4(+) T-Cell Population Structure
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2014 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 1, p. e1004059-Article in journal (Refereed) Published
Abstract [en]

Altered DNA methylation patterns in CD4(+) T-cells indicate the importance of epigenetic mechanisms in inflammatory diseases. However, the identification of these alterations is complicated by the heterogeneity of most inflammatory diseases. Seasonal allergic rhinitis (SAR) is an optimal disease model for the study of DNA methylation because of its welldefined phenotype and etiology. We generated genome-wide DNA methylation (N-patients = 8, N-controls = 8) and gene expression (N-patients = 9, N-controls = 10) profiles of CD4(+) T-cells from SAR patients and healthy controls using Illuminas HumanMethylation450 and HT-12 microarrays, respectively. DNA methylation profiles clearly and robustly distinguished SAR patients from controls, during and outside the pollen season. In agreement with previously published studies, gene expression profiles of the same samples failed to separate patients and controls. Separation by methylation (N-patients = 12, N-controls = 12), but not by gene expression (N-patients = 21, N-controls = 21) was also observed in an in vitro model system in which purified PBMCs from patients and healthy controls were challenged with allergen. We observed changes in the proportions of memory T-cell populations between patients (N-patients = 35) and controls (N-controls = 12), which could explain the observed difference in DNA methylation. Our data highlight the potential of epigenomics in the stratification of immune disease and represents the first successful molecular classification of SAR using CD4(+) T cells.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-107871 (URN)10.1371/journal.pgen.1004059 (DOI)000336525000030 ()
Available from: 2014-06-23 Created: 2014-06-23 Last updated: 2019-02-11
Gustafsson, M., Edström, M., Gawel, D., Nestor, C., Wang, H., Zhang, H., . . . Benson, M. (2014). Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment. Genome Medicine, 6(17)
Open this publication in new window or tab >>Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment
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2014 (English)In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 6, no 17Article in journal (Refereed) Published
Abstract [en]

Background: Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases. Methods: We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases. Results: The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4(+) T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification. Conclusions: In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles.

Place, publisher, year, edition, pages
BioMed Central, 2014
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-106873 (URN)10.1186/gm534 (DOI)000334631300002 ()
Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2018-04-10
Gustafsson, M., Nestor, C., Zhang, H., Barabasi, A.-L., Baranzini, S., Brunak, S., . . . Benson, M. (2014). Modules, networks and systems medicine for understanding disease and aiding diagnosis. Genome Medicine, 6(82)
Open this publication in new window or tab >>Modules, networks and systems medicine for understanding disease and aiding diagnosis
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2014 (English)In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 6, no 82Article, review/survey (Refereed) Published
Abstract [en]

Many common diseases, such as asthma, diabetes or obesity, involve altered interactions between thousands of genes. High-throughput techniques (omics) allow identification of such genes and their products, but functional understanding is a formidable challenge. Network-based analyses of omics data have identified modules of disease-associated genes that have been used to obtain both a systems level and a molecular understanding of disease mechanisms. For example, in allergy a module was used to find a novel candidate gene that was validated by functional and clinical studies. Such analyses play important roles in systems medicine. This is an emerging discipline that aims to gain a translational understanding of the complex mechanisms underlying common diseases. In this review, we will explain and provide examples of how network-based analyses of omics data, in combination with functional and clinical studies, are aiding our understanding of disease, as well as helping to prioritize diagnostic markers or therapeutic candidate genes. Such analyses involve significant problems and limitations, which will be discussed. We also highlight the steps needed for clinical implementation.

Place, publisher, year, edition, pages
BioMed Central, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-112648 (URN)10.1186/s13073-014-0082-6 (DOI)000344570000001 ()25473422 (PubMedID)
Note

Funding Agencies|European Commission under the Seventh Framework Programme, CASyM; Swedish Medical Research Council; Linkoping University

Available from: 2014-12-05 Created: 2014-12-05 Last updated: 2017-12-05
Edström, M., Dahle, C., Vrethem, M., Gustafsson, M., Benson, M., Jenmalm, M. & Ernerudh, J. (2014). Regulatory T cells in Multiple Sclerosis – Indications of impaired function of suppressive capacity and a role for chemokines.
Open this publication in new window or tab >>Regulatory T cells in Multiple Sclerosis – Indications of impaired function of suppressive capacity and a role for chemokines
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

BACKGROUND Regulatory T cells (Treg) are critical for immune regulation and homeostasis. In multiple sclerosis (MS), the function of these cells has been shown to be impaired, although the underlying mechanism has yet to be shown. In the current study, we aimed to characterize and assess the phenotypical, functional and transcriptional characteristics of memory and naïve Treg in MS patients and controls.

MATERIAL AND METHODS 27 patients with relapsing-remitting disease were included, along with 29 healthy controls. Flow cytometry was used for detailed phenotyping of Treg subpopulations CD4+CD45RA+/- and CD4dimCD25++ and their expression of FOXP3, CD39 and HELIOS. CFSE (proliferation marker) and CD69 (activation marker) were used to investigate the functional capacity of Treg. A microarray was employed for genome-wide transcriptional characterization of isolated Treg.

RESULTS CD4+CD45RA–CD25++ activated Treg displayed a higher expression of FOXP3 and CD39 than resting CD4+CD45RA+CD25+ Treg, while no significant phenotypical differences were observed in Treg subpopulations between patients and controls. However, a lower anti-proliferative capacity was observed in activated Treg of MS patients compared with those of controls (p<0.05), while suppression of activation was similar to controls. Gene set enrichment analysis (GSEA) of microarray data revealed enrichment for the GO gene set ‘chemokine receptor binding’ in MS Treg.

CONCLUSION Although numerical phenotypical assessment of resting and activated Tregs did not reveal any significant difference between patients and controls, functional co-culturing experiments showed an impaired function in activated Treg of MS patients. Furthermore, GSEA revealed immune-related gene sets overexpressed in Treg of MS patients, possibly containing clues to the functional impairment. In particular over-activity in chemokine signalling in Treg would be of interest for further investigation.

Keywords
EBI3, FOXP3, multiple sclerosis, RORC, T cells, transcription factors
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-108908 (URN)
Available from: 2014-07-11 Created: 2014-07-11 Last updated: 2018-01-11Bibliographically approved
Nestor, C. E., Dadfa, E., Ernerudh, J., Gustafsson, M., Björkander, J. F., Benson, M. & Zhang, H. (2014). Sublingual immunotherapy alters expression of IL-4 and its soluble and membrane-bound receptors. Allergy. European Journal of Allergy and Clinical Immunology, 69(11), 1564-1566
Open this publication in new window or tab >>Sublingual immunotherapy alters expression of IL-4 and its soluble and membrane-bound receptors
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2014 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, no 11, p. 1564-1566Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley, 2014
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-109429 (URN)10.1111/all.12505 (DOI)000343851200016 ()25130266 (PubMedID)
Available from: 2014-08-18 Created: 2014-08-18 Last updated: 2018-01-11
Zhang, H., Gustafsson, M., Nestor, C. E., Chung, K. F. & Benson, M. (2014). Targeted omics and systems medicine: personalising care. The Lancet Respiratory Medicine, 2(10), 785-787
Open this publication in new window or tab >>Targeted omics and systems medicine: personalising care
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2014 (English)In: The Lancet Respiratory Medicine, ISSN 2213-2600, E-ISSN 2213-2619, Vol. 2, no 10, p. 785-787Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-111133 (URN)10.1016/S2213-2600(14)70188-2 (DOI)000342692100015 ()
Available from: 2014-10-08 Created: 2014-10-08 Last updated: 2017-12-05Bibliographically approved
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