Research group Gunnar Nilsson

Denna sida på svenska

Mast Cell Biology Group 

From the left: Maria Ekoff, Katarina Lyberg, Elin Rönnberg Höckerlind, Joakim Dahlin, Anna Nilsson, Gunnar Nilsson, Harissios Vliagoftis (Guest Professor), Jennine Grootens.
Not in the picture: Avinash Ravidran and Theo Gulen.

Research focus

Mast cells are (in)famous for their role as effector cells causing the symptoms in allergy and anaphylactic chock. However, we don’t have mast cells to cause problems for us but to protect us. They are an essential part of our host defense system, sensing both endogenous and exogenous “danger signals”, and react to these by initiating an inflammatory response. Mast cells have a unique capacity to recognize different molecules and to react to these by releasing specific sets of mediators. Given the great capacity to release powerful mediators, such as histamine proteases, lipid mediators and cytokines, mast cells are also associated with a number of different diseases, where these cells and their mediators are part of the pathology.  Examples of diseases where mast cells are involved are asthma, chronic inflammatory skin diseases, cancer and systemic mastocytosis. The focus for our research is to understand the role of mast cells in health and disease and to study regulatory mechanisms for mast cell activation and mediator release.

Aktiverad mastcell

Group members


Professor

Gunnar Nilsson

Phone: +46-(0)8-517 702 05
Organizational unit: Group G Nilsson
E-mail: Gunnar.P.Nilsson@ki.se

PhD, professor, group leader 

Gunnar Nilsson got his PhD degree in immunology from Uppsala University in 1989. He moved on to a postdoctoral position with Dr. Lawrence B. Schwartz, Medical College of Virginia, Richmond, VA where he was part of the seminal finding of stem cell factor as an essential growth and differentiation factor for human mast cells. He returned to Uppsala University in 1992 where he set up his own research group at the department of pathology. Between 1994-1996 he was a guest scientist with Dr. Dean Metcalfe, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD. Since 2003 he is working at the Karolinska Institutet, Stockholm, where he is PI for a group on mast cell biology. He is member of several international and national organizations. He has published more than 150 scientific articles, mainly within the area of mast cell functions in health and disease. 

Senior lab manager

Maria Ekoff

Organizational unit: Group G Nilsson
E-mail: Maria.Ekoff@ki.se

PhD, Senior Lab Manager 

Maria did her undergraduate studies in Molecular Biotechnology at Uppsala University. She received her PhD in Immunology at the department of Medicine at Karolinska Institutet in 2008 and thereafter did post doctoral training at the Institute of Environmental Medicine, Karolinska Institutet. She returned to the department of Medicine in 2014 as a senior lab manager for the mast cell group.  
Associated

Theo Gulen

E-mail: Theo.Gulen@ki.se

MD, PhD

Theo is specialist in internal medicine, clinical immunology and allergology and currently serves as a consultant physician in the Respiratory Diseases and Allergy clinic, Karolinska University Hospital, Huddinge. He received his PhD from the Karolinska Institutet in 2014 on a project on clonal mast cell disorders and anaphylactic reactions. His current research focuses on mast cell activation disorders to characterize patient phenotypes and mechanisms leading to this uncontrolled mast cell activation.

PhD, Postdoc 

Joakim did his undergraduate studies in Molecular Biotechnology Engineering at Uppsala University. In 2013, he received his PhD in medical sciences from the Department of Medical Biochemistry and Microbiology, Uppsala University. He continued his research at the same department until 2015, when he started as a postdoctoral fellow in professor Gunnar Nilsson’s group. 

Postdoc

Elin Rönnberg Höckerlind

Organizational unit: Group G Nilsson
E-mail: elin.ronnberg.hockerlind@ki.se

Postdoc

Elin obtained her master in biology in 2008 at Uppsala University. In 2014, she received her PhD in medical biochemistry at the department of anatomy, physiology and biochemistry at the Swedish university of agricultural sciences. She continued her research in the same group until 2016 when she started as a postdoc in Gunnar Nilsson’s group.

 

 

PhD student

Avinash Ravindran

Phone: +46-(0)70-410 96 68
Organizational unit: Group G Nilsson
E-mail: avinash.ravindran@ki.se

MSc, PhD Student  

Avinash received his Master Degree in Immunology and Immunogenetics from the University of Manchester, UK in 2011. He obtained a KID funded PhD position in professor Gunnar Nilsson’s group in 2014 and is working on a project started as a joint collaboration between professor Gunnar Nilsson and Dr Jenny Mjösberg at CIM, KI Huddinge.  

R&D trainee

Jennine Grootens

Organizational unit: Group G Nilsson
E-mail: jennine.grootens@ki.se

MSc, PhD student 

Jennine received her Master’s degree in Biomedical Sciences in 2013 at Utrecht University in the Netherlands. She started with a KID funded PhD position at Karolinska Institutet in 2014. Jennine is part of a collaborative project with Dr. Johanna Ungerstedt at the department of hematology and HERM, KI Huddinge.

Projects

Systemic Mastocytosis - Theo Gülen, Joakim Dahlin, Katarina Lyberg, Jennine Grootens 

Aktiverad mastcell

Systemic mastocytosis (SM) is a rare and sometimes fatal disorder, in which the mast cell lineage development is dysfunctional. The disease is associated with an accumulation of mast cells in the body and symptoms caused by the release of mast cell mediators. The long-term goal is to find markers that have a prognostic value for the disease, as well as to identify specific targets that can be used for clinical therapeutic interventions. Several projects are ongoing:

Identification of dysfunctional regulatory pathways in SM
Investigation of developmental checkpoints in the mast cell lineage that might be corrupted.
Identification of biomarkers that can be used for diagnostic and/or prognostic purposes.
Studies of risk factors for the development of anaphylaxis

Regulatory functions of microRNAs in mast cells

In this project we study microRNA-based regulatory mechanisms underlying mast cell-activating diseases. The main objective is to identify microRNAs and their target genes regulating mast cell functions, including growth and reactivity. The project is conceived with two specific aims: 

1) To identify genes and pathways regulated by identified microRNAs in mast cells 

2) To evaluate plasma microRNAs as biomarkers and diagnostic tools in mast cell-activating diseases 

MicroRNAs belong to a big class of small, non-coding RNAs that regulate gene expression by targeting mRNAs for translational repression and/or degradation. These molecules are emerging as important modulators of cellular pathways such as growth, proliferation, apoptosis and inflammatory responses. Mast cell activation occurs in a variety of acute and chronic inflammatory states, playing an important role in the pathogenesis of several different types of diseases. Some of these diseases, such as allergy, asthma, anaphylaxis, urticaria and mastocytosis, are particularly associated with mast cell activation and the symptoms are related to mast cell mediators, and in some cases hyperplasia. However, the etiology and why mast cells are prone to be activated are for many of these diseases not fully deciphered. One area that has attracted a lot of attention recently is the role of microRNA in regulating cellular functions and the use of circulating miRNAs as biomarkers. However, the current knowledge about the role of microRNAs) in regulating mast cell functions is very limited.  

Asthma 

Role of interleukin-33 in the development and exacerbation of allergic asthma – Ying Lei, Anna Nilsson

The airway epithelium is considered an essential controller of inflammatory immune responses to allergens, viruses and environmental pollutants that contribute to asthma pathogenesis. Recent experimental and clinical studies have implicated the novel epithelial cells-derived cytokines interleukin-33 (IL-33) in the pathogenesis of respiratory allergy and asthma. The interactions between IL-33 and mast cells and type 2 cytokine–producing innate lymphoid cells (ILC2s) could be promising therapeutic targets for allergic asthma. We sought to investigate the interplays between mast cells, ILC2 cells and IL-33, and their contribution to allergic lung responses by applying our asthma models in both wild type and genetically modified mice. The long-term goal of the study is to translate the conclusions from our well-established in vivo models to subjects with asthma. 

Human lung mast cell heterogeneity – Joakim Dahlin, Avinash Ravindran 

Lung mast cells are infamous for their devastating role in allergic asthma. Human mast cells are classically divided into two distinct subsets based on their expression of the proteases chymase and tryptase. In this project we further explore the heterogeneity of human lung mast cells, with the ultimate goal to find the characteristic subset of the mast cells causing asthma exacerbations. 

The interaction between innate lymphoid cells of type 2 and mast cells in allergic airway inflammation – Avinash Ravindran 

Both mast cells and innate lymphoid cells of type 2 have an important role for the development of allergic airway inflammation. The focus of this project is to study the interaction between mast cells and innate lymphoid cells of type 2, and its implication for acute and chronic airway inflammation. 

Activation pathways and mast cell mediators 

Inhibition of mast cell activation responses – Maria Ekoff 

The main focus of this project is to identify substances with the ability to inhibit mast cell release of inflammatory mediators. Mast cells are long-lived effector cells of the immune system perhaps best known for their involvement in allergic diseases. Upon activation, the mast cell releases a variety of inflammatory substances (histamine, leukotrienes, proteases and cytokines) that cause the symptoms we associate with allergy. Today allergy is treated primarily with anti-histamines, i.e. treating the symptoms rather than the cause. A more direct approach would be to prevent/reduce mast cell release. Since mast cell mediators also play a part in many inflammatory diseases, this approach could be used as a novel strategy for treatment also in these settings. A more long-term goal is to perform large scale screenings to find substances or combinations thereof to reduce/abolish mast cell activation. Effective candidate-substances are then tested more extensively in vitro, ex vivo (biopsies) and in vivo using animal models.  

Selected publications

Histone deacetylase inhibitor SAHA mediates mast cell death and epigenetic silencing of constitutively active D816V KIT in systemic mastocytosis.
Lyberg K, Ali H, Grootens J, Kjellander M, Tirfing M, Arock M, et al
Oncotarget 2017 Feb;8(6):9647-9659

Assessment of in vivo mast cell reactivity in patients with systemic mastocytosis.
Gülen T, Möller Westerberg C, Lyberg K, Ekoff M, Kolmert J, Bood J, et al
Clin. Exp. Allergy 2017 Jul;47(7):909-917

Interleukin 33 exacerbates antigen driven airway hyperresponsiveness, inflammation and remodeling in a mouse model of asthma.
Sjöberg L, Nilsson A, Lei Y, Gregory J, Adner M, Nilsson G
Sci Rep 2017 Jun;7(1):4219

KIT signaling is dispensable for human mast cell progenitor development.
Dahlin J, Ekoff M, Grootens J, Löf L, Amini R, Hagberg H, et al
Blood 2017 10;130(16):1785-1794

Detection of circulating mast cells in advanced systemic mastocytosis.
Dahlin J, Ungerstedt J, Grootens J, Sander B, Gülen T, Hägglund H, et al
Leukemia 2016 09;30(9):1953-6

The interleukin-33 receptor ST2 is important for the development of peripheral airway hyperresponsiveness and inflammation in a house dust mite mouse model of asthma.
Zoltowska A, Lei Y, Fuchs B, Rask C, Adner M, Nilsson G
Clin. Exp. Allergy 2016 Mar;46(3):479-90

Vaccination against IL-33 Inhibits Airway Hyperresponsiveness and Inflammation in a House Dust Mite Model of Asthma.
Lei Y, Boinapally V, Zoltowska A, Adner M, Hellman L, Nilsson G
PLoS ONE 2015 ;10(7):e0133774

Interleukin-33 exacerbates allergic bronchoconstriction in the mice via activation of mast cells.
Sjöberg L, Gregory J, Dahlén S, Nilsson G, Adner M
Allergy 2015 May;70(5):514-21

Knockdown of the antiapoptotic Bcl-2 family member A1/Bfl-1 protects mice from anaphylaxis.
Ottina E, Lyberg K, Sochalska M, Villunger A, Nilsson G
J. Immunol. 2015 Feb;194(3):1316-22

Flushing, fatigue, and recurrent anaphylaxis: a delayed diagnosis of mastocytosis.
Gülen T, Hägglund H, Dahlén S, Sander B, Dahlén B, Nilsson G
Lancet 2014 May;383(9928):1608

Intraperitoneal influx of neutrophils in response to IL-33 is mast cell-dependent.
Enoksson M, Möller-Westerberg C, Wicher G, Fallon P, Forsberg-Nilsson K, Lunderius-Andersson C, et al
Blood 2013 Jan;121(3):530-6

Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.
Oschatz C, Maas C, Lecher B, Jansen T, Björkqvist J, Tradler T, et al
Immunity 2011 Feb;34(2):258-68

Mast cells as sensors of cell injury through IL-33 recognition.
Enoksson M, Lyberg K, Möller-Westerberg C, Fallon P, Nilsson G, Lunderius-Andersson C
J. Immunol. 2011 Feb;186(4):2523-8

Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion.
Fischer M, Harvima I, Carvalho R, Möller C, Naukkarinen A, Enblad G, et al
J. Clin. Invest. 2006 Oct;116(10):2748-56

Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim.
Möller C, Alfredsson J, Engström M, Wootz H, Xiang Z, Lennartsson J, et al
Blood 2005 Aug;106(4):1330-6

 

Links

 

 

Centre for Allergy Research at Karolinska Institutet

European Mast cell and Basophil Research Network (EMBRN)

European Competence Network on Mastocytosis (ECNM)