Human myeloid cells in cancer, inflammation, and infection

Myeloid cells are a part of innate immunity, playing a major role in orchestrating innate and adaptive immune responses. While work performed in experiment model systems has significantly increased our knowledge on fundamental myeloid cell functions, studies in well-designed clinical cohorts are important for understanding their functions in human health and disease, such as in cancer, infection and chronic inflammation. In this thesis, distinct populations of human myeloid cells were investigated in three different clinical contexts: Langerhans cell histiocytosis (LCH), an inflammatory myeloid neoplasia; inflammatory bowel disease (IBD), a chronic disorder of the gastrointestinal tract; and COVID-19, an acute viral infection.

We found that neutrophils, rather than antigen presenting mononuclear phagocytes (MNPs) such as monocytes and dendritic cells (DC), are the main cellular source of the regulatory cytokine IL-23 in colon tissue of newly diagnosed and treatment-naïve children with IBD (paper I). Moreover, we demonstrated that inflammation-responsive intestinal stroma has a capacity to shape the monocyte-derived macrophage pool, and that phenotypes modelled in fibroblast-macrophage co-culture systems were reflected in the IBD tissue (paper II). In addition, while the role of IL-23 is well-established in IBD, we also proposed its potential involvement in the immunopathogenesis of LCH (paper III). Furthermore, proficient delineation of LCH cells, that are neoplastic MNP found in LCH lesions, from the normal MNPs was performed at single-cell resolution, allowing identification of two major LCH cell populations, corresponding to DC type 2 and monocytes/DC type 3 lineages (paper IV). Lastly, a comprehensive map over major alterations in MNP responses in COVID-19 was depicted, where MNPs profile, alone, could predict a cluster of non-survivors (paper V).

Taken together, this data provides important input in our understanding of the role of MNPs in human disease, also showing that we only scratch the surface of myeloid cell functions in cancer, inflammation, and infection, as many outstanding questions remain.

List of scientific papers

I. Egle Kvedaraite, Magda Lourda, Maja Ideström, Puran Chen, Selma Olsson-Åkefeldt, Marianne Forkel, Désirée Gavhed, Ulrik Lindforss, Jenny Mjösberg, Jan-Inge Henter, Mattias Svensson. Tissue-infiltrating neutrophils represent the main source of IL-23 in the colon of patients with IBD. Gut. 2016 vol 65 (10), 1632–1641.
https://doi.org/10.1136/gutjnl-2014-309014

II. Egle Kvedaraite, Magda Lourda, Natalia Mouratidou, Indranil Sinha, Efthymia Kokkinou, Tea Soini, Aline Van Acker, Nelly Rahkonen, Kirsten Moll, David Unnersjö-Jess, Mira Akber, Ruta Nadisauskaite, Jessica Jansson, Anastasios Damdimopoulos, Niels Vandamme, Chiara Sorini, Eduardo J Villablanca, Helena Jonsson Rolandsdotter, Maja Ideström, Jenny Mjösberg, Henrik Arnell, Jan-Inge Henter, Mattias Svensson. Inflammation responsive intestinal stroma shapes the macrophage pool. [Submitted]

III. Egle Kvedaraite, Magda Lourda, HongYa Han, Bianca Tesi, Jenée Mitchell, Maja Ideström, Natalia Mouratidou, George Rassidakis, Tatiana von Bahr Greenwood, Fleur Cohen-Aubart, Martin Jädersten, Selma Olsson Åkefeldt, Mattias Svensson, George Kannourakis, Yenan T. Bryceson, Julien Haroche, Jan-Inge Henter. Patients with both Langerhans cell histiocytosis and Crohn’s disease highlight a common role of interleukin-23. Acta Paediatrica. 2021 vol 110 (4), 1315–1321.
https://doi.org/10.1111/apa.15590

IV. Egle Kvedaraite, Ahad Khalilnezhad, Marion Chevrier, Paul Milne, Hong Kai Lee, Daniel W. Hagey, Tatiana von Bahr Greenwood, Nicole Yee Shin Lee, Lara Minnerup, Tan Yingrou, Charles-Antoine Dutertre, Nathan Benac, You Yi Hwang, Josephine Lum, Amos Hong Pheng Loh, Karen Wei Weng Teng, Shabnam Khalilnezhad, Xu Weili, Anastasia Resteu, Tey Hong Liang, Ng Lai Guan, Anis Larbi, Shanshan Wu Howland, Samir EL Andaloussi, Jorge Braier, Georgios Rassidakis, Laura Galluzzo, Andrzej Dzionek, Matthew Collin, Jan-Inge Henter, Jinmiao Chen, Florent Ginhoux. Senescent Langerhans cell histiocytosis cells arise from both dendritic cell (DC) and monocyte/DC3 lineages. [Submitted]

V. Egle Kvedaraite, Laura Hertwig, Indranil Sinha, Andrea Ponzetta, Ida Hed Myrberg, Magda Lourda, Majda Dzidic, Mira Akber, Jonas Klingström, Elin Folkesson, Jagadeeswara Rao Muvva, Puran Chen, Sara Gredmark-Russ, Susanna Brighenti, Anna Norrby-Teglund, Lars I. Eriksson, Olav Rooyackers, Soo Aleman, Kristoffer Strålin, Hans-Gustaf Ljunggren, Florent Ginhoux, Niklas K. Björkström, Jan-Inge Henter, Mattias Svensson, and Karolinska KI/K COVID-19 Study Group. Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity. Proceedings of the National Academy of Sciences. 2021 vol 118 (6), e2018587118.
https://doi.org/10.1073/pnas.2018587118