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Kokkinou, E., Pandey, R. V., Mazzurana, L., Gutierrez-Perez, I., Tibbitt, C. A., Weigel, W., . . . Mjösberg, J. (2022). CD45RA+CD62L- ILCs in human tissues represent a quiescent local reservoir for the generation of differentiated ILCs. Science immunology, 7(70), Article ID eabj8301.
Open this publication in new window or tab >>CD45RA+CD62L- ILCs in human tissues represent a quiescent local reservoir for the generation of differentiated ILCs
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2022 (English)In: Science immunology, E-ISSN 2470-9468, Vol. 7, no 70, article id eabj8301Article in journal (Refereed) Published
Abstract [en]

Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naïve-like ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA+ ILCs. CD45RA+CD62L+ ILCs (CD62L+ ILCs) resembled circulating naïve ILCs because they lacked the transcriptional, metabolic, epigenetic, and cytokine production signatures of differentiated ILCs. CD45RA+CD62L- ILCs (CD62L- ILCs) were epigenetically similar to CD62L+ ILCs but showed a transcriptional, metabolic, and cytokine production signature that was more akin to differentiated ILCs. CD62L+ and CD62L- ILCs contained uni- and multipotent precursors of ILC1s/NK cells and ILC3s. Differentiation of CD62L+ and CD62L- ILCs led to metabolic reprogramming including up-regulation of genes associated with glycolysis, which was needed for their effector functions after differentiation. CD62L- ILCs with preferential differentiation capacity toward IL-22-producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease. These data suggested distinct differentiation potential of CD62L+ and CD62L- ILCs between tissue microenvironments and identified that manipulation of these cells is a possible approach to restore tissue-immune homeostasis.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:shh:diva-4471 (URN)10.1126/sciimmunol.abj8301 (DOI)35427178 (PubMedID)
Available from: 2022-05-11 Created: 2022-05-11 Last updated: 2022-05-11Bibliographically approved
Han, J. K., Bachert, C., Fokkens, W., Desrosiers, M., Wagenmann, M., Lee, S. E., . . . Hopkins, C. (2021). Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): A randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Respiratory Medicine, 9(10), 1141-1153, Article ID S2213-2600(21)00097-7.
Open this publication in new window or tab >>Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): A randomised, double-blind, placebo-controlled, phase 3 trial
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2021 (English)In: The Lancet Respiratory Medicine, ISSN 2213-2600, E-ISSN 2213-2619, Vol. 9, no 10, p. 1141-1153, article id S2213-2600(21)00097-7Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Chronic rhinosinusitis with nasal polyps affects approximately 2-4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps.

METHODS: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49-52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797.

FINDINGS: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians -0·73, 95% CI -1·11 to -0·34; p<0·0001) and nasal obstruction VAS score during weeks 49-52 also significantly improved (-3·14, -4·09 to -2·18; p<0·0001). Adverse events considered related to study treatment were reported in 30 (15%) of 206 patients receiving mepolizumab and 19 (9%) of 201 receiving placebo. On-treatment serious adverse events occurred in 12 (6%) patients receiving mepolizumab and 13 (6%) receiving placebo; none were considered related to treatment in those receiving mepolizumab. One death was reported in the placebo group (myocardial infarction; death occurred 99 days after the last dose) and was considered unrelated to the treatment.

INTERPRETATION: Mepolizumab treatment improved nasal polyp size and nasal obstruction compared with placebo, with no new safety indications, in patients with recurrent, refractory severe chronic rhinosinusitis with nasal polyps. These findings suggest that mepolizumab provides an effective add-on treatment option to standard of care in this population.

FUNDING: GlaxoSmithKline.

National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:shh:diva-4281 (URN)10.1016/S2213-2600(21)00097-7 (DOI)33872587 (PubMedID)
Available from: 2022-01-05 Created: 2022-01-05 Last updated: 2022-01-22Bibliographically approved
Vanpouille, C., Günaydın, G., Jangard, M., Clerici, M., Margolis, L., Broliden, K. & Introini, A. (2021). The progestin medroxyprogesterone acetate affects HIV-1 production in human lymphoid tissue explants in a dose-dependent and glucocorticoid-like fashion. Viruses, 13(11), Article ID 2303.
Open this publication in new window or tab >>The progestin medroxyprogesterone acetate affects HIV-1 production in human lymphoid tissue explants in a dose-dependent and glucocorticoid-like fashion
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2021 (English)In: Viruses, E-ISSN 1999-4915, Vol. 13, no 11, article id 2303Article in journal (Refereed) Published
Abstract [en]

The association between the use of the injectable contraceptive depot medroxyprogesterone acetate and HIV-1 susceptibility has been addressed mainly in respect to the changes occurring in the female genital mucosa and blood. However, one of the main sites of HIV-1 pathogenesis is lymphoid organs. To investigate the immunoregulatory effect of medroxyprogesterone acetate (MPA) at this site, human tonsillar tissue explants were infected ex vivo with either a CCR5 (BaL) or CXCR4 (LAI) HIV-1 variant and the release of p24gag and cytokines was measured in culture supernatant. The response to MPA was compared with that elicited by treatment with progesterone (P4) and dexamethasone (DEX), which selectively binds the glucocorticoid receptor, in donor-matched explant cultures. MPA treatment reduced the replication of both tested HIV-1 strains as well as the production of the mediators of inflammation IL-1β, IL-17A and CCL5, but not CCL20, in a similar way to DEX, whereas P4 had no effect on HIV-1 replication. The magnitude of both MPA and DEX-mediated responses was proportional to the length of exposure and/or administered dose. Blockage of the progesterone and glucocorticoid receptors with mifepristone abolished all observed changes in HIV-1 and cytokine production, and was associated with increased IL-22 levels in HIV-infected explants. Our data indicate that elevated doses of MPA may affect the immune responses in lymphoid tissue in a glucocorticoid-like fashion with an immediate impact on local HIV-1 replication.

Keywords
DMPA, HIV-1, Cytokines, Glucocorticoids, Hormonal contraception, Lymphoid tissue, Progesterone, Sex hormones, Tissue explants, Tonsils
National Category
Infectious Medicine
Identifiers
urn:nbn:se:shh:diva-4270 (URN)10.3390/v13112303 (DOI)34835109 (PubMedID)
Available from: 2022-01-04 Created: 2022-01-04 Last updated: 2024-01-17Bibliographically approved
Wu, S., Hammarstedt-Nordenvall, L., Jangard, M., Cheng, L., Radu, S. A., Angelidou, P., . . . Ternhag, A. (2021). Tonsillar microbiota: A cross-sectional study of patients with chronic tonsillitis or tonsillar hypertrophy. mSystems, 6(2), Article ID e01302-20.
Open this publication in new window or tab >>Tonsillar microbiota: A cross-sectional study of patients with chronic tonsillitis or tonsillar hypertrophy
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2021 (English)In: mSystems, E-ISSN 2379-5077, Vol. 6, no 2, article id e01302-20Article in journal (Refereed) Published
Abstract [en]

Chronic tonsillitis (CT) and tonsillar hypertrophy (TH) are common tonsillar diseases that are related to infection and inflammation. Little is known about tonsillar microbiota and its role in CT and TH. This study aims to identify palatine tonsillar microbiota both on the surface and in the core tissues of CT and TH patients. In total, 22 palatine tonsils were removed and collected from CT and TH patients who underwent surgery. The surface and core microbiota in the tonsils of CT and TH patients were compared using 16S rRNA gene sequencing of V3-V4 regions. Differential tonsillar microbiotas were found in the CT versus TH patients and surface versus core tissues. Further, a higher relative abundance of bacterial genera, including Haemophilus, Streptococcus, Neisseria, Capnocytophaga, Kingella, Moraxella, and Lachnospiraceae [G-2] in patients with TH and Dialister, Parvimonas, Bacteroidales [G-2], Aggregatibacter, and Atopobium in patients with CT, was observed. Of these, the differential genera of Dialister, Parvimonas, and Neisseria served as key factors in the tonsillar microbiota network. Notably, four representable tonsillar microbial types were identified, with one, consisting of a higher abundance of Haemophilus and Neisseria, exclusively detected in the TH patients. This study analyzed the different tonsillar microbiota from the surface and core tissues of CT and TH patients. Several bacteria and various microbial types related to CT and TH were identified, along with potential bacterial networks and related immune pathways.

IMPORTANCE: The human microbiota has been shown to be functionally connected to infectious and inflammation-related diseases. So far, only limited studies had been performed on tonsillar microbiota, although tonsils play an essential role in the human immune defense system and encountered numerous microorganisms. Our work presented different tonsillar microbiota from surface and core tissues of chronic tonsillitis (CT) and tonsillar hypertrophy (TH) patients. Notably, one tonsillar microbiota type, which contains a higher abundance of Haemophilus and Neisseria, was only detected in the TH patients. Furthermore, certain bacteria, such as Haemophilus, Neisseria, Dialister, and Parvimonas, may serve as microbial biomarkers to discriminate CT patients from TH patients. These data provide important microbiota data in the tonsillar research area and are highly useful for researchers both in the oral microbiome field and clinical field.

Keywords
16S rRNA gene sequencing, chronic tonsillitis, microbiota, tonsillar hypertrophy, tonsillar tissues
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:shh:diva-4021 (URN)10.1128/mSystems.01302-20 (DOI)33688019 (PubMedID)
Available from: 2021-04-27 Created: 2021-04-27 Last updated: 2022-02-10Bibliographically approved
Jangard, M., Svedberg, M., Gladh, H., Araya Holmqvist, S., Ryott, M. & Kumlin, M. (2018). Nasal irrigation with hot saline provides better postoperative outcome after fess compared to the traditional use of nasal packing. In: : . Paper presented at ERS 2018 27th Congress of the European Rhinologic Society, London, Storbritannien, 22-26 april 2018.
Open this publication in new window or tab >>Nasal irrigation with hot saline provides better postoperative outcome after fess compared to the traditional use of nasal packing
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2018 (English)Conference paper, Oral presentation only (Other academic)
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:shh:diva-3230 (URN)
Conference
ERS 2018 27th Congress of the European Rhinologic Society, London, Storbritannien, 22-26 april 2018
Available from: 2019-02-07 Created: 2019-02-07 Last updated: 2020-06-02Bibliographically approved
Grün, N., Mbuya, W., Ternhag, A., Ramqvist, T., Ahlberg, A., Jangard, M., . . . Hammarstedt-Nordenvall, L. (2017). Human papillomavirus prevalence in mouthwashes of patients undergoing tonsillectomy shows dominance of HPV69, without the corresponding finding in the tonsils.. Infectious diseases (London, England), 49(8), 588-593
Open this publication in new window or tab >>Human papillomavirus prevalence in mouthwashes of patients undergoing tonsillectomy shows dominance of HPV69, without the corresponding finding in the tonsils.
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2017 (English)In: Infectious diseases (London, England), ISSN 2374-4243, Vol. 49, no 8, p. 588-593Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The role of human papillomavirus (HPV) in tonsillar squamous cell carcinomas (TSCC) is of interest, since a considerable proportion of TSCC in Sweden and other Western countries is HPV positive. Nevertheless, the natural history of HPV in normal tonsils, and the progression from localized infection to pre-malignant lesion to cancer are poorly understood. The aim of this study was to investigate whether HPV types found in mouthwash samples correlated to those in tonsillar tissue from the same individuals undergoing tonsillectomy.

METHODS: Mouthwash samples from 232 patients, aged 3-56 years, undergoing tonsillectomy, the majority with chronic tonsillitis, were collected at the time of surgery and analysed for the presence of 27 HPV types by a bead based multiplex assay.

RESULTS: An HPV prevalence of 10.3% (24/232) was observed in mouthwash samples, with HPV 69 being the dominant type (10/24). Ten patients were positive for high risk HPV (HPV 16, 33, 35, 45, 56, 59). None of the tonsils resected from patients with HPV-positive mouthwash samples were positive for HPV.

CONCLUSIONS: Despite an oral HPV prevalence of 10.3% in mouthwash samples from tonsillectomized patients, with dominance of HPV 69, none of the corresponding tonsillar samples exhibited the presence of HPV.

Keywords
HPV in tonsilectomized, HPV69, Oral HPV, vaccination
National Category
Infectious Medicine
Identifiers
urn:nbn:se:shh:diva-2613 (URN)10.1080/23744235.2017.1300319 (DOI)28293975 (PubMedID)
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2020-06-02Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3772-2026

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