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3. Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome

Author

Notarnicola, Antonella, Preger, Charlotta, Lundström, Susanna L., Renard, Nuria, Wigren, Edvard, Van Gompel, Eveline, Galindo-Feria, Angeles S., Persson, Helena, Fathi, Maryam, Grunewald, Johan, Jakobsson, Per-Johan, Gräslund, Susanne, Lundberg, Ingrid E., and Fernandes-Cerqueira, Cátia

Published
2022
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12. Disease‐specific plasma protein profiles in patients with fever after traveling to tropical areas.

Author

Sundling, Christopher, Yman, Victor, Mousavian, Zaynab, Angenendt, Sina, Foroogh, Fariba, von Horn, Ellen, Lautenbach, Maximilian Julius, Grunewald, Johan, Färnert, Anna, and Sondén, Klara

Abstract

Fever is common among individuals seeking healthcare after traveling to tropical regions. Despite the association with potentially severe disease, the etiology is often not determined. Plasma protein patterns can be informative to understand the host response to infection and can potentially indicate the pathogen causing the disease. In this study, we measured 49 proteins in the plasma of 124 patients with fever after travel to tropical or subtropical regions. The patients had confirmed diagnoses of either malaria, dengue fever, influenza, bacterial respiratory tract infection, or bacterial gastroenteritis, representing the most common etiologies. We used multivariate and machine learning methods to identify combinations of proteins that contributed to distinguishing infected patients from healthy controls, and each other. Malaria displayed the most unique protein signature, indicating a strong immunoregulatory response with high levels of IL10, sTNFRI and II, and sCD25 but low levels of sCD40L. In contrast, bacterial gastroenteritis had high levels of sCD40L, APRIL, and IFN‐γ, while dengue was the only infection with elevated IFN‐α2. These results suggest that characterization of the inflammatory profile of individuals with fever can help to identify disease‐specific host responses, which in turn can be used to guide future research on diagnostic strategies and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Immune mapping of human tuberculosis and sarcoidosis lung granulomas.

Author

Carow, Berit, Muliadi, Victoria, Skålén, Kristina, Yokota, Chika, Kathamuthu, Gokul Raj, Setiabudiawan, Todia Pediatama, Lange, Christoph, Scheu, Katrin, Gaede, Karoline I., Goldmann, Torsten, Pandita, Ankur, Masood, Kiran Iqbal, Pervez, Shahid, Grunewald, Johan, Hasan, Zahra, Levin, Max, and Rottenberg, Martin E.

Subjects
SARCOIDOSIS, FOLLICULAR dendritic cells, T helper cells, TUBERCULOSIS, GRANULOMA, LUNGS
Abstract

Tuberculosis (TB) and sarcoidosis are both granulomatous diseases. Here, we compared the immunological microenvironments of granulomas from TB and sarcoidosis patients using in situ sequencing (ISS) transcriptomic analysis and multiplexed immunolabeling of tissue sections. TB lesions consisted of large necrotic and cellular granulomas, whereas "multifocal" granulomas with macrophages or epitheloid cell core and a T-cell rim were observed in sarcoidosis samples. The necrotic core in TB lesions was surrounded by macrophages and encircled by a dense T-cell layer. Within the T-cell layer, compact B-cell aggregates were observed in most TB samples. These B-cell clusters were vascularized and could contain defined B-/T-cell and macrophage-rich areas. The ISS of 40-60 immune transcripts revealed the enriched expression of transcripts involved in homing or migration to lymph nodes, which formed networks at single-cell distances in lymphoid areas of the TB lesions. Instead, myeloid-annotated regions were enriched in CD68, CD14, ITGAM, ITGAX, and CD4 mRNA. CXCL8 and IL1B mRNA were observed in granulocytic areas in which M. tuberculosis was also detected. In line with ISS data indicating tertiary lymphoid structures, immune labeling of TB sections expressed markers of high endothelial venules, follicular dendritic cells, follicular helper T cells, and lymph-node homing receptors on T cells. Neither ISS nor immunolabeling showed evidence of tertiary lymphoid aggregates in sarcoidosis samples. Together, our finding suggests that despite their heterogeneity, the formation of tertiary immune structures is a common feature in granulomas from TB patients. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Rheumatoid Arthritis–Specific Autoimmunity in the Lung Before and at the Onset of Disease.

Author

Joshua, Vijay, Loberg Haarhaus, Malena, Hensvold, Aase, Wähämaa, Heidi, Gerstner, Christina, Hansson, Monika, Israelsson, Lena, Stålesen, Ragnhild, Sköld, Magnus, Grunewald, Johan, Klareskog, Lars, Grönwall, Caroline, Réthi, Bence, Catrina, Anca, and Malmström, Vivianne

Subjects
AUTOANTIBODY analysis, RHEUMATOID arthritis risk factors, B cells, BRONCHOALVEOLAR lavage, IMMUNOGLOBULINS, SEQUENCE analysis, GENETIC mutation, LUNGS, MONOCLONAL antibodies, RISK assessment, GENE expression, NEUTROPHILS, AGE factors in disease, DESCRIPTIVE statistics, PHENOTYPES
Abstract

Objective: The lung is implicated as a site for breach of tolerance prior to onset of seropositive rheumatoid arthritis (RA). To substantiate this, we investigated lung‐resident B cells in bronchoalveolar lavage (BAL) samples from untreated early RA patients and anti–citrullinated protein antibody (ACPA)–positive individuals at risk for developing RA. Methods: Single B cells (n = 7,680) were phenotyped and isolated from BAL samples from individuals at risk of RA (n = 3) and at RA diagnosis (n = 9). The immunoglobulin variable region transcripts were sequenced and selected for expression as monoclonal antibodies (n = 141). Monoclonal ACPAs were tested for reactivity patterns and binding to neutrophils. Results: Using our single‐cell approach, we found significantly increased proportions of B lymphocytes in ACPA+ compared to ACPA– individuals. Memory and double‐negative B cells were prominent in all subgroups. Upon antibody re‐expression, 7 highly mutated citrulline‐autoreactive clones originating from different memory B cell subsets were identified, both in individuals at risk of RA and early RA patients. Lung IgG variable gene transcripts from ACPA+ individuals carried frequent mutation‐induced N‐linked Fab glycosylation sites (P < 0.001), often in the framework 3 of the variable region. Two of the lung ACPAs bound to activated neutrophils, 1 from an individual at risk of RA and 1 from an early RA patient. Conclusion: T cell–driven B cell differentiation resulting in local class switching and somatic hypermutation are evident in lungs before as well as in early stages of ACPA+ RA. Our findings add to the notion of lung mucosa being a site for initiation of citrulline autoimmunity preceding seropositive RA. [ABSTRACT FROM AUTHOR]

Published
2023
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26. Sarcoidosis

Author

Grunewald, Johan, Grutters, Jan C., Arkema, Elizabeth V., Saketkoo, Lesley Ann, Moller, David R., and Müller-Quernheim, Joachim

Published
2019
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27. Peripheral blood lymphopenia in sarcoidosis associates with HLA-DRB1 alleles but not with lung immune cells and organ involvement.

Author

Darlington, Pernilla, Melin, Jonas, Rivera, Natalia, Grunewald, Johan, Eklund, Anders, and Kullberg, Susanna

Subjects
SARCOIDOSIS, LYMPHOPENIA, HLA histocompatibility antigens, ALLELES, LUNGS, THERAPEUTICS, BRONCHOALVEOLAR lavage
Abstract

Different human leukocyte antigen (HLA) alleles associate with disease phenotypes in sarcoidosis. Peripheral blood (PB) lymphopenia is reported as more common in sarcoidosis patients with worse prognosis. The mechanisms behind are unrecognized but a PB depletion due to lymphocytes migrating to lung and/or extra pulmonary organs has been suggested. Insights into associations between HLA alleles, lung immune cells, clinical phenotype including extra pulmonary manifestations (EPM), and PB lymphopenia may provide mechanistic clues and enable adequate intervention in this patient group. In this situdy,141 treatment naïve, newly diagnosed patients were retrospectively identified in a Swedish cohort of sarcoidosis patients. Data on HLA-DRB1 alleles, lung immune cells from bronchoalveolar lavage fluid (BALF), PB lymphocytes and clinical parameters including treatment and disease course (chronic vs. resolving) were collected. The patients were followed for 2 years. PB lymphopenia associated with male sex, development of non-resolving disease, a need for first- and second-line systemic immunosuppressant treatment and HLA- DRB1*07. No correlation between BALF and PB lymphocytes, and no difference in EPM was detected between patients with and without PB lymphopenia. In conclusion, PB lymphopenia is associated with a more severe disease phenotype and carriage of the HLA-DRB1*07 allele. The results do not lend support to the hypothesis about sarcoidosis PB lymphopenia being due to a migration of PB lymphocytes to other organs. Rather, they provide a basis for future studies on the connection between HLA-DRB1*07 and PB lymphopenia mechanisms. [ABSTRACT FROM AUTHOR]

Published
2023
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35. High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences

Author

Rivera, Natalia V., Ronninger, Marcus, Shchetynsky, Klementy, Franke, Andre, Nöthen, Markus M., Müller-Quernheim, Joachim, Schreiber, Stefan, Adrianto, Indra, Karakaya, Bekir, van Moorsel, Coline H. M., Navratilova, Zdenka, Kolek, Vitezslav, Rybicki, Benjamin A., Iannuzzi, Michael C., Petrek, Martin, Grutters, Jan C., Montgomery, Courtney, Fischer, Annegret, Eklund, Anders, Padyukov, Leonid, and Grunewald, Johan

Published
2016
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38. Monocytes in sarcoidosis are potent tumour necrosis factor producers and predict disease outcome

Author

Lepzien, Rico, Liu, Sang, Czarnewski, Paulo, Nie, Mu, Österberg, Björn, Baharom, Faezzah, Pourazar, Jamshid, Rankin, Gregory, Eklund, Anders, Bottai, Matteo, Kullberg, Susanna, Blomberg, Anders, Grunewald, Johan, and Smed-Sörensen, Anna

Subjects
Sarcoidosis, Sarcoidosis, Pulmonary, Tumor Necrosis Factor-alpha, Respiratory Medicine and Allergy, Original Research Articles, Humans, Interstitial Lung Disease, Bronchoalveolar Lavage Fluid, Monocytes, Lungmedicin och allergi
Abstract

Background Pulmonary sarcoidosis is an inflammatory disease characterised by granuloma formation and heterogeneous clinical outcome. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine contributing to granuloma formation and high levels of TNF have been shown to associate with progressive disease. Mononuclear phagocytes (MNPs) are potent producers of TNF and highly responsive to inflammation. In sarcoidosis, alveolar macrophages have been well studied. However, MNPs also include monocytes/monocyte-derived cells and dendritic cells, which are poorly studied in sarcoidosis, despite their central role in inflammation. Objective To determine the role of pulmonary monocyte-derived cells and dendritic cells during sarcoidosis. Methods We performed in-depth phenotypic, functional and transcriptomic analysis of MNP subsets from blood and bronchoalveolar lavage (BAL) fluid from 108 sarcoidosis patients and 30 healthy controls. We followed the clinical development of patients and assessed how the repertoire and function of MNP subsets at diagnosis correlated with 2-year disease outcome. Results Monocytes/monocyte-derived cells were increased in blood and BAL of sarcoidosis patients compared to healthy controls. Interestingly, high frequencies of blood intermediate monocytes at time of diagnosis associated with chronic disease development. RNA sequencing analysis showed highly inflammatory MNPs in BAL of sarcoidosis patients. Furthermore, frequencies of BAL monocytes/monocyte-derived cells producing TNF without exogenous stimulation at time of diagnosis increased in patients that were followed longitudinally. In contrast to alveolar macrophages, the frequency of TNF-producing BAL monocytes/monocyte-derived cells at time of diagnosis was highest in sarcoidosis patients that developed progressive disease. Conclusion Our data show that pulmonary monocytes/monocyte-derived cells are highly inflammatory and can be used as a predictor of disease outcome in sarcoidosis patients., Phenotypic, transcriptomic and functional mapping of blood and pulmonary mononuclear phagocytes in sarcoidosis patients found that frequency and function of pulmonary monocytes at time of diagnosis predict 2-year outcome in sarcoidosis https://bit.ly/2JX8fhr

Published
2021

39. Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk

Author

Fischer, Annegret, Ellinghaus, David, Nutsua, Marcel, Hofmann, Sylvia, Montgomery, Courtney G., Iannuzzi, Michael C., Rybicki, Benjamin A., Petrek, Martin, Mrazek, Frantisek, Pabst, Stefan, Grohé, Christian, Grunewald, Johan, Ronninger, Marcus, Eklund, Anders, Padyukov, Leonid, Mihailovic-Vucinic, Violeta, Jovanovic, Dragana, Sterclova, Martina, Homolka, Jiri, Nöthen, Markus M., Herms, Stefan, Gieger, Christian, Strauch, Konstantin, Winkelmann, Juliane, Boehm, Bernhard O., Brand, Stephan, Büning, Carsten, Schürmann, Manfred, Ellinghaus, Eva, Baurecht, Hansjörg, Lieb, Wolfgang, Nebel, Almut, Müller-Quernheim, Joachim, Franke, Andre, and Schreiber, Stefan

Published
2015
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42. Objective and Subjective Sleep in Rheumatoid Arthritis and Severe Seasonal Allergy : Preliminary Assessments of the Role of Sickness, Central and Peripheral Inflammation

Author

Tamm, Sandra, Lensmar, Catarina, Andreasson, Anna, Axelsson, John, Morén, Anton Forsberg, Grunewald, Johan, Gyllfors, Par, Karshikoff, Bianka, Kosek, Eva, Lampa, Jon, Höglund, Caroline Olgart, Strand, Victoria, Cervenka, Simon, and Lekander, Mats

Subjects
rheumatoid arthritis, Reumatologi och inflammation, inflammation, Nature and Science of Sleep, Respiratory Medicine and Allergy, sleep, allergy, Lungmedicin och allergi, Rheumatology and Autoimmunity
Abstract

Sandra Tamm,1– 3 Catarina Lensmar,1 Anna Andreasson,2 John Axelsson,1,2 Anton Forsberg Morén,4 Johan Grunewald,5 Pär Gyllfors,6 Bianka Karshikoff,1,2 Eva Kosek,1,7 Jon Lampa,8 Caroline Olgart Höglund,1,5,9 Victoria Strand,6 Simon Cervenka,4 Mats Lekander1,2 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 2Stress Research Institute, Stockholm University, Stockholm, Sweden; 3Department of Psychiatry, University of Oxford, Oxford, UK; 4Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services,Region Stockholm, Stockholm, Sweden; 5Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 6Asthma & Allergy Clinic at S:t Görans Hospital, Stockholm, Sweden; 7Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; 8Department of Medicine, Rheumatology Unit, Center of Molecular Medicine (CMM), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 9Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SwedenCorrespondence: Sandra TammStress Research Institute, Stockholm University, Stockholm, 106 91, SwedenEmail sandra.tamm@su.seIntroduction: Disturbed sleep in inflammatory disorders such as allergy and rheumatoid arthritis (RA) is common and may be directly or indirectly related to disease processes, but has not been well characterized in these patient groups, especially not with objective methods.Aim: The present study aimed to characterize objective and subjective sleep in patients with allergy or RA using sleep diaries, one-channel EEG and actigraphy. It also aimed to investigate if sleep measures were associated with central immune activation, assessed using translocator protein (TSPO) positron emission tomography, as well as cytokine markers of peripheral inflammation and disease-specific symptoms or general symptoms of sickness.Methods: In total, 18 patients with seasonal pollen allergy, 18 patients with RA and 26 healthy controls were included in the study. Allergy patients and matched controls were assessed twice, in and out of pollen season, and RA patients and controls were assessed once. Sleep was recorded for approximately 1 week at each occasion.Results: Patients with allergy had increased levels of slow-wave sleep during pollen season. In contrast, patients with RA had less SWS compared to healthy controls, while no differences were observed in sleep duration or subjective sleep quality. Across groups, neither proinflammatory cytokines, grey matter TSPO levels nor general sickness symptoms were associated with objective or subjective measures of sleep. Rhinitis, but not conjunctivitis, was correlated to worse subjective sleep and more slow wave sleep in allergy. Functional status, but not disease activity, predicted lower subjective sleep in RA.Conclusion: This study tentatively indicates that both patients with allergy and RA display sleep alterations but does not support inflammation as an independent predictor of the sleep disturbance across these patient groups.Keywords: sleep, inflammation, allergy, rheumatoid arthritis

Published
2021

50. Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis

Author

Wahlstrom, Jan, Dengjel, Jorn, Persson, Bengt, Duyar, Huseyin, Rammensee, Hans-Georg, Stevanovic, Stefan, Eklund, Anders, Weissert, Robert, and Grunewald, Johan

Subjects
Histocompatibility antigens -- Identification and classification, Histocompatibility antigens -- Research, HLA histocompatibility antigens -- Identification and classification, HLA histocompatibility antigens -- Research, Peptides -- Health aspects, Sarcoidosis -- Diagnosis, Sarcoidosis -- Drug therapy, Sarcoidosis -- Research
Abstract

Sarcoidosis is an inflammatory disease of unknown etiology, most commonly affecting the lungs. Activated [CD4.sup.+] T cells accumulate in the lungs of individuals with sarcoidosis and are considered to be [...]

Published
2007

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