Tissue-infiltrating neutrophils represent the main source of IL-23 in the colon of patients with IBD.

OBJECTIVE: In IBD, interleukin-23 (IL-23) and its receptor (IL-23R) are implicated in disease initiation and progression. Novel insight into which cells produce IL-23 at the site of inflammation at an early stage of IBD will promote the development of new tools for diagnosis, treatment and patient monitoring. We examined the cellular source of IL-23 in colon tissue of untreated newly diagnosed paediatric patients with IBD. DESIGN: Colon tissues from IBD and non-IBD patients were analysed by quantitative real-time PCR (qPCR), immunofluorescence confocal microscopy and flow cytometry after appropriate sample preparation. Blood samples from IBD and non-IBD patients and healthy controls were analysed using flow cytometry and qPCR. RESULTS: We discovered that tissue-infiltrating neutrophils were the main source of IL-23 in the colon of paediatric patients with IBD, while IL-23(+) human leucocyte antigen-DR(+) or IL-23(+)CD14(+) cells were scarce or non-detectable, respectively. The colonic IL-23(+) neutrophils expressed C-X-C motif (CXC)R1 and CXCR2, receptors for the CXC ligand 8 (CXCL8) chemokine family, and a corresponding CXCR1(+)CXCR2(+)IL-23(+)subpopulation of neutrophils was also identified in the blood of both patients with IBD and healthy individuals. However, CXCL8-family chemokines were only elevated in colon tissue from patients with IBD. CONCLUSIONS: This study provides the first evidence of CXCR1(+)CXCR2(+)IL-23-producing neutrophils that infiltrate and accumulate in inflamed colon tissue of patients with IBD. Thus, this novel source of IL-23 may play a key role in disease progression and will be important to take into consideration in the development of future strategies to monitor, treat and prevent IBD.

Detection of IL-17A-producing peripheral blood monocytes in Langerhans cell histiocytosis patients.

Langerhans cell histiocytosis (LCH) is a rare disease of unknown cause with manifestations ranging from isolated granulomatous lesions to life-threatening multi-system organ involvement. This disorder is further characterized by infiltration of immune cells in affected tissues and an association with interleukin (IL)-17A has been reported. Here, we investigated the presence of IL-17A-producing cells among peripheral blood mononuclear cells isolated from LCH patients and observed a high percentage of IL-17A(+) monocytes in peripheral blood of LCH patients compared to controls. The IL-17A(+) monocytes were also positive for the transcription factor retinoic acid orphan receptor (ROR) γt and showed increased mRNA levels for both IL-17A and RORγt. Notably, IL-17A was produced by all monocyte subsets and the expression level was positively associated with LCH disease activity. These data support a role for monocytes in the pathogenesis of LCH. Future therapeutic approaches may consider identification of patients who may benefit from IL-17A-targeted interventions.

Targeting BCL2 family in human myeloid dendritic cells: a challenge to cure diseases with chronic inflammations associated with bone loss.

Rheumatoid arthritis (RA) and Langerhans cell histiocytosis (LCH) are common and rare diseases, respectively. They associate myeloid cell recruitment and survival in inflammatory conditions with tissue destruction and bone resorption. Manipulating dendritic cell (DC), and, especially, regulating their half-life and fusion, is a challenge. Indeed, these myeloid cells display pathogenic roles in both diseases and may be an important source of precursors for differentiation of osteoclasts, the bone-resorbing multinucleated giant cells. We have recently documented that the proinflammatory cytokine IL-17A regulates long-term survival of DC by inducing BCL2A1 expression, in addition to the constitutive MCL1 expression. We summarize bibliography of the BCL2 family members and their therapeutic targeting, with a special emphasis on MCL1 and BCL2A1, discussing their potential impact on RA and LCH. Our recent knowledge in the survival pathway, which is activated to perform DC fusion in the presence of IL-17A, suggests that targeting MCL1 and BCL2A1 in infiltrating DC may affect the clinical outcomes in RA and LCH. The development of new therapies, interfering with MCL1 and BCL2A1 expression, to target long-term surviving inflammatory DC should be translated into preclinical studies with the aim to increase the well-being of patients with RA and LCH.

Reduction of rotavirus as a cause of nosocomial diarrhoea in northern Stockholm after introducing the rotavirus vaccine.

Background: Vaccination against rotavirus was offered in Stockholm to children born on 1 March 2014 and onwards with 85% coverage after two years. We investigated changes in nosocomial diarrhoea 2010-2018 in children admitted to Astrid Lindgren Children's Hospital, Stockholm, Sweden. Methods: We retrospectively identified cases from diagnostic and virology department registers. Complications and chronic medical conditions were retrieved from the case records. Children <18 years of age who developed diarrhoea ≥48 h after admission for another diagnosis and had a faecal sample submitted to the virology department were included. Results: There were 474 episodes of nosocomial diarrhoea. Of these, 401 (85%) occurred in children with chronic medical conditions. In children <5 years the rates of nosocomial rotavirus gastroenteritis, with 95% confidence intervals, significantly decreased from 0.34 (0.25-0.45) per 100 admissions prevaccination to 0.09 (0.04-0.17) postvaccination and from 0,66 (0.48-0.88) to 0.16 (0.07-0.30) cases per 1000 hospital days. Postvaccination norovirus became the most frequent pathogen. Virus-positive cases were more common in young children and in winter months. Conclusions: Before the initiation of rotavirus vaccination, norovirus and rotavirus were equally common causes of nosocomial diarrhoea. Postvaccination, rotavirus was reduced by approximately 75% while the frequency of other viruses did not change.

All-cause gastroenteritis hospitalisations of children decreased after the introduction of rotavirus vaccine in Stockholm.

BACKGROUND: In Stockholm, Sweden, rotavirus vaccination was offered to children born after 1 March 2014. Our aim was to describe rates of hospitalisation due to community-acquired gastroenteritis before and after the introduction of the vaccine, and aetiology, underlying medical conditions and complications in admitted children. METHODS: We retrospectively included patients from our catchment area hospitalised with a diagnosis of gastroenteritis during ten infection seasons 2008/2009-2017/2018, whereof six seasons prevaccination and four seasons postvaccination. We studied virus detection data and the patients' medical records. RESULTS: We included 3718 episodes in 3513 children. In 2967 (80%), stools were tested with virus isolation, ELISA, PCR, or bacterial culture; 479 (16%) tested negative. The incidence rates, with 95% confidence intervals, for children <5 years hospitalised for rotavirus gastroenteritis were 2.9 (2.8-3.1) per 1000 person-years prevaccination and 0.65 (0.56-0.74) postvaccination, for a rate ratio (RR) of 0.22 (0.19-0.26, p < .001). The rates for all-cause gastroenteritis were 5.6 (5.4-5.9) prevaccination and 2.5 (2.3-2.7) postvaccination, RR 0.45 (0.42-0.50, p < .001). In 5-17-year-old children norovirus dominated with little change over time. Of patients <5 years, those with underlying conditions constituted a larger proportion postvaccination than prevaccination (30.7% vs. 24.2%, p < .001). A complication other than dehydration, most commonly seizures, arose in 8.8% of the patients <5 years prevaccination and 11.4% postvaccination (p < .05). CONCLUSIONS: Rotavirus vaccination reduced the number of children <5 years requiring hospital care for gastroenteritis. We saw no replacement of rotavirus by other viruses.

Long-term Prognosis of Tuberculosis Infection and Disease in Swedish Children.

BACKGROUND: Reports of the outcome of treatment of tuberculosis (TB) disease and infection (TBI) in children are scarce. Since 2010, we routinely use interferon-gamma release assays in addition to clinical history for the exclusion of TBI, although the safety of this approach has been questioned. We present the frequency of recurrent TB or progression to TB after treatment for TB disease or TB infection, respectively, and progression to disease in children considered TB uninfected at our pediatric TB clinic. METHODS: We included 4707 patients from 1990 to 2017. At the initial assessment, 96 (2.0%) had previously received TB treatment, 253 (5.4%) had TB disease, 1625 (35%) had TBI and 2733 (58%) children were considered uninfected. Patients were passively followed at our clinic, at the adult TB clinics in Stockholm and at the Swedish national TB registry. RESULTS: During a median follow-up time of 8.4 years, we found 36 cases of TB disease, with true relapses in 3/243 (1.2%) successfully treated TB patients. Preventive treatment of TBI reduced the risk of progression to TB by 85%, from 4.3% (15/349) to 0.6% (8/1262). In children considered uninfected, the risk of later developing TB was 0.07% (2/2733). CONCLUSIONS: The effectiveness of TB management was acceptable. Our routine procedures for the exclusion of TBI appear safe.

Chemoresistance of human monocyte-derived dendritic cells is regulated by IL-17A.

Dendritic cells initiate adaptive immune responses, leading either to control cancer by effector T cells or to exacerbate cancer by regulatory T cells that inhibit IFN-γ-mediated Th1-type response. Dendritic cells can also induce Th17-type immunity, mediated by IL-17A. However, the controversial role of this cytokine in cancer requires further investigations. We generated dendritic cells from peripheral blood monocytes to investigate lifespan, phenotype and chemoresistance of dendritic cells, treated with IL-17A with or without IFN-γ. Studying the expression of Bcl-2 family members, we demonstrated that dendritic cells constitutively express one pro-survival Bcl-2 member: MCL1. Immature dendritic cells were CD40(low)HLADR(low) CD1a(+) MCL1(+), did not express CD14, CD68 or BCL2A1, and displayed a short 2-day lifespan. IL-17A-treated DC exhibited a semi-mature (CD40(high) HLADR(low)) pre-M2 (CCL22(+) CD206(+) CD163(+) IL1RN(+) IL-10(-) CXCL10(-) IL-12(-)) mixed (CD1a(+) CD14+ CD68(+)) macrophage-dendritic cell phenotype. They efficiently exerted mannose receptor-mediated endocytosis and did not produce superoxide anions, in the absence of TLR engagement. Interestingly, IL-17A promoted a long-term survival of dendritic cells, beyond 12 days, that correlated to BCL2A1 induction, a pro-survival Bcl-2 family member. BCL2A1 transcription was activated by NF-κB, downstream of IL-17A transduction. Thus, immature dendritic cells only express MCL1, whereas IL-17A-treated dendritic cells concomitantly expressed two pro-survival Bcl-2 family members: MCL1 and BCL2A1. These latter developed chemoresistance to 11 of the 17 chemotherapy agents tested. However, high doses of either vinblastine or cytarabine decreased MCL1 expression and induced dendritic cell death. When IL-17A is produced in vivo, administration of anti-IL-17A biotherapy may impair dendritic cell survival by targeting BCL2A1 expression. Consequently, depending on the effector or regulatory role of dendritic cells, blocking IL-17A, may be either dangerous or beneficial for cancer outcomes, thus contributing to the apparent controversy around the role of IL-17A in cancer.