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

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.

Identification of a Human Natural Killer Cell Lineage-Restricted Progenitor in Fetal and Adult Tissues.

Natural killer (NK) cells are cytotoxic lymphocytes and play a vital role in controlling viral infections and cancer. In contrast to B and T lymphopoiesis where cellular and regulatory pathways have been extensively characterized, the cellular stages of early human NK cell commitment remain poorly understood. Here we demonstrate that a Lin(-)CD34(+)CD38(+)CD123(-)CD45RA(+)CD7(+)CD10(+)CD127(-) population represents a NK lineage-restricted progenitor (NKP) in fetal development, umbilical cord blood, and adult tissues. The newly identified NKP has robust NK cell potential both in vitro and in vivo, generates functionally cytotoxic NK cells, and lacks the ability to produce T cells, B cells, myeloid cells, and innate lymphoid-like cells (ILCs). Our findings identify an early step to human NK cell commitment and provide new insights into the human hematopoietic hierarchy.

Human Blood and Tonsil Plasmacytoid Dendritic Cells Display Similar Gene Expression Profiles but Exhibit Differential Type I IFN Responses to Influenza A Virus Infection.

Influenza A virus (IAV) infection constitutes an annual health burden across the globe. Plasmacytoid dendritic cells (PDCs) are central in antiviral defense because of their superior capacity to produce type I IFNs in response to viruses. Dendritic cells (DCs) differ depending on their anatomical location. However, only limited host-pathogen data are available from the initial site of infection in humans. In this study, we investigated how human tonsil PDCs, likely exposed to virus because of their location, responded to IAV infection compared with peripheral blood PDCs. In tonsils, unlike in blood, PDCs are the most frequent DC subset. Both tonsil and blood PDCs expressed several genes necessary for pathogen recognition and immune response, generally in a similar pattern. MxA, a protein that renders cells resistant to IAV infection, was detected in both tonsil and blood PDCs. However, despite steady-state MxA expression and contrary to previous reports, at high IAV concentrations (typically cytopathic to other immune cells), both tonsil and blood PDCs supported IAV infection. IAV exposure resulted in PDC maturation by upregulation of CD86 expression and IFN-α secretion. Interestingly, blood PDCs secreted 10-fold more IFN-α in response to IAV compared with tonsil PDCs. Tonsil PDCs also had a dampened cytokine response to purified TLR ligands compared with blood PDCs. Our findings suggest that tonsil PDCs may be less responsive to IAV than blood PDCs, highlighting the importance of studying immune cells at their proposed site of function.

Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3-ILC1/NK cell transdifferentiation.

The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1ß plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1ß and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.

Randomised trial showed no difference in behavioural symptoms between surgical methods treating paediatric obstructive sleep apnoea.

AIM: Our previous randomised controlled trial of children with obstructive sleep apnoea (OSA) showed no significant differences between adenotonsillectomy (ATE) and adenotonsillotomy (ATT) in improving nocturnal respiration and quality of life after 1 year. The aim of this report was to evaluate the effects on behavioural symptoms using the Strengths and Difficulties Questionnaire (SDQ). METHODS: Children between 2 and 6 years with OSA were randomised to ATT or ATE. Parents, blinded to method, answered the SDQ while their child underwent polysomnography before and 1 year after surgery. Differences between the total SDQ scores were analysed between the treatment groups. RESULTS: The SDQ was filled out in 87% of the cases preoperatively, and in 86% postoperatively. At follow-up, the mean total SDQ score was 9.6 SD ± 5.1 in the ATE group (n = 31), and 8.2 ± 6.7 in the ATT group (n = 37), P = .09. The mean total SDQ score for all was preoperatively 10.6 ± 5.0, and postoperatively 8.8 ± 6.0, P = .0002. CONCLUSION: There were no significant differences in SDQ scores between the groups at follow-up, indicating that the more conservative ATT is a treatment option in paediatric OSA. The whole group of patients showed a significant improvement after surgery.

Postoperative morbidity after adenotonsillectomy versus adenopharyngoplasty in young children with obstructive sleep apnea: an RCT.

PURPOSE: In our previous randomized controlled trial (RCT), comparing adenotonsillectomy (ATE) with adenopharyngoplasty (APP) in children with severe obstructive sleep apnea (OSA), there were no differences in respiratory sleep parameters or quality of life. The purpose of the present report was to evaluate postoperative morbidity from this RCT. METHODS: The study was a blinded RCT in 83 children (ATE = 47; APP = 36), 2-4 years of age, with an obstructive apnea-hypopnea index of ≥ 10. Pain was assessed from the first until the tenth day after surgery with a logbook that reported pain by child (FPS-R, Faces Pain Scale-Revised) and caregiver (visual analogue scale), analgesic use, return to normal diet, and weight change. Bleeding, infection, satisfaction with treatment, speech, and swallowing were assessed with a questionnaire and medical records 6 months after surgery. RESULTS: Sixty-four children (77%) returned the logbook and 65 (78%) answered the questionnaire. The median (interquartile range) day the children graded themselves as pain free (FPS-R = 0) was 7 (6-10) after ATE, compared with 9 (7 to > 10) after APP (p = 0.018). There were no other significant differences between the groups regarding any other pain-related outcomes, bleeding, infection, satisfaction, swallowing, or speech, but three children (11%) reported impaired speech after APP compared to none after ATE (p = 0.067). CONCLUSION: The results regarding postoperative morbidity were in favor of ATE and the results from our previous report showed no advantages of APP. Therefore, APP should not be recommended in young, otherwise healthy children with OSA.

Cytokine-induced endogenous production of prostaglandin D2 is essential for human group 2 innate lymphoid cell activation.

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) play a key role in the initiation and maintenance of type 2 immune responses. The prostaglandin (PG) D2-chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) receptor axis potently induces cytokine production and ILC2 migration. OBJECTIVE: We set out to examine PG production in human ILC2s and the implications of such endogenous production on ILC2 function. METHODS: The effects of the COX-1/2 inhibitor flurbiprofen, the hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor KMN698, and the CRTH2 antagonist CAY10471 on human ILC2s were determined by assessing receptor and transcription factor expression, cytokine production, and gene expression with flow cytometry, ELISA, and quantitative RT-PCR, respectively. Concentrations of lipid mediators were measured by using liquid chromatography-tandem mass spectrometry and ELISA. RESULTS: We show that ILC2s constitutively express HPGDS and upregulate COX-2 upon IL-2, IL-25, and IL-33 plus thymic stromal lymphopoietin stimulation. Consequently, PGD2 and its metabolites can be detected in ILC2 supernatants. We reveal that endogenously produced PGD2 is essential in cytokine-induced ILC2 activation because blocking of the COX-1/2 or HPGDS enzymes or the CRTH2 receptor abolishes ILC2 responses. CONCLUSION: PGD2 produced by ILC2s is, in a paracrine/autocrine manner, essential in cytokine-induced ILC2 activation. Hence we provide the detailed mechanism behind how CRTH2 antagonists represent promising therapeutic tools for allergic diseases by controlling ILC2 function.

Postoperative pain and bleeding after adenotonsillectomy versus adenotonsillotomy in pediatric obstructive sleep apnea: an RCT.

PURPOSE: Our previous randomized controlled trial (RCT) of children with obstructive sleep apnea (OSA) showed no significant differences between adenotonsillectomy (ATE) and adenotonsillomy (ATE) in improving nocturnal respiration and symptoms after one year. This is the continuous report with the evaluation of postoperative morbidity concerning bleeding and pain. METHODS: A double-blinded RCT including 79 children, aged 2-6 years, with moderate to severe OSA, randomized to either ATE (n = 40) or ATT (n = 39). From one to ten days postoperatively, parents filled in a logbook with six pain-related outcomes (parent and child grading pain at different levels, days of analgesic use and return to normal diet). Peri- and postoperative bleeding were also registered. RESULTS: 63 patients (80%) returned the logbook. There were significant differences between groups in only two of the six pain-related outcomes in favor of the ATT group; first day when the children graded themselves as pain free (p = 0.021, Log Rank Test), and first day the caregiver estimated pain VAS ≤ 5 (p = 0.007, Log Rank Test). Two (5%) cases of postoperative bleeding occurred in the ATE group, one of which needed a return to theatre. No case of postoperative bleeding was seen in the ATT group. CONCLUSIONS: The results from this RCT are in line with previous comparative studies between ATT and ATE. Children operated with ATT had significantly less postoperative pain in one-third of the outcomes, and less bleeding than ATE. However, as the differences in morbidity between the surgical methods were minor the clinical significance is uncertain. TRIAL REGISTRATION: This study was approved by the Swedish Regional Ethics Board in Stockholm, Sweden (Dnr 2011/925-32 and 2013/2274-32) and registered at ClinicalTrials.gov (Trial registration number NCT01676181).

Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells.

BACKGROUND: Vitamin D deficiency is a risk factor for inflammatory bowel disease (IBD). The IL-23-driven tissue-resident group 3 innate lymphoid cells (ILC3s) play essential roles in intestinal immunity, and targeting IL-23/12 is a promising approach in IBD therapy. OBJECTIVE: We set out to define the role of 1α,25-dihydroxy vitamin D3 (1,25D) in regulating functional responses of human mucosal ILC3s to IL-23 plus IL-1ß stimulation. METHODS: Transcriptomes of sorted tonsillar ILC3s were assessed by using microarray analysis. ILC3 cytokine production, proliferation, and differentiation were determined by means of flow cytometry, ELISA, and multiplex immunoassay. Intestinal cell suspensions and ILC3s sorted from gut biopsy specimens of patients with IBD were also analyzed along with plasma 25-hydroxy vitamin D3 (25D) detection. RESULTS: ILC3s stimulated with IL-23 plus IL-1ß upregulated the vitamin D receptor and responded to 1,25D with downregulation of the IL-23 receptor pathway. Consequently, 1,25D suppressed IL-22, IL-17F, and GM-CSF production from tonsillar and gut ILC3s. In parallel, 1,25D upregulated genes linked to the IL-1ß signaling pathway, as well as the IL-1ß-inducible cytokines IL-6, IL-8, and macrophage inflammatory protein 1α/ß. The 1,25D-triggered skewing in ILC3 function was not accompanied or caused by changes in viability, proliferation, or phenotype. Finally, we confirmed low 25D plasma levels in patients with IBD with active inflammation. CONCLUSION: In light of the beneficial targeting of IL-23/12 in patients with IBD, 1,25D appears as an interesting therapeutic agent that inhibits the IL-23 receptor pathway, providing a novel mechanism for how ILC3s could be manipulated to regulate intestinal inflammation.

Prostaglandin E2 suppresses human group 2 innate lymphoid cell function.

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are involved in the initial phase of type 2 inflammation and can amplify allergic immune responses by orchestrating other type 2 immune cells. Prostaglandin (PG) E2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation. OBJECTIVE: We set out to investigate how PGE2 regulates human ILC2 function. METHODS: The effects of PGE2 on human ILC2 proliferation and intracellular cytokine and transcription factor expression were assessed by means of flow cytometry. Cytokine production was measured by using ELISA, and real-time quantitative PCR was performed to detect PGE2 receptor expression. RESULTS: PGE2 inhibited GATA-3 expression, as well as production of the type 2 cytokines IL-5 and IL-13, from human tonsillar and blood ILC2s in response to stimulation with a combination of IL-25, IL-33, thymic stromal lymphopoietin, and IL-2. Furthermore, PGE2 downregulated the expression of IL-2 receptor α (CD25). In line with this observation, PGE2 decreased ILC2 proliferation. These effects were mediated by the combined action of E-type prostanoid receptor (EP) 2 and EP4 receptors, which were specifically expressed on ILC2s. CONCLUSION: Our findings reveal that PGE2 limits ILC2 activation and propose that selective EP2 and EP4 receptor agonists might serve as a promising therapeutic approach in treating allergic diseases by suppressing ILC2 function.

Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers.

Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue-residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue-resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44- ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL-13 when exposed to IL-33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR-3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment.

Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid.

Amniotic fluid (AF) surrounds the growing fetus, and cells derived from AF are commonly used for diagnosis of genetic diseases. Intra-amniotic infections are strongly linked to preterm birth, which is the leading cause of perinatal mortality worldwide. Surprisingly little is known, however, about mature hematopoietic cells in AF, which could potentially be involved in immune responses during pregnancy. In this study, we show that the dominating population of viable CD45+ cells in AF is represented by a subset of fetal CD103+ group 3 innate lymphoid cells (ILCs) producing high levels of IL-17 and TNF. Fetal CD103+ ILC3s could also be detected at high frequency in second-trimester mucosal tissues (e.g., the intestine and lung). Taken together, our data indicate that CD103+ ILC3s accumulate with gestation in the fetal intestine and subsequently egress to the AF. The dominance of ILC3s producing IL-17 and TNF in AF suggests that they could be involved in controlling intra-amniotic infections and inflammation and as such could be important players in regulating subsequent premature birth.

Low inter-examiner agreement of the Friedman staging system indicating limited value in patient selection.

PURPOSE: The Friedman staging system is a clinical method for selecting patients with obstructive sleep apnoea who are likely to benefit from uvulopalatopharyngoplasty. The objective of this study was to evaluate the system by determining its inter-examiner agreement. METHODS: Twelve patients with obstructive sleep apnoea were examined by 14 doctors. The Friedman stage was derived from tonsil size and tongue position, and a Cohen's kappa analysis was performed to assess inter-examiner agreement. RESULTS: One hundred and sixty-eight ratings were performed. The median kappa for tongue position was 0.32 (first and third quartiles: 0.21 and 0.44) and was 0.62 (0.50 and 0.63) for tonsil size. The median kappa for the Friedman stage was 0.38 (0.24 and 0.55), which corresponds to only a slight or fair agreement. CONCLUSION: The Friedman staging system demonstrated a low inter-examiner agreement, indicating that the system is an uncertain method for selecting patients for uvulopalatopharyngoplasty. LEVEL OF EVIDENCE: 2B.

SKUP3 randomised controlled trial: polysomnographic results after uvulopalatopharyngoplasty in selected patients with obstructive sleep apnoea.

OBJECTIVE: To assess the 6-month efficacy of uvulopalatopharyngoplasty (UPPP) compared with expectancy in selected patients with obstructive sleep apnoea syndrome (OSAS). DESIGN: A prospective single-centre randomised controlled trial with two parallel arms stratified by Friedman stage and body mass index (BMI). PARTICIPANTS: 65 consecutive patients with moderate to severe OSAS (apnoea-hypopnoea index (AHI) ≥15 events/h sleep), BMI <36 kg/m(2), Epworth sleepiness scale ≥8, Friedman stage I or II. INTERVENTION: Surgical treatment with UPPP. The control group underwent UPPP after a delay of 6 months. OUTCOMES: Changes in AHI and other polysomnography parameters at baseline compared with the 6-month follow-up. RESULTS: All patients (32 in the intervention group and 33 in the control group) completed the trial. The mean (SD) AHI in the intervention group decreased significantly (p<0.001) by 60% from 53.3 (19.7) events/h to 21.1 (16.7) events/h . In the control group the mean AHI decreased by 11% from 52.6 (21.7) events/h to 46.8 (22.8) events/h, with a significant difference between the groups (p<0.001). The mean time in the supine position and the BMI were unchanged in both groups. Subgroup analyses for Friedman stage, BMI group and tonsil size all showed significant reductions in AHI in the intervention group compared with controls. There were no severe complications after surgery. CONCLUSIONS: This trial demonstrates the efficacy of UPPP in treating selected patients with OSAS with a mean reduction in AHI of 60% compared with 11% in controls, a highly significant and clinically relevant difference between the groups. TRIAL REGISTRATION NUMBER: NCT01659671.

[New Swedish National care process for pediatric obstructive sleep disordered breathing]. / Nytt vårdförlopp för barn med OSDB är godkänt att tas i bruk.

Obstructive sleep disordered breathing (OSDB) is a spectrum from habitual snoring and labored breathing to obstructive sleep apnea (OSA), which is common and potentially serious in children. The process contains a new question at child care centers, directed at caretakers with children at age 18 months and 3 years, concerning habitual snoring (3 times a week or more). A primary care doctor verifies the suspicion of OSDB in case of a positive answer to one of 7 additional questions or 4 status findings (e.g. tonsil hypertrophy). The process starts with the suspicion of OSDB, from the age of 18 months to 18 years, and ends when symptoms are improved after watchful waiting or upper airway surgery. National equality is a goal, with increased access to nocturnal respiratory recordings of children with comorbidities or doubtful cases. Also, with short waiting time to first visit at ORL department, and to surgery. Children with comorbidities or severe symptoms get postoperative follow-ups with a nurse after 6 months. The new ICD code for OSDB is R06.8A.

National Knowledge-Driven Management of Obstructive Sleep Apnea-The Swedish Approach.

INTRODUCTION: This paper describes the development of "Swedish Guidelines for OSA treatment" and the underlying managed care process. The Apnea Hypopnea Index (AHI) is traditionally used as a single parameter for obstructive sleep apnea (OSA) severity classification, although poorly associated with symptomatology and outcome. We instead implement a novel matrix for shared treatment decisions based on available evidence. METHODS: A national expert group including medical and dental specialists, nurses, and patient representatives developed the knowledge-driven management model. A Delphi round was performed amongst experts from all Swedish regions (N = 24). Evidence reflecting treatment effects was extracted from systematic reviews, meta-analyses, and randomized clinical trials. RESULTS: The treatment decision in the process includes a matrix with five categories from a "very weak"" to "very strong" indication to treat, and it includes factors with potential influence on outcome, including (A) OSA-related symptoms, (B) cardiometabolic comorbidities, (C) frequency of respiratory events, and (D) age. OSA-related symptoms indicate a strong incitement to treat, whereas the absence of symptoms, age above 65 years, and no or well-controlled comorbidities indicate a weak treatment indication, irrespective of AHI. CONCLUSIONS: The novel treatment matrix is based on the effects of treatments rather than the actual frequency of respiratory events during sleep. A nationwide implementation of this matrix is ongoing, and the outcome is monitored in a prospective evaluation by means of the Swedish Sleep Apnea Registry (SESAR).

Adenotonsillotomy versus adenotonsillectomy in pediatric obstructive sleep apnea: A 5-year RCT.

Objectives: Adenotonsillectomy (ATE) is a common treatment for pediatric obstructive sleep apnea (OSA). Intracapsular adenotonsillotomy (ATT) is associated with less postoperative morbidity. Our previous randomized controlled trial (RCT) compared ATE and ATT in otherwise healthy children with moderate to severe OSA. No differences in polysomnographic (PSG) and OSA-18 were found between the groups at one-year follow-up. This study presents the long-term results of the RCT. Methods: Non-obese children (n = 79, 2-6 years) who had undergone either ATE (n = 40) or ATT (n = 39) were offered PSG and OSA-18 questionnaire five-years after surgery. Primary outcome was the group difference in postoperative Obstructive Apnea/Hypopnea Index (OAHI). ATE was recommended to the ATT group if they had a relapse of OSA. Results: The follow-up was completed by 45 of 79 (57%) children; 28 (35%) drop-outs, and six of 39(15%) in the ATT group were excluded after ATE. After ATE(n = 17), OAHI decreased from mean 12.3(SD 8.0) to 0.6(0.7), and after ATT(n = 28) from 12.6(7.4) to 0.5(0.6), a mean difference in postoperative OAHI of 0.1(95% CI -0.3 - 0.5). Sensitivity analyses did not change the results. The median OSA-18 decreased in the ATE group from 57(interquartile range 47-79) to 27(22-36), and in the ATT group from 67(53-79) to 32(25-44), without group differences for postoperative values. Conclusion: The results of this five-year follow-up of otherwise healthy OSA-children showed a high drop-out rate, but indicates that ATT could be an effective treatment for pediatric OSA. However, ATT warrants follow-up due to the risk of recurrence, and further studies are needed.

Correlations between objective and subjective outcomes after adenotonsillar surgery in children with OSA.

Objectives: To investigate whether the OSA-18 questionnaire and a postoperative patient-reported outcome measure (PROM) question correlated with polysomnography (PSG) data. Methods: A prospective study of otherwise healthy young children with moderate to severe obstructive sleep apnea (OSA) to investigate if the obstructive apnea-hypopnea index (OAHI) before and 6-12 months after adenotonsil surgery correlated with the OSA-18 total symptom score (TSS) and the sleep disturbance subscale (SDS), as well as a PROM question on symptom improvement with responses on a 4-grade Likert scale. Results: Of 201 children, 173 (86%) had complete data of OAHI and OSA-18 pre- and postoperatively. The mean age was 3.2 years (SD 1.0) and the mean OAHI was 15.9 (11.3). Significant correlations between changes in the OAHI and OSA-18 were found, both TSS (r = 0.29, p < .001) and SDS (r = 0.53, p < .001). A total of 136 (68%) patients responded to the PROM question, the majority of whose symptoms had disappeared (n = 102) or almost disappeared (n = 30). Four patients had unchanged symptoms, and none had worsening symptoms. A correlation was found between the PROM question and a change in the OAHI (r = 0.36, p < .001), as well as a change in the OSA-18 TSS (r = 0.24, p = .006) and the SDS (r = 0.34, p < .001). The specificity of the PROM question for prediction of a postoperative OAHI < 2 was 82%, and the sensitivity was 38%. Conclusion: Changes in the OAHI significantly correlated with changes in the OSA-18, especially with the sleep disturbance scale, which could be an alternative for evaluation at follow-ups. Level of Evidence: 3.

Effectiveness of Tonsillectomy vs Modified Uvulopalatopharyngoplasty in Patients With Tonsillar Hypertrophy and Obstructive Sleep Apnea: The TEAMUP Randomized Clinical Trial.

Importance: Modified uvulopalatopharyngoplasty (mUPPP) is a surgical treatment for selected adults with obstructive sleep apnea (OSA). Tonsillectomy (TE) alone is a less extensive alternative treatment. Objective: To investigate whether mUPPP is more effective than TE alone in treating adult patients with tonsillar hypertrophy and moderate to severe OSA. Design, Setting, and Participants: This blinded randomized clinical trial compared the effectiveness of mUPPP with TE alone before surgery and 6 months postsurgery in adults with tonsillar hypertrophy (sizes 2, 3, or 4 according to the Friedman staging) and moderate to severe OSA in a university hospital in Stockholm, Sweden. Participants underwent surgery from January 2016 to February 2021; the last postsurgery follow-up was completed in September 2021. Data analyses were performed from January to September 2022. Interventions: mUPPP vs TE alone. Main Outcomes and Measures: Between-group differences on the apnea-hypopnea index (AHI) and Epworth sleepiness scale (ESS). Results: The study cohort comprised 93 patients (mean [SD] age, 41.6 [9.4] years; 80 [86%] men; race/ethnicity were not considered) with a mean (SD) body mass index of 29.0 (2.8), calculated as weight in kg divided by height in m2. Of these, 90 participants (97%) completed the protocol (mUPPP, n = 45; TE, n = 45). The mean (SD) AHI score (number of events per hour [events/h]) for the mUPPP group decreased by 43%, from 51.0 (22.6) to 28.0 (20.0) events/h; and for the TE group, 56%, from 56.9 (25.1) to 24.7 (22.6) events/h. The mean between-group difference in AHI score was 9.2 events/h (95% CI, 0.5 to 17.9), with a small effect size (Cohen d = 0.44) in favor of TE. For ESS scores, the between-group difference was also small, only 1.1 (95% CI, -1.3 to 3.4; Cohen d = 0.21). Neither difference was considered to be clinically relevant. Conclusions and Relevance: This randomized clinical trial demonstrated that mUPPP was not more effective than TE alone in treating patients with tonsillar hypertrophy and moderate to severe OSA. However, there was a small difference in favor of TE. Because TE alone is less extensive, it could be considered as an alternative to mUPPP in this selected group of patients with OSA. Trial Registration: ClinicalTrials.gov Identifier: NCT02523248.

CD45RA+CD62L- ILCs in human tissues represent a quiescent local reservoir for the generation of differentiated ILCs.

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.