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Nilsson, Gunnar
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Publications (10 of 15) Show all publications
Maric, J., Ravindran, A., Mazzurana, L., Van Acker, A., Rao, A., Kokkinou, E., . . . Mjosberg, J. (2019). Cytokine-induced endogenous production of prostaglandin D-2 is essential for human group 2 innate lymphoid cell activation. Journal of Allergy and Clinical Immunology, 143(6), 2202-2214.e5
Open this publication in new window or tab >>Cytokine-induced endogenous production of prostaglandin D-2 is essential for human group 2 innate lymphoid cell activation
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2019 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 6, p. 2202-2214.e5Article in journal (Refereed) Published
Abstract [en]

Objective: We set out to examine PG production in human ILC2s and the implications of such endogenous production on ILC2 function. Methods: The effects of the COX-1/2 inhibitor flurbiprofen, the hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor KMN698, and the CRTH2 antagonist CAY10471 on human ILC2s were determined by assessing receptor and transcription factor expression, cytokine production, and gene expression with flow cytometry, ELISA, and quantitative RT-PCR, respectively. Concentrations of lipid mediators were measured by using liquid chromatography-tandem mass spectrometry and ELISA. Results: We show that ILC2s constitutively express HPGDS and upregulate COX-2 upon IL-2, IL-25, and IL-33 plus thymic stromal lymphopoietin stimulation. Consequently, PGD2 and its metabolites can be detected in ILC2 supernatants. We reveal that endogenously produced PGD2 is essential in cytokine-induced ILC2 activation because blocking of the COX-1/2 or HPGDS enzymes or the CRTH2 receptor abolishes ILC2 responses. Conclusion: PGD2 produced by ILC2s is, in a paracrine/autocrine manner, essential in cytokine-induced ILC2 activation. Hence we provide the detailed mechanism behind how CRTH2 antagonists represent promising therapeutic tools for allergic diseases by controlling ILC2 function.

Place, publisher, year, edition, pages
MOSBY-ELSEVIER, 2019
Keywords
Group 2 innate lymphoid cells, prostaglandin D-2, chemoattractant receptor-homologous molecule expressed on T(H)2 cells, allergy
National Category
Immunology Immunology in the medical area Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-387922 (URN)10.1016/j.jaci.2018.10.069 (DOI)000470113200024 ()30578872 (PubMedID)
Funder
Swedish Research Council, 521-2013-2791Swedish Foundation for Strategic Research , ICA120023Swedish Research CouncilSwedish Foundation for Strategic Research Swedish Cancer Society, 130396Swedish Society for Medical Research (SSMF)German Research Foundation (DFG)Swedish Heart Lung Foundation, HLF 20150640; HLF 20140469
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved
Rönnberg, E., Ghaib, A., Ceriol, C., Enoksson, M., Arock, M., Säfholm, J., . . . Nilsson, G. (2019). Divergent Effects of Acute and Prolonged Interleukin 33 Exposure on Mast Cell IgE-Mediated Functions. Frontiers in Immunology, 10, Article ID 1361.
Open this publication in new window or tab >>Divergent Effects of Acute and Prolonged Interleukin 33 Exposure on Mast Cell IgE-Mediated Functions
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1361Article in journal (Refereed) Published
Abstract [en]

Background: Epithelial cytokines, including IL-33 and Thymic stromal lymphopoietin (TSLP), have attracted interest because of their roles in chronic allergic inflammation-related conditions such as asthma. Mast cells are one of the major targets of IL-33, to which they respond by secreting cytokines. Most studies performed thus far have investigated the acute effects of IL-33 on mast cells. In the current study, we investigated how acute vs. prolonged exposure of mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation.

Methods: Human lung mast cells (HLMCs), cord blood-derived mast cells (CBMCs), and the ROSA mast cell line were used for this study. Receptor expression and the levels of mediators were measured after treatment with IL-33 and/or TSLP.

Results: IL-33 induced the release of cytokines. Prolonged exposure to IL-33 increased while TSLP reduced intracellular levels of tryptase. Acute IL-33 treatment strongly potentiated IgE-mediated activation. In contrast, 4 days of exposure to IL-33 decreased IgE-mediated activation, an effect that was accompanied by a reduction in Fc epsilon RI expression.

Conclusion: We show that IL-33 plays dual roles in mast cells, in which its acute effects include cytokine release and the potentiation of IgE-mediated degranulation, whereas prolonged exposure to IL-33 reduces IgE-mediated activation. We conclude that mast cells act quickly in response to the alarmin IL-33 to initiate an acute inflammatory response, whereas extended exposure to IL-33 during prolonged inflammation reduces IgE-mediated responses. This negative feedback effect suggests the presence of a novel regulatory pathway that modulates IgE-mediated human mast cell responses.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
Fc epsilon RI, IgE, IL-33, mast cells, TSLP
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-390195 (URN)10.3389/fimmu.2019.01361 (DOI)000472212500001 ()31275312 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research AstraZenecaSwedish Heart Lung FoundationTore Nilsons Stiftelse för medicinsk forskningLars Hierta Memorial FoundationSwedish Society for Medical Research (SSMF)Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-08-08 Created: 2019-08-08 Last updated: 2019-08-08Bibliographically approved
Nilsson, G. & Dahlin, J. S. (2019). New insights into the origin of mast cells [Letter to the editor]. Allergy. European Journal of Allergy and Clinical Immunology, 74(4), 844-845
Open this publication in new window or tab >>New insights into the origin of mast cells
2019 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, no 4, p. 844-845Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
WILEY, 2019
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-382019 (URN)10.1111/all.13668 (DOI)000462915600026 ()30427067 (PubMedID)
Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-04-18Bibliographically approved
Grootens, J., Ungerstedt, J. S., Ekoff, M., Rönnberg, E., Klimkowska, M., Amini, R.-M., . . . Dahlin, J. S. (2019). Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis. EBioMedicine, 43, 150-158
Open this publication in new window or tab >>Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 43, p. 150-158Article in journal (Refereed) Published
Abstract [en]

Background: Systemic mastocytosis (SM) is a haematological disease characterised by organ infiltration by neoplastic mast cells. Almost all SM patients have a mutation in the gene encoding the tyrosine kinase receptor KIT causing a D816V substitution and autoactivation of the receptor. Mast cells and CD34(+) haematopoietic progenitors can carry the mutation: however, in which progenitor cell subset the mutation arises is unknown. We aimed to investigate the distribution of the D816V mutation in single mast cells and single haematopoietic stem and progenitor cells.

Methods: Fluorescence-activated single-cell index sorting and KIT D816V mutation assessment were applied to analyse mast cells and >10,000 CD34(+) bone marrow progenitors across 10 haematopoietic progenitor subsets. In vitro assays verified cell-forming potential.

Findings: We found that in SM 60-99% of the mast cells harboured the KIT D816V mutation. Despite increased frequencies of mast cells in SM patients compared with control subjects, the haematopoietic progenitor subset frequencies were comparable. Nevertheless, the mutation could be detected throughout the haematopoietic landscape of SM patients, from haematopoietic stem cells to more lineage-primed progenitors. In addition, we demonstrate that Fc epsilon RI+ bone marrow progenitors exhibit mast cell-forming potential, and we describe aberrant CD45RA expression on SM mast cells for the first time.

Interpretation: The KIT D816V mutation arises in early haematopoietic stem and progenitor cells and the mutation frequency is approaching 100% in mature mast cells, which express the aberrant marker CD45RA.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2019
Keywords
Systemic Mastocytosis, Single-cell, Mast cell, Mast cell progenitor, CD45RA, Haematopoiesis, Haematopoietic stem cells, KIT D816V
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-387962 (URN)10.1016/j.ebiom.2019.03.089 (DOI)000470091600028 ()30975542 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Cancer Research Funds of RadiumhemmetMagnus Bergvall FoundationTore Nilsons Stiftelse för medicinsk forskningStockholm County Council
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved
Ravindran, A., Rönnberg, E., Dahlin, J. S., Mazzurana, L., Säfholm, J., Orre, A.-C., . . . Nilsson, G. (2018). An Optimized Protocol for the Isolation and Functional Analysis of Human Lung Mast Cells. Frontiers in Immunology, 9, Article ID 2193.
Open this publication in new window or tab >>An Optimized Protocol for the Isolation and Functional Analysis of Human Lung Mast Cells
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2193Article in journal (Refereed) Published
Abstract [en]

Background: Mast cells are tissue-resident inflammatory cells defined by their high granularity and surface expression of the high-affinity IgE receptor, Fc + RI, and CD117/KIT, the receptor for stem cell factor (SCF). There is a considerable heterogeneity among mast cells, both phenotypically and functionally. Human mast cells are generally divided into two main subtypes based on their protease content; the mucosa-associated MCT (tryptase positive and chymase negative mast cell) and the connective tissue associated-residing MCTC (tryptase and chymase positive mast cell). Human lung mast cells exhibit heterogeneity in terms of cellular size, expression of cell surface receptors, and secreted mediators. However, knowledge about human lung mast cell heterogeneity is restricted to studies using immunohistochemistry or purified mast cells. Whereas the former is limited by the number of cellular markers that can be analyzed simultaneously, the latter suffers from issues related to cell yield.

Aim: To develop a protocol that enables isolation of human lung mast cells at high yields for analysis of functional properties and detailed analysis using single-cell based analyses of protein (flow cytometry) or RNA (RNA-sequencing) expression.

Methods: Mast cells were isolated from human lung tissue by a sequential combination of washing, enzymatic digestion, mechanical disruption, and density centrifugation using Percoll (WEMP). As a comparison, we also isolated mast cells using a conventional enzyme-based protocol. The isolated cells were analyzed by flow cytometry.

Results: We observed a significant increase in the yield of total human lung CD45(+) immune cells and an even more pronounced increase in the yield of CD117(+) mast cells with the WEMP protocol in comparison to the conventional protocols. In contrast, the frequency of the rare lymphocyte subset innate lymphoid cells group 2 (ILC2) did not differ between the two methods.

Conclusion: The described WEMP protocol results in a significant increase in the yield of human lung mast cells compared to a conventional protocol. Additionally, the WEMP protocol enables simultaneous isolation of different immune cell populations such as lymphocytes, monocytes, and granulocytes while retaining their surface marker expression that can be used for advanced single-cell analyses including multi-color flow cytometry and RNA-sequencing.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
mast cells, lung, enzymatic digestion protocols, human mast cells, mast cell isolation
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-367035 (URN)10.3389/fimmu.2018.02193 (DOI)000446444600001 ()30344519 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Swedish Heart Lung FoundationAstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceThe Karolinska Institutet's Research Foundation
Available from: 2018-11-29 Created: 2018-11-29 Last updated: 2018-11-29Bibliographically approved
Halova, I., Rönnberg, E., Draberova, L., Vliagoftis, H., Nilsson, G. P. & Draber, P. (2018). Changing the threshold-Signals and mechanisms of mast cell priming. Immunological Reviews, 282(1), 73-86
Open this publication in new window or tab >>Changing the threshold-Signals and mechanisms of mast cell priming
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2018 (English)In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 282, no 1, p. 73-86Article in journal (Refereed) Published
Abstract [en]

Mast cells play a key role in allergy and other inflammatory diseases involving engagement of multivalent antigen with IgE bound to high-affinity IgE receptors (FcεRIs). Aggregation of FcεRIs on mast cells initiates a cascade of signaling events that eventually lead to degranulation, secretion of leukotrienes and prostaglandins, and cytokine and chemokine production contributing to the inflammatory response. Exposure to pro-inflammatory cytokines, chemokines, bacterial and viral products, as well as some other biological products and drugs, induces mast cell transition from the basal state into a primed one, which leads to enhanced response to IgE-antigen complexes. Mast cell priming changes the threshold for antigen-mediated activation by various mechanisms, depending on the priming agent used, which alone usually do not induce mast cell degranulation. In this review, we describe the priming processes induced in mast cells by various cytokines (stem cell factor, interleukins-4, -6 and -33), chemokines, other agents acting through G protein-coupled receptors (adenosine, prostaglandin E2, sphingosine-1-phosphate, and β-2-adrenergic receptor agonists), toll-like receptors, and various drugs affecting the cytoskeleton. We will review the current knowledge about the molecular mechanisms behind priming of mast cells leading to degranulation and cytokine production and discuss the biological effects of mast cell priming induced by several cytokines.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
cell priming, chemokines, cytokine receptors, cytokines, high-affinity IgE receptor, mast cell
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-343008 (URN)10.1111/imr.12625 (DOI)000424876400006 ()29431203 (PubMedID)
Funder
Swedish Research Council, K2012-57X-13029-14-6
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-05-15Bibliographically approved
Grootens, J., Ungerstedt, J. S., Nilsson, G. & Dahlin, J. S. (2018). Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells. BLOOD ADVANCES, 2(17), 2273-2281
Open this publication in new window or tab >>Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells
2018 (English)In: BLOOD ADVANCES, ISSN 2473-9529, Vol. 2, no 17, p. 2273-2281Article, review/survey (Refereed) Published
Abstract [en]

Hematopoietic stem cells differentiate into all types of blood cells, including peripheral tissue-resident mast cells. The early mast cell differentiation takes place in the bone marrow, after which the progenitor cells enter the circulation and mature once reaching their target organ. Early results from single-cell culture experiments and colony-forming assays have produced the classic hierarchical tree model of hematopoiesis. The introduction of high-throughput, single-cell RNA sequencing is now revolutionizing our understanding of the differentiation process, questioning the classic tree-based models. By integrating the results from early cell culture experiments with single-cell transcriptomics, we present a differentiation landscape model of hematopoiesis and discuss it with focus on mast cells. The review also describes how the hematologic neoplasm systemic mastocytosis can be used to model human hematopoiesis using naturally occurring cell barcoding by means of the common KIT D816V mutation.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY, 2018
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-367138 (URN)10.1182/bloodadvances.2018019539 (DOI)000444247300012 ()30206100 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyTore Nilsons Stiftelse för medicinsk forskningMagnus Bergvall Foundation
Available from: 2018-11-29 Created: 2018-11-29 Last updated: 2018-11-29Bibliographically approved
Zoltowska Nilsson, A. M., Lei, Y., Adner, M. & Nilsson, G. P. (2018). Mast cell dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma. American Journal of Physiology - Lung cellular and Molecular Physiology, 314(3), L484-L492
Open this publication in new window or tab >>Mast cell dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma
2018 (English)In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 314, no 3, p. L484-L492Article in journal (Refereed) Published
Abstract [en]

Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated to the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM) induced asthma. Mast cell deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh+MC-WT) or ST2 deficient bone marrow derived mast cells (Wsh+MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh+MC-ST2KO compared to Wsh+MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in BALF and lung, the aggravated AHR in Wsh+MC-ST2KO mice, seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in bronchoalveolar lavage fluid. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role in the development of AHR.

Keywords
HDM mouse model, IL-33, ST2, airway hyperresponsiveness (AHR), mast cells
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-343006 (URN)10.1152/ajplung.00270.2017 (DOI)000428403800014 ()29146574 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung FoundationThe Karolinska Institutet's Research Foundation
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-07-19Bibliographically approved
Wennstig, A. K., Garmo, H., Isacsson, U., Gagliardi, G., Rintela, N., Lagerqvist, B., . . . Nilsson, G. (2018). The relationship between radiation doses to coronary arteries and later intervention requiring coronary stenosis in breast cancer. Paper presented at 11th European Breast Cancer Conference (EBCC), MAR 21-23, 2018, Barcelona, SPAIN. European Journal of Cancer, 92, S61-S62
Open this publication in new window or tab >>The relationship between radiation doses to coronary arteries and later intervention requiring coronary stenosis in breast cancer
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2018 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 92, p. S61-S62Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-357181 (URN)000429103100150 ()
Conference
11th European Breast Cancer Conference (EBCC), MAR 21-23, 2018, Barcelona, SPAIN
Available from: 2018-08-14 Created: 2018-08-14 Last updated: 2018-08-14Bibliographically approved
Gülen, T., Möller Westerberg, C., Lyberg, K., Ekoff, M., Kolmert, J., Bood, J., . . . Dahlén, B. (2017). Assessment of in vivo mast cell reactivity in patients with systemic mastocytosis.. Clinical and Experimental Allergy, 47(7), 909-917
Open this publication in new window or tab >>Assessment of in vivo mast cell reactivity in patients with systemic mastocytosis.
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2017 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 47, no 7, p. 909-917Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Patients with systemic mastocytosis (SM) have clinical signs of mast cell (MC) activation and increased levels of MC mediators. It is unclear whether the increased mediator levels are caused by increased numbers of tissue MCs, or whether these cells in affected individuals have a hyperactive phenotype.

OBJECTIVE: To determine reactivity of the skin and the airways to directly acting mediators and indirectly acting mast cell secretagogues in subjects with SM.

METHODS: were measured, as well as ex vivo basophil histamine release.

RESULTS: Mast cell mediators in the blood and urine were significantly higher in patients with SM than in HC and A controls. Responsiveness to local activation of skin MCs (by morphine) and airway MCs (by mannitol) was similar in SM and HC groups. Likewise, end-organ responsiveness in the skin to histamine, and in the airways to methacholine, was similar in all three subject groups. There was no evidence of increased basophil reactivity in SM patients.

CONCLUSIONS AND CLINICAL RELEVANCE: Mast cells in the skin and airways of subjects with SM do not exhibit hyper-reactivity towards the MC-activating stimuli morphine and mannitol, respectively. Therefore, the highly elevated baseline levels of MC mediators in SM are most likely due to increased MC numbers, rather than altered MC responsiveness. The underlying mechanisms could involve leakage of MC mediators, or dysfunctions in mediator synthesis, storage and release. One clinical implication of our study is that there is no contraindication to perform skin tests using morphine in subjects with mastocytosis.

Keywords
histamine, mannitol, mast cell reactivity, mastocytosis, prostaglandin D2, tryptase
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-343002 (URN)10.1111/cea.12914 (DOI)28258965 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyStockholm County CouncilSwedish Heart Lung Foundation
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-03-16Bibliographically approved
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