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1. Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis

Author

Abboud, Miguel R, Aytac, Sevkiye Selin, Bosse, Franziskus Johannes, Choo, Sharon, Drabko, Katarzyna, Onkologii, Klinika, Elfeky, Reem, El-Ghoneimy, Dalia Helmy, Fadoo, Zehra, Greenwood, Tatiana, Gustafsson, Britt, Hagelberg, Stefan, Hasle, Henrik, Hästbacka, Johanna, Jadrešin, Oleg, Jädersten, Martin, Kaya, Zuhre, Lecumberri, Ranon, Marques, Laura, Mushtaq, Naureen, Naqvi, Ahmed, Neves, João Farela, Nunes, Susana, Paucar, Martin, Payne, Jeanette H., Rascon, Jelena, Ruuska, Terhi Susanna, Saribeyoglu, Ebru Tugrul, Sundin, Mikael C., Svedenkrans, Jenny, Świderska, Natalia, Tedgård, Ulf, Tvedt, Tor Henrik, Ünüvar, Ayşegül, Van Laar, Jan A. M., Weitzman, Sheila, Winiarski, Jacek, Yaseen, Muhamma Zohaib, Yildiz, Mehmet, Zantomio, Daniela, Øra, Ingrid, Øverland, Torstein, Chiang, Samuel C. C., Covill, Laura E., Tesi, Bianca, Campbell, Tessa M., Schlums, Heinrich, Nejati-Zendegani, Jelve, Mördrup, Karina, Wood, Stephanie, Theorell, Jakob, Sekine, Takuya, Al-Herz, Waleed, Akar, Himmet Haluk, Belen, Fatma Burcu, Chan, Mei Yoke, Devecioglu, Omer, Aksu, Tekin, Ifversen, Marianne, Malinowska, Iwona, Sabel, Magnus, Unal, Ekrem, Unal, Sule, Introne, Wendy J., Krzewski, Konrad, Gilmour, Kimberly C., Ehl, Stephan, Ljunggren, Hans-Gustaf, Nordenskjöld, Magnus, Horne, AnnaCarin, Henter, Jan-Inge, Meeths, Marie, and Bryceson, Yenan T.

Published
2024
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2. A topological data analysis based classification method for multiple measurements

Author

Riihimäki, Henri, Chachólski, Wojciech, Theorell, Jakob, Hillert, Jan, and Ramanujam, Ryan

Subjects
Computer Science - Machine Learning, Mathematics - Algebraic Topology, Statistics - Machine Learning
Abstract

Machine learning models for repeated measurements are limited. Using topological data analysis (TDA), we present a classifier for repeated measurements which samples from the data space and builds a network graph based on the data topology. When applying this to two case studies, accuracy exceeds alternative models with additional benefits such as reporting data subsets with high purity along with feature values. For 300 examples of 3 tree species, the accuracy reached 80% after 30 datapoints, which was improved to 90% after increased sampling to 400 datapoints. Using data from 100 examples of each of 6 point processes, the classifier achieved 96.8% accuracy. In both datasets, the TDA classifier outperformed an alternative model. This algorithm and software can be beneficial for repeated measurement data common in biological sciences, as both an accurate classifier and a feature selection tool., Comment: 8 pages, 7 figures

Published
2019

3. The single-cell transcriptional landscape of innate and adaptive lymphocytes in pediatric-onset colitis

Author

Kokkinou, Efthymia, Soini, Tea, Pandey, Ram Vinay, van Acker, Aline, Theorell, Jakob, Czarnewski, Paulo, Kvedaraite, Egle, Vandamme, Niels, Lourda, Magda, Sorini, Chiara, Weigel, Whitney, Carrasco, Anna, Tibbitt, Christopher Andrew, Schlums, Heinrich, Lindforss, Ulrik, Nordenvall, Caroline, Ljunggren, Malin, Ideström, Maja, Svensson, Mattias, Henter, Jan-Inge, Villablanca, Eduardo J., Bryceson, Yenan T., Rolandsdotter, Helena, and Mjösberg, Jenny

Published
2023
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4. Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis

Author

Theorell, Jakob, primary, Harrison, Ruby, additional, Williams, Robyn, additional, Raybould, Matthew I. J., additional, Zhao, Meng, additional, Fox, Hannah, additional, Fower, Andrew, additional, Miller, Georgina, additional, Wu, Zoe, additional, Browne, Eleanor, additional, Mgbachi, Victor, additional, Sun, Bo, additional, Mopuri, Rohini, additional, Li, Ying, additional, Waters, Patrick, additional, Deane, Charlotte M., additional, Handel, Adam, additional, Makuch, Mateusz, additional, and Irani, Sarosh R., additional

Published
2024
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6. Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis

Author

Chiang, Samuel C. C., Covill, Laura E., Tesi, Bianca, Campbell, Tessa M., Schlums, Heinrich, Nejati-Zendegani, Jelve, Mördrup, Karina, Wood, Stephanie, Theorell, Jakob, Sekine, Takuya, Al-Herz, Waleed, Akar, Himmet Haluk, Belen, Fatma Burcu, Chan, Mei Yoke, Devecioglu, Omer, Aksu, Tekin, Ifversen, Marianne, Malinowska, Iwona, Sabel, Magnus, Unal, Ekrem, Unal, Sule, Introne, Wendy J., Krzewski, Konrad, Gilmour, Kimberly C., Ehl, Stephan, Abboud, Miguel R, Aytac, Sevkiye Selin, Bosse, Franziskus Johannes, Choo, Sharon, Drabko, Katarzyna, Onkologii, Klinika, Elfeky, Reem, El-Ghoneimy, Dalia Helmy, Fadoo, Zehra, Greenwood, Tatiana, Gustafsson, Britt, Hagelberg, Stefan, Hasle, Henrik, Hästbacka, Johanna, Jadrešin, Oleg, Jädersten, Martin, Kaya, Zuhre, Lecumberri, Ranon, Marques, Laura, Mushtaq, Naureen, Naqvi, Ahmed, Neves, João Farela, Nunes, Susana, Paucar, Martin, Payne, Jeanette H., Rascon, Jelena, Ruuska, Terhi Susanna, Saribeyoglu, Ebru Tugrul, Sundin, Mikael C., Svedenkrans, Jenny, Świderska, Natalia, Tedgård, Ulf, Tvedt, Tor Henrik, Ünüvar, Ayşegül, Van Laar, Jan A. M., Weitzman, Sheila, Winiarski, Jacek, Yaseen, Muhamma Zohaib, Yildiz, Mehmet, Zantomio, Daniela, Øra, Ingrid, Øverland, Torstein, Ljunggren, Hans-Gustaf, Nordenskjöld, Magnus, Horne, AnnaCarin, Henter, Jan-Inge, Meeths, Marie, and Bryceson, Yenan T.

Abstract

•TCR-triggered T-cell and Fc receptor–triggered NK-cell assays are most accurate for diagnosing defective cytotoxic lymphocyte exocytosis.•The standard K562 cell assay has high interindividual variability and is affected by expanded NK-cell subsets and transportation stress.

Published
2024
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8. Diversification and Functional Specialization of Human NK Cell Subsets

Author

Cichocki, Frank, Schlums, Heinrich, Theorell, Jakob, Tesi, Bianca, Miller, Jeffrey S., Ljunggren, Hans-Gustaf, Bryceson, Yenan T., Compans, Richard W, Series editor, Cooper, Max D., Series editor, Honjo, Tasuku, Series editor, Oldstone, Michael B. A., Series editor, Vogt, Peter K., Series editor, Malissen, Bernard, Series editor, Aktories, Klaus, Series editor, Kawaoka, Yoshihiro, Series editor, Rappuoli, Rino, Series editor, Galan, Jorge E., Series editor, Ahmed, Rafi, Series editor, Vivier, Eric, editor, Di Santo, James, editor, and Moretta, Alessandro, editor

Published
2016
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9. Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

Author

Schlums, Heinrich, Jung, Moonjung, Han, Hongya, Theorell, Jakob, Bigley, Venetia, Chiang, Samuel C.C., Allan, David S.J., Davidson-Moncada, Jan K., Dickinson, Rachel E., Holmes, Tim D., Hsu, Amy P., Townsley, Danielle, Winkler, Thomas, Wang, Weixin, Aukrust, Pål, Nordøy, Ingvild, Calvo, Katherine R., Holland, Steve M., Collin, Matthew, Dunbar, Cynthia E., and Bryceson, Yenan T.

Published
2017
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14. Rituximab abrogates aquaporin-4–specific germinal center activity in patients with neuromyelitis optica spectrum disorders

Author

Damato, Valentina, primary, Theorell, Jakob, additional, Al-Diwani, Adam, additional, Kienzler, Anne-Kathrin, additional, Makuch, Mateusz, additional, Sun, Bo, additional, Handel, Adam, additional, Akdeniz, Deniz, additional, Berretta, Antonio, additional, Ramanathan, Sudarshini, additional, Fower, Andrew, additional, Whittam, Daniel, additional, Gibbons, Emily, additional, McGlashan, Nicholas, additional, Green, Edward, additional, Huda, Saif, additional, Woodhall, Mark, additional, Palace, Jacqueline, additional, Sheerin, Fintan, additional, Waters, Patrick, additional, Leite, Maria I., additional, Jacob, Anu, additional, and Irani, Sarosh R., additional

Published
2022
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15. Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis

Author

Al-Diwani, Adam, primary, Theorell, Jakob, additional, Damato, Valentina, additional, Bull, Joshua, additional, McGlashan, Nicholas, additional, Green, Edward, additional, Kienzler, Anne Kathrin, additional, Harrison, Ruby, additional, Hassanali, Tasneem, additional, Campo, Leticia, additional, Browne, Molly, additional, Easton, Alistair, additional, Soleymani majd, Hooman, additional, Tenaka, Keiko, additional, Iorio, Raffaele, additional, Dale, Russell C, additional, Harrison, Paul, additional, Geddes, John, additional, Quested, Digby, additional, Sharp, David, additional, Lee, Soon Tae, additional, Nauen, David W, additional, Makuch, Mateusz, additional, Lennox, Belinda, additional, Fowler, Darren, additional, Sheerin, Fintan, additional, Waters, Patrick, additional, Leite, M Isabel, additional, Handel, Adam E, additional, and Irani, Sarosh R, additional

Published
2022
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21. Synaptic autoimmunity: new insights into LGI1 antibody-mediated neuronal dysfunction

Author

Ramberger, Melanie, Berretta, Antonio, Tan, Jeanne, Sun, Bo, Michael, Sophia, Yeo, Tianrong, Theorell, Jakob, Bashford-Rogers, Rachael, Paneva, Sofija, O’dowd, Victoria, Dedi, Neesha, Topia, Sarfaraj, Griffin, Robert, Ramirez-Franco, Jorge, El Far, Oussama, Baulac, Stéphanie, Leite, Maria, Sen, Arjune, Jeans, Alexander, Mcmillan, David, Marshall, Diane, Anthony, Daniel, Lightwood, Daniel, Waters, Patrick, Irani, Sarosh, HAL-SU, Gestionnaire, Nuffield Department of Clinical Neurosciences [Oxford], University of Oxford, UCB Pharma S.A.[Braine-l'Alleud], UCB Pharma [Brussels], Unité de Neurobiologie des canaux Ioniques et de la Synapse (UNIS - Inserm U1072), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and ANR-17-CE16-0022,LoGIK,Modulation de l'excitabilité neuronale par LGI1(2017)

Subjects
immunology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, encephalitis, antibody, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, LGI1, autoimmune, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
Abstract

International audience; Autoantibodies against leucine-rich glioma inactivated 1 (LGI1) are found in patients with limbic encephalitis and focal seizures. Here, we generate patient-derived monoclonal antibodies (mAbs) against LGI1. We explore their sequences and binding characteristics, plus their pathogenic potential using transfected HEK293T cells, rodent neuronal preparations, and behavioural and electrophysiological assessments in vivo after mAb injections into the rodent hippocampus. In live cell-based assays, LGI1 epitope recognition was examined with patient sera (n = 31), CSFs (n = 11), longitudinal serum samples (n = 15), and using mAbs (n = 14) generated from peripheral B cells of two patients. All sera and 9/11 CSFs bound both the leucine-rich repeat (LRR) and the epitempin repeat (EPTP) domains of LGI1, with stable ratios of LRR:EPTP antibody levels over time. By contrast, the mAbs derived from both patients recognized either the LRR or EPTP domain. mAbs against both domain specificities showed varied binding strengths, and marked genetic heterogeneity, with high mutation frequencies. LRR-specific mAbs recognized LGI1 docked to its interaction partners, ADAM22 and ADAM23, bound to rodent brain sections, and induced internalization of the LGI1-ADAM22/23 complex in both HEK293T cells and live hippocampal neurons. By contrast, few EPTP-specific mAbs bound to rodent brain sections or ADAM22/23-docked LGI1, but all inhibited the docking of LGI1 to ADAM22/23. After intrahippocampal injection, and by contrast to the LRR-directed mAbs, the EPTP-directed mAbs showed far less avid binding to brain tissue and were consistently detected in the serum. Post-injection, both domain-specific mAbs abrogated long-term potentiation induction, and LRR-directed antibodies with higher binding strengths induced memory impairment. Taken together, two largely dichotomous populations of LGI1 mAbs with distinct domain binding characteristics exist in the affinity matured peripheral autoantigen-specific memory pools of individuals, both of which have pathogenic potential. In human autoantibody-mediated diseases, the detailed characterization of patient mAbs provides a valuable method to dissect the molecular mechanisms within polyclonal populations.

Published
2020

25. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms

Author

Ramberger, Melanie, primary, Berretta, Antonio, primary, Tan, Jeanne M M, primary, Sun, Bo, primary, Michael, Sophia, primary, Yeo, Tianrong, primary, Theorell, Jakob, primary, Bashford-Rogers, Rachael, primary, Paneva, Sofija, primary, O’Dowd, Victoria, primary, Dedi, Neesha, primary, Topia, Sarfaraj, primary, Griffin, Robert, primary, Ramirez-Franco, Jorge, primary, El Far, Oussama, primary, Baulac, Stéphanie, primary, Leite, Maria I, primary, Sen, Arjune, primary, Jeans, Alexander, primary, McMillan, David, primary, Marshall, Diane, primary, Anthony, Daniel, primary, Lightwood, Daniel, primary, Waters, Patrick, primary, and Irani, Sarosh R, primary

Published
2020
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26. Adaptive NK cells in people exposed to Plasmodium falciparum correlate with protection from malaria

Author

Hart, Geoffrey T., primary, Tran, Tuan M., additional, Theorell, Jakob, additional, Schlums, Heinrich, additional, Arora, Gunjan, additional, Rajagopalan, Sumati, additional, Sangala, A.D. Jules, additional, Welsh, Kerry J., additional, Traore, Boubacar, additional, Pierce, Susan K., additional, Crompton, Peter D., additional, Bryceson, Yenan T., additional, and Long, Eric O., additional

Published
2019
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32. Understanding chronic immunodeficiency disorders through assessment of cytotoxic lymphocyte function

Author

Theorell, Jakob and Theorell, Jakob

Abstract

Representing an evolving and diverse group of syndromes, immunodeficiencies can currently be viewed as a spectrum of disorders where a dysfunction of the immune system plays a significant etiologic role. Cytotoxic lymphocytes are immune cells that are pivotal for the eradication of infected and malignant cells. They also contribute to immune-regulation. Congruently, patients with defects in cytotoxic lymphocyte function show increased susceptibility to infections, malignancies and inflammation. This work focuses on the role of cytotoxic lymphocytes in syndromes where their pathophysiological involvement is suspected, but not established. The first study investigates the variability in cytotoxic effector functions introduced by commonly used pharmacological substances, knowledge that is important for the interpretation of patient data. The second study establishes a robust and sensitive addition to the arsenal of diagnostic assays for cytotoxic lymphocyte dysfunctions. The third study shows that myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), linked to viral infections and hypothesized to be caused by immune dysregulation, is not a syndrome where a substantial fraction of the patients has any obvious primary defect in lymphocyte cytotoxicity. The fourth and the fifth studies identify and functionally dissect the impact of autoantibodies directed against an inhibitory cytotoxic lymphocyte receptor, NKG2A, in patients with systemic lupus erythematosus (SLE), an autoimmune disorder. In summary, the studies expand our knowledge and toolbox for assessing lymphocyte cytotoxicity and highlight the complexity of interpreting experiments investigating cytotoxic lymphocyte function in the context of chronic immunodeficiency disorders. Furthermore, they provide clinically relevant insights about the role of cytotoxic lymphocytes in both ME/CFS and SLE.

Published
2017

36. The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing

Author

Björklund, Åsa K., Forkel, Marianne, Picelli, Simone, Konya, Viktoria, Theorell, Jakob, Friberg, Danielle, Sandberg, Rickard, Mjosberg, Jenny, Björklund, Åsa K., Forkel, Marianne, Picelli, Simone, Konya, Viktoria, Theorell, Jakob, Friberg, Danielle, Sandberg, Rickard, and Mjosberg, Jenny

Abstract

Innate lymphoid cells (ILCs) are increasingly appreciated as important participants in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations have been reported. Here we have delineated the heterogeneity of human ILCs through single-cell RNA sequencing of several hundreds of individual tonsil CD127(+) ILCs and natural killer (NK) cells. Unbiased transcriptional clustering revealed four distinct populations, corresponding to ILC1 cells, ILC2 cells, ILC3 cells and NK cells, with their respective transcriptomes recapitulating known as well as unknown transcriptional profiles. The single-cell resolution additionally divulged three transcriptionally and functionally diverse subpopulations of ILC3 cells. Our systematic comparison of single-cell transcriptional variation within and between ILC populations provides new insight into ILC biology during homeostasis, with additional implications for dysregulation of the immune system.

Published
2016
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41. Long-term Protective Changes in Adipose Tissue After Gastric Bypass.

Author

Hoffstedt, Johan, Andersson, Daniel P., Hogling, Daniel Eriksson, Theorell, Jakob, Näslund, Erik, Thorell, Anders, Ehrlund, Anna, Rydén, Mikael, Arner, Peter, and Eriksson Hogling, Daniel

Subjects
ADIPOSE tissues, GASTRIC bypass, OBESITY in women, TYPE 2 diabetes, LIPOLYSIS, ADIPOSE tissue physiology, ADIPOSE tissue surgery, BARIATRIC surgery, HUMAN body composition, COMPARATIVE studies, FAT cells, GENETIC disorders, INSULIN resistance, LIPID metabolism disorders, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, OBESITY, POSTOPERATIVE period, RESEARCH, TIME, TUMOR necrosis factors, EVALUATION research, CASE-control method, ADIPONECTIN
Abstract

Objective: Although long-term weight regain may occur after bariatric surgery, many patients are protected against relapse or development of type 2 diabetes. The study objective was to investigate whether this involves beneficial changes in adipose function.Research Design and Methods: Forty-nine obese women were investigated before and 2 and 5 years after Roux-en-Y gastric bypass (RYGB). At the 5-year follow-up, 30 subjects were pairwise matched for BMI and age to 30 control women. Clinical parameters and fine-needle biopsies from subcutaneous abdominal adipose tissue were obtained; fat cell size and number, lipolysis, adiponectin, and proinflammatory protein secretion were determined.Results: After 2 years, BMI decreased from 43 to 29 kg/m2, which was accompanied by improvements in insulin sensitivity (HOMA of insulin resistance [HOMA-IR]), increased circulating and adipose secreted adiponectin, and decreased adipose lipolysis and fat cell size but no change in adipocyte number. Between 2 and 5 years after surgery, BMI had increased to 31 kg/m2. This was associated with slightly increased HOMA-IR and unaltered circulating or adipose secreted adiponectin but higher secretion of tumor necrosis factor-α and increased lipolysis and number of fat cells but no change in adipocyte size. All these parameters, except lipolysis, were significantly more favorable compared with those in matched control subjects. Furthermore, the relationship between HOMA-IR and circulating adiponectin was less steep than in control subjects.Conclusions: RYGB improves long-term insulin sensitivity and adipose phenotypes beyond the control state despite weight regain. Postoperative beneficial alterations in adipose function may be involved in the diabetes-protective effect of bariatric surgery. [ABSTRACT FROM AUTHOR]

Published
2017
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43. Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production

Author

Chiang, Samuel C. C., Theorell, Jakob, Entesarian, Miriam, Meeths, Marie, Mastafa, Monika, Al-Herz, Waleed, Frisk, Per, Gilmour, Kimberly C., Ifversen, Marianne, Langenskiold, Cecilia, Machaczka, Maciej, Naqvi, Ahmed, Payne, Jeanette, Perez-Martinez, Antonio, Sabel, Magnus, Unal, Ekrem, Unal, Sule, Winiarski, Jacek, Nordenskjold, Magnus, Ljunggren, Hans-Gustaf, Henter, Jan-Inge, Bryceson, Yenan T., Chiang, Samuel C. C., Theorell, Jakob, Entesarian, Miriam, Meeths, Marie, Mastafa, Monika, Al-Herz, Waleed, Frisk, Per, Gilmour, Kimberly C., Ifversen, Marianne, Langenskiold, Cecilia, Machaczka, Maciej, Naqvi, Ahmed, Payne, Jeanette, Perez-Martinez, Antonio, Sabel, Magnus, Unal, Ekrem, Unal, Sule, Winiarski, Jacek, Nordenskjold, Magnus, Ljunggren, Hans-Gustaf, Henter, Jan-Inge, and Bryceson, Yenan T.

Abstract

Cytotoxic lymphocytes, encompassing cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, kill pathogen-infected, neoplastic, or certain hematopoietic cells through the release of perforin-containing lytic granules. In the present study, we first performed probability-state modeling of differentiation and lytic granule markers on CD8(+) T cells to enable the comparison of bona fide CTLs with NK cells. Analysis identified CD57(bright) expression as a reliable phenotype of granule marker-containing CTLs. We then compared CD3(+)CD8(+)CD57(bright) CTLs with NK cells. Healthy adult peripheral blood CD3(+)CD8(+)CD57(bright) CTLs expressed more granzyme B but less perforin than CD3(-)CD56(dim) NK cells. On stimulation, such CTLs degranulated more readily than other T-cell subsets, but had a propensity to degranulate that was similar to NK cells. Remarkably, the CTLs produced cytokines more rapidly and with greater frequency than NK cells. In patients with biallelic mutations in UNC13D, STX11, or STXBP2 associated with familial hemophagocytic lymphohistiocytosis, CTL and NK cell degranulation were similarly impaired. Therefore, cytotoxic lymphocyte subsets have similar requirements for Munc13-4, syntaxin-11, and Munc18-2 in lytic granule exocytosis. The present results provide a detailed comparison of human CD3(+)CD8(+)CD57(bright) CTLs and NK cells and suggest that analysis of CD57(bright) CTL function may prove useful in the diagnosis of primary immunodeficiencies including familial hemophagocytic lymphohistiocytosis., De två (2) första författarna delar förstaförfattarskapet.

Published
2013
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44. Systemic Lupus Erythematosus Immune Complexes Increase the Expression of SLAM Family Members CD319 (CRACC) and CD229 (LY-9) on Plasmacytoid Dendritic Cells and CD319 on CD56(dim) NK Cells

Author

Hagberg, Niklas, Theorell, Jakob, Schlums, Heinrich, Eloranta, Maija-Leena, Bryceson, Yenan T., Rönnblom, Lars, Hagberg, Niklas, Theorell, Jakob, Schlums, Heinrich, Eloranta, Maija-Leena, Bryceson, Yenan T., and Rönnblom, Lars

Abstract

Patients with systemic lupus erythematosus (SLE) display an activated type I IFN system due to unceasing IFN-a release from plasmacytoid dendritic cells (pDCs) stimulated by nucleic acid-containing immune complexes (ICs). NK cells strongly promote the IFN-a production by pDCs; therefore, we investigated surface molecules that could be involved in the pDC-NK cell cross-talk. In human PBMCs stimulated with RNA-containing ICs (RNA-ICs), the expression of the signaling lymphocyte activation molecule (SLAM) family receptors CD319 and CD229 on pDCs and CD319 on CD56(dim) NK cells was selectively increased. Upregulation of CD319 and CD229 on RNA-IC-stimulated pDCs was induced by NK cells or cytokines (e. g., GM-CSF, IL-3). IFN-alpha-producing pDCs displayed a higher expression of SLAM molecules compared with IFN-a 2 pDCs. With regard to signaling downstream of SLAM receptors, pDCs expressed SHIP-1, SHP-1, SHP-2, and CSK but lacked SLAM-associated protein (SAP) and Ewing's sarcoma-activated transcript 2 (EAT2), indicating that these receptors may act as inhibitory receptors on pDCs. Furthermore, pDCs from patients with SLE had decreased expression of CD319 on pDCs and CD229 on CD56 dim NK cells, but RNA-IC stimulation increased CD319 and CD229 expression. In conclusion, this study reveals that the expression of the SLAM receptors CD319 and CD229 is regulated on pDCs and NK cells by lupus ICs and that the expression of these receptors is specifically altered in SLE. These results, together with the observed genetic association between the SLAM locus and SLE, suggest a role for CD319 and CD229 in the SLE disease process.

Published
2013
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45. Epstein-Barr Virus Coinfection in Children Boosts Cytomegalovirus-Induced Differentiation of Natural Killer Cells

Author

Saghafian-Hedengren, Shanie, Sohlberg, Ebba, Theorell, Jakob, Carvalho-Queiroz, Claudia, Nagy, Noemi, Persson, Jan-Olov, Nilsson, Caroline, Bryceson, Yenan T., Sverremark-Ekström, Eva, Saghafian-Hedengren, Shanie, Sohlberg, Ebba, Theorell, Jakob, Carvalho-Queiroz, Claudia, Nagy, Noemi, Persson, Jan-Olov, Nilsson, Caroline, Bryceson, Yenan T., and Sverremark-Ekström, Eva

Abstract

During childhood, infections with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) can occur in close temporal proximity. Active, as well as latent, CMV infection is associated with enlarged subsets of differentiated natural killer (NK) and cytotoxic T cells. How EBV infection may influence CMV-driven immune differentiation is not known. We found that EBV coinfection selectively influenced the NK cell compartment of CMV-seropositive (CMV+) children. Coinfected children had significantly higher proportions of peripheral-blood NKG2C(+) NK cells than CMV+ EBV- children. Ex vivo NK cell degranulation after target cell stimulation and plasma IL-15 levels were significantly higher in CMV+ children. EBV coinfection was related to the highest levels of plasma interleukin-15 (IL-15) and IL-12p70. Remarkably, in vitro EBV infection of peripheral blood mononuclear cells (PBMC) from EBV- CMV+ children increased NKG2C(+) NK cell proportions. A similar tendency was seen in cocultures of PBMC with EBV+ lymphoblastoid B-cell lines (LCL) and IL-15. After K562 challenge, NKG2C(+) NK cells excelled in regard to degranulation and production of gamma interferon, regardless of whether there was previous coculture with LCL. Taken together, our data suggest that dual latency with these herpesviruses during childhood could contribute to an in vivo environment supporting differentiation and maintenance of distinct NK cell populations. This viral imprint may affect subsequent immune responses through altered distributions of effector cells., AuthorCount:9

Published
2013
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49. NKG2C+CD57+ CD56dim NK cells are enriched following Epstein-Barr virus transformed lymphoblastoid cell line co-culture with peripheral blood mononuclear cells from cytomegalovirus+ donors (P4359)

Author

Saghafian-Hedengren, Shanie, primary, Sohlberg, Ebba, additional, Theorell, Jakob, additional, Queiroz-Carvalho, Claudia, additional, Nagy, Noémi, additional, Nilsson, Caroline, additional, Bryceson, Yenan, additional, and Sverremark-Ekström, Eva, additional

Published
2013
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50. Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production

Author

Chiang, Samuel C. C., primary, Theorell, Jakob, additional, Entesarian, Miriam, additional, Meeths, Marie, additional, Mastafa, Monika, additional, Al-Herz, Waleed, additional, Frisk, Per, additional, Gilmour, Kimberly C., additional, Ifversen, Marianne, additional, Langenskiöld, Cecilia, additional, Machaczka, Maciej, additional, Naqvi, Ahmed, additional, Payne, Jeanette, additional, Perez-Martinez, Antonio, additional, Sabel, Magnus, additional, Unal, Ekrem, additional, Unal, Sule, additional, Winiarski, Jacek, additional, Nordenskjöld, Magnus, additional, Ljunggren, Hans-Gustaf, additional, Henter, Jan-Inge, additional, and Bryceson, Yenan T., additional

Published
2013
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