Clinical Lung and Allergy Research Unit (CLARU)

Group members

Projects

TESLA (Tissue-resident lymphocytes in asthma)

We recently demonstrated a rapid accumulation of activated innate lymphoid cells type 2 (ILC2) in bronchioalveolar fluid following allergen-provocation in humans.

The overall aim of this project is to determine the role for ILC2 and other tissue residing lymphocytes in asthma with particular focus on how the asthmatic lung microenvironment regulates lymphocyte function and plasticity and the effect of novel biological treatments on ILC2 and other tissue residing lymphocytes.

Our immune-characterizations are conducted using single-cell (sc) techniques such as scRNA-sequencing and multidimensional flow cytometry at our lab at the Center for Infectious Medicine (CIM).

The project is lead by Professor Jenny Mjösberg.

Defining the metabolic signatures of tissue resident human ILCs in asthma

Induction of any immune response requires metabolic changes. While a number of genes and pathways have been evaluated in T cells, the factors that link activation to alterations in metabolic state remains to be profiled in depth for human ILCs.

Using the latest techniques in metabolic profiling and single cell mutli-omics, we aim to map the metabolic profiles of human ILCs in asthma. Our aim is to assess whether biological therapies can impact upon cell intrinsic metabolism. We are also seeking to determine how host metabolic state (e.g. obesity) can alter the ILC phenotypes during asthma.

The project is lead by Dr Chris Tibbitt, who also conducts independent research at the Center for Infectious Medicine (CIM).

BIOCROSS (BIOmarkers in CROSS-sectional) and 3TR-ABC (asthma biologics cohort)

BIOCROSS, is a collaborative project in Sweden that studies well-characterized patients with mild and severe asthma, healthy controls and comparison groups of patients with other lung diseases.

The study approaches clinical everyday life by collecting the non-invasive samples of blood, urine, saliva and exhaled air. This is to perform a large number of analyses of the body's own substances and molecules with complementary techniques like transcriptomics, proteomics, metabolomics, lipidomics, genomics and epigenetics.

Collection of samples and molecular analyses take place according to detailed protocols and SOPs and are compiled with a broad systems biology strategy with the overall aim of discovering new biomarker profiles. This integration of information thus means that physiological and clinical measurement variables are compared with the biomarker patterns identified in blood, urine, saliva and exhaled air.

In 2023 we will start the 3TR (taxonomy, treatment, targets and remission) study ABC. This study shares many features with the BIOCROSS study but is performed in an international consortium and includes tissue samples from patients with severe asthma.

The projects are lead by Professor Sven-Erik Dahlén.

Mastocytosis

Mastocytosis encompasses a heterogeneous group of disorders characterized by accumulation of clonal mast cells (MCs) in the skin and/or internal organs. Patients typically present with a broad variety of recurrent clinical symptoms, including severe anaphylaxis. However, not all patients with mastocytosis experience anaphylactic reactions.

Our research concerns the mechanistic aspects of mastocytosis and ways to predict anaphylaxis as well as improving prophylactic and symptomatic treatment of these patients.

The project is lead by Dr Theo Gülen.

Collaborations

Collaborations, Karolinska Institutet

• Mikael Adner, Anna James and Jesper Säfholm, Experimental Asthma and Allergy Research Unit, Institute of Environmental Medicine.
• Craig Wheelock, Johan Kolmert, Integrative Metabolics, Institute of Environmental Medicine.
• Apostolos Bossios and Nikolaos Lazarinis, Lung and Airway research, Institute of Environmental Medicine. 
• Erik Melén, CLINTEC, Södersjukhuset, Karolinska Institutet and Sachs' Children and Youth Hospital, Stockholm, Sweden.

Other collaborations 

• Mattias Jangard, Maria Kumlin, ENT Unit, Research Laboratory, Sophiahemmet University, Stockholm, Sweden.
• Thomas Höchdörfer, AstraZeneca.

Research support

• The Swedish Heart and Lung Foundation.
• Karolinska Institutet.
• Region Stockholm.
• The 3TR study receives funding from Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 831434. 
  The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

Selected publications

1. CD45RA+CD62L- ILCs in human tissues represent a quiescent local reservoir for the generation of differentiated ILCs.
   Kokkinou E, Pandey RV, Mazzurana L, Gutierrez-Perez I, Tibbitt CA, Weigel W, Soini T, Carrasco A, Rao A, Nagasawa M, Bal SM, Jangard M, Friberg D, Lindforss U, Nordenvall C, Ljunggren M, Haapaniemi S, Keita ÅV, Söderholm J, Hedin C, Spits H, Bryceson YT, Mjösberg J
   Sci Immunol 2022 04;7(70):eabj830
    
2. Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing.
   Mazzurana L, Czarnewski P, Jonsson V, Wigge L, Ringnér M, Williams TC, Ravindran A, Björklund ÅK, Säfholm J, Nilsson G, Dahlén SE, Orre AC, Al-Ameri M, Höög C, Hedin C, Szczegielniak S, Almer S, Mjösberg J
   Cell Res 2021 05;31(5):554-568
    
3. Expression of c-Kit discriminates between two functionally distinct subsets of human type 2 innate lymphoid cells.
   Hochdörfer T, Winkler C, Pardali K, Mjösberg J
   Eur J Immunol 2019 06;49(6):884-893
    
4. Activation of group 2 innate lymphoid cells after allergen challenge in asthmatic patients.
   Winkler C, Hochdörfer T, Israelsson E, Hasselberg A, Cavallin A, Thörn K, Muthas D, Shojaee S, Lüer K, Müller M, Mjösberg J, Vaarala O, Hohlfeld J, Pardali K
   J Allergy Clin Immunol 2019 07;144(1):61-69.e7
    
5. Cytokine-induced endogenous production of prostaglandin D2 is essential for human group 2 innate lymphoid cell activation.
   Maric J, Ravindran A, Mazzurana L, Van Acker A, Rao A, Kokkinou E, Ekoff M, Thomas D, Fauland A, Nilsson G, Wheelock CE, Dahlén SE, Ferreirós N, Geisslinger G, Friberg D, Heinemann A, Konya V, Mjösberg J
   J Allergy Clin Immunol 2019 06;143(6):2202-2214.e5
    
6. Prostaglandin E2 suppresses human group 2 innate lymphoid cell function.
   Maric J, Ravindran A, Mazzurana L, Björklund ÅK, Van Acker A, Rao A, Friberg D, Dahlén SE, Heinemann A, Konya V, Mjösberg J
   J Allergy Clin Immunol 2018 05;141(5):1761-1773.e6
    
7. The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing.
   Björklund ÅK, Forkel M, Picelli S, Konya V, Theorell J, Friberg D, Sandberg R, Mjösberg J
   Nat Immunol 2016 Apr;17(4):451-60
    
8. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation.
   Sparreman Mikus M, Kolmert J, Andersson LI, Östling J, Knowles RG, Gómez C, Ericsson M, Thörngren JO, Emami Khoonsari P, Dahlén B, Kupczyk M, De Meulder B, Auffray C, Bakke PS, Beghe B, Bel EH, Caruso M, Chanez P, Chawes B, Fowler SJ, Gaga M, Geiser T, Gjomarkaj M, Horváth I, Howarth PH, Johnston SL, Joos G, Krug N, Montuschi P, Musial J, Niżankowska-Mogilnicka E, Olsson HK, Papi A, Rabe KF, Sandström T, Shaw DE, Siafakas NM, Uhlén M, Riley JH, Bates S, Middelveld RJM, Wheelock CE, Chung KF, Adcock IM, Sterk PJ, Djukanovic R, Nilsson P, Dahlén SE, James A,
   Eur Respir J 2022 02;59(2):
    
9. Distinct plasma biomarkers confirm the diagnosis of mastocytosis and identify increased risk of anaphylaxis.
   Gülen T, Teufelberger A, Ekoff M, Westerberg CM, Lyberg K, Dahlén SE, Dahlén B, Nilsson G
   J Allergy Clin Immunol 2021 09;148(3):889-894