The host genetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have previously been studied based on cases from the earlier waves of the pandemic in 2020 and 2021, identifying 51 genomic loci associated with infection and/or severity. SARS-CoV-2 has shown rapid sequence evolution, increasing transmissibility, particularly for Omicron variants, which raises the question of whether this affected the host genetic factors. We performed a genome-wide association study of SARS-CoV-2 infection with Omicron variants, including more than 150,000 cases from four cohorts. We identified 13 genome-wide significant loci, of which only five were previously described as associated with SARS-CoV-2 infection. The strongest signal was a single nucleotide polymorphism in an intron of ST6GAL1, a gene affecting immune development and function, connected to three other associated loci (harboring MUC1, MUC5AC and MUC16) through O-glycan biosynthesis. Our study provides robust evidence for individual genetic variation related to glycosylation, translating into susceptibility to SARS-CoV-2 infections with Omicron variants. Genome-wide analyses identify 13 loci associated with susceptibility to infection with SARS-CoV-2 Omicron variants, including variation in ST6GAL1, previously associated with influenza susceptibility, and other genes involved in glycosylation processes.

The JAK2V617F mutation is associated with increased cardiovascular risk, including ischaemic stroke. This study investigates the prevalence of additional mutations in ischaemic cerebrovascular patients with and without JAK2V617F to better understand the mechanisms contributing to thrombotic risk. We examined 63 patients with the JAK2V617F mutation and 126 matched controls from a cohort of 591 ischaemic cerebrovascular patients. Somatic mutations were assessed using targeted next-generation sequencing (NGS). Serum thromboinflammatory markers were evaluated in a subset of patients. Additional somatic mutations were more common in JAK2V617F-positive patients than in controls (47.6% vs. 30.2%, p = 0.028). Patients with JAK2V617F had a higher prevalence of other mutations with variant allele frequencies (VAFs) above 10% (23.8% vs. 7.9%, p = 0.005), a pattern that persisted in cases with JAK2V617F <1% (p = 0.019). In JAK2V617F-positive patients, additional somatic mutations were associated with higher monocyte levels, even when excluding myeloproliferative neoplasms patients (p = 0.011). Patients with other clonal haematopoiesis of indeterminate potential mutations exhibited higher vascular cell adhesion molecule 1 (p = 0.027), soluble urokinase plasminogen activator receptor (p = 0.010) and IL-10 (p = 0.045), as well as higher neutrophil to lymphocyte ratio (p = 0.002). Ischaemic cerebrovascular patients with the JAK2V617F mutation more frequently harbour other somatic mutations and at higher VAF. This may reflect a more advanced clonal profile with relevance for vascular risk in JAK2V617F-positive individuals.

Endothelial damage may play a key role in several non-infectious toxicities following hematopoietic stem cell transplantation (HSCT). We explored damage to the endothelial glycocalyx in 113 children undergoing HSCT by measuring syndecan-1 plasma levels. Syndecan-1 levels were elevated in patients with severe sinusoidal obstruction syndrome (SOS) and steroid-refractory/dependent acute graft-versus-host disease, but remained low in milder cases. In patients with SOS, high syndecan-1 levels were associated with prolonged diuretic treatment and thrombocytopenia. These findings provide new insights into the pathophysiology of endothelial-related toxicities after HSCT and may lead to the development of more individualized and targeted therapeutic approaches.

BACKGROUND:Triclosan, an antibacterial agent with structural similarity to thyroxine, is used in personal and industrial products. Increasing evidence demonstrates a negative influence of triclosan on both the endocrine and the immune system. OBJECTIVES:The aim of this in vitro study was to characterize the effect of triclosan on cytokine responses of peripheral blood mononuclear cells (PBMCs). METHODS:Human PBMCs were exposed to triclosan and stimulated with lipopolysaccharide (LPS) or phytohemagglutinin-L (PHA-L) to stimulate primarily monocytes/macrophages of the innate immune system and T lymphocytes of the adaptive immune system, respectively, for 20-22 h. Cell viability was assessed. The cytokine response was quantified. Triclosan was measured in cell homogenate. RESULTS:The LPS-induced secretion of interleukin (IL)-1β and IL-10 by PBMCs was enhanced by co-incubation with 0.003, 0.3 and 3.0 µM triclosan, while the induced secretion of tumor necrosis factor (TNF)-α and IL-6 increased after co-incubation with 3.0 µM triclosan. The PHA-L-induced secretion of IL-2 was inhibited after co-exposure to 3.0 µM triclosan and of several further cytokines after co-exposure to 9.0 µM triclosan. The percentage of dead cells was increased in cultures incubated with 9 µM triclosan. After incubation of PBMCs with triclosan, triclosan was detected intracellularly. DISCUSSION:Our observations indicate a dose-dependent uptake of triclosan in PBMCs, and that triclosan enhances the cytokine secretion by LPS-stimulated PBMC, while inhibiting the pro-inflammatory response by PHA-stimulated PBMCs. Further investigations of the effect of triclosan are needed to uncover the potential risk of exposure to triclosan.

Background:Microorganisms involved in cerebral abscess (CA) and cervical necrotizing soft tissue infection (NSTI) are frequently commensals of the oral cavity. Yet, the reasons for their ability to cause severe opportunistic infections remains unknown. The purpose of this study was to evaluate the dental characteristics and examine the stimulated immune response in patients with a history of CA or cervical NSTI. Methods:This observational study includes a clinical dental examination, and the collection of blood samples from 18 previous CA patients and four previous cervical NSTI patients. Whole blood cells were stimulated with LPS, R848, Poly I:C and anti-CD3/-CD28 beads in TruCulture tubes. The concentrations of TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17A, IFN-α, and IFN-γ were subsequently measured by Luminex technology and compared with corresponding values from a healthy reference group. P-values of ≤ 0.001 were considered statistically significant. Results:For patients with previous CA, decreased production of IFN-α, IFN-γ, and IL-12 was seen after stimulation of cells with LPS and Poly I:C (p ≤ 0.001). Moreover, cells from patients with previous cervical NSTI showed decreased production of IFN-α and IFN-γ after stimulation with LPS and Poly I:C (p ≤ 0.001). Nineteen out of 22 participants (86%) had oral pathologic conditions at the dental examination. Conclusion:The cytokine secretion for the LPS- and Poly I:C-stimulus suggests an impaired proinflammatory response within the innate immune response against bacterial and viral pathogens. A high prevalence of oral pathologic conditions was found at the clinical dental examinations. However, none of the patients experienced recurrence of CA or NSTI.

Periodontitis has been suggested to play a role in the etiology of systemic lupus erythematosus (SLE). However, evidence remains limited, and the underlying mechanisms are unclear. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans are strongly linked to periodontitis. Here, we evaluate the levels of circulating antibodies against these bacteria in patients with SLE and healthy controls and analyze their association with SLE-related autoantibodies. Serum IgG antibodies against P. gingivalis, A. actinomycetemcomitans leukotoxin A (LtxA), and two control bacteria (Capnocytophaga ochracea and Escherichia coli) were quantified in 223 patients with SLE and 301 healthy controls. Data was analyzed with ANCOVA and logistic regressions adjusting for age, sex, and smoking status. Exposure to P. gingivalis and A. actinomycetemcomitans, as estimated from antibody levels, was associated with SLE (Odds Ratios (ORs) = 3.0, p = 0.0002 and OR = 2.61, p = 0.0007, respectively). An additive interaction on SLE susceptibility was observed for exposure to P. gingivalis and smoking, with an attributable proportion due to interaction (AP) = 0.72 (95% CI = 0.41-1.02). Anti-A. actinomycetemcomitans LtxA antibodies were elevated in patients positive for anti-dsDNA antibodies (p = 0.02) and nominally increased in those positive for anti-cardiolipin antibodies (p = 0.06). Elevated levels of antibodies against P. gingivalis and A. actinomycetemcomitans in patients with SLE suggest a role for these bacteria, or periodontitis, in the immunopathogenesis of SLE. An additive interaction with smoking was observed for P. gingivalis, and A. actinomycetemcomitans exposure was associated with anti-DSNA antibody positivity, supporting a link between these bacteria and SLE.

AIM:To determine (i) the parameters used by dental professionals to evaluate patients with periodontitis, (ii) the prevalence of periodontitis using different case definitions and (iii) associations between periodontitis and diabetes mellitus, cardiovascular disease and rheumatoid arthritis among adult patients in private practices in Denmark. MATERIALS AND METHODS:This nationwide descriptive study used data collected from private practices using the DentalSuite electronic dental record system between 2000 and 2022. Patients 18 years or older with a Danish social security number were included in the study. Prevalences of periodontitis were calculated using periodontal registrations and different case definitions for periodontitis. Registrations of selected comorbidities along with periodontitis, namely diabetes mellitus, cardiovascular diseases and rheumatoid arthritis, were also collected. RESULTS:A total of 1,473,428 individuals were included in the study, of whom 782,464 (53%) were females. About 302,604 (20.5%) patients complied with the periodontal probing depth ≥ 5 mm PD case definition. Furthermore, 130,688 (8.9%) patients had periodontal parameters that fulfilled the more specific 2018 AAP/EFP classification. Periodontal probing depth registrations were available for 24% of the patients. Patients identified with periodontitis had higher prevalences of the selected comorbidities compared to the population as a whole. CONCLUSIONS:In private practices in Denmark, probing pocket depth was the most frequently registered periodontal parameter used for screening and monitoring periodontitis. The selected comorbidities appeared to be more prevalent in patients with periodontitis.

Background Patients hospitalized with severe odontogenic infections (SOI) receive empiric intravenous antibiotics. Microbiological cultivation and antibiotic susceptibility testing are commonly performed, although the clinical value is debated.Objective To assess the value of routine microbiological cultivation and susceptibility testing in patients hospitalized with SOI.Design This retrospective cohort study included patients hospitalized with SOI, at the University Hospital of Copenhagen, Denmark, from November 2012 to 2019. Data on microbiological cultivation, bacterial identification and antibiotic susceptibility testing were obtained from hospital records. Statistical analysis included χ² test, Fisher's exact test, analysis of variance and logistic regression.Results A total of 384 patients were included, with microbiological data available for 243 patients. Antibiotic treatment was modified in 47 patients and in seven cases, the modification was based on cultivation and antibiotic susceptibility testing. Higher age was associated with the need for cultivation and susceptibility testing (p = 0.006). The infections were polymicrobial, predominantly involving resident oral microbiota. Streptococcus was the most frequent genus (34% of isolates). Penicillin resistance was observed in 30% of all isolates.Conclusion Testing rarely influences antibiotic management in SOI. Higher age showed limited predictive value. The high prevalence of penicillin resistance among patients with SOI warrants further investigation.

OBJECTIVE:Necrotizing soft-tissue infection (NSTI) in the head and neck area may develop from odontogenic infections. The aim of this study was to characterize patients with NSTI in the head and neck with odontogenic origin in a well-defined prospectively collected cohort.MATERIAL AND METHODS:Patients with NSTI in the head and neck, hospitalized between 2013 and 2017 at Copenhagen University Hospital and registered in the Scandinavian INFECT database were included. Medical records of identified patients and from the INFECT database were screened for a defined set of data including the primary focus of infection, comorbidities, predisposing factors, clinical and radiographic diagnostics, course of treatment, and treatment outcome.RESULTS:Thirty-five patients with NSTI in the head and neck area were included in the study. A total of 54% had odontogenic origin, primarily from mandibular molars, and 94% had radiographic signs of infectious oral conditions. Overall, comorbidities were reported in 51% with cardiovascular disease being the most prevalent. In 20%, no comorbidities or predisposing conditions could be identified. The overall 30-day mortality rate was 9%.CONCLUSIONS:More than half of NSTI cases in the head and neck region had an odontogenic origin, and special attention should be paid to infections related to mandibular molars.

BACKGROUND:The JAK2V617F mutation is a driver of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) and is also implicated in cardiovascular diseases. Thrombosis in MPN involves JAK2V617F-associated platelet activation and endothelial dysfunction, all potentially influenced by chronic inflammation. Whether the mutation affects thromboinflammatory markers similarly in non-MPN patients remains unclear. METHOD:We conducted a study involving 63 ischemic cerebrovascular patients with the JAK2V617F mutation, matched with 63 patients without the mutation. Serum samples were analyzed for 12 thromboinflammatory markers during the acute phase and at three months follow-up. RESULTS:Overall, there was no significant difference in thromboinflammatory markers between cases and controls. However, subgroup analysis of patients with a JAK2V617F allele burden ≥1 % (n = 15) showed higher levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) at baseline (p = 0.018), and elevated Interleukin-10 (IL-10) (p = 0.004) and Tumor Necrosis Factor α (TNF-α) (p = 0.018) at follow-up compared to controls. Regression analysis revealed an association between higher JAK2V617F allele burden and increased VCAM-1 at baseline (p < 0.001), and higher VCAM-1 (p = 0.012), IL-10 (p = 0.003), and TNF-α (p = 0.034) at follow-up. CONCLUSION:In ischemic cerebrovascular patients, the JAK2V617F mutation is associated with elevated markers of endothelial dysfunction and chronic inflammation. This underscores the role of inflammation in thrombosis driven by the JAK2V617F mutation.

Severe intestinal mucositis (IM) increases the risk of bloodstream infections (BSI) and inflammatory toxicity during acute lymphoblastic leukaemia (ALL) induction treatment. However, the implications of IM in subsequent ALL therapy phases after achieving remission remain unknown. This study investigated the relationship between IM (measured by plasma citrulline and the chemokine CCL20) and the development of BSI and systemic inflammation (reflected by C-reactive protein, CRP) in children with ALL during high-dose methotrexate (HDMTX) treatment, an important part of ALL consolidation therapy. The study compared patients treated according to the NOPHO ALL 2008 protocol (n = 52) and the ALLTogether1 protocol (n = 42), both with identical HDMTX procedures but different scheduling. One week post-HDMTX, citrulline dropped to median levels of 14.5 and 16.9 μM for patients treated according to the NOPHO ALL 2008 and ALLTogether1 protocols, respectively (p = 0.11). In a protocol and neutrophil count-adjusted analysis, hypocitrullinaemia (<10 μmol/L) was associated with increased odds of BSI within 3 weeks from HDMTX (OR = 26.2, p = 0.0074). Patients treated according to the NOPHO ALL 2008 protocol exhibited increased mucosal- and systemic inflammation post-HDMTX compared to patients treated according to ALLTogether1, with increased CCL20 (14.6 vs. 3.7 pg/mL, p < 0.0001) and CRP levels (10.0 vs. 1.0 mg/L, p < 0.0001). Both citrulline and CCL20 correlated with CRP for these patients (rs = -0.44, p = 0.0016 and rs = 0.35, p = 0.016, respectively). These results suggest that hypocitrullinaemia following HDMTX increases the risk of BSI, confirming previous observations from more intensive treatments. Moreover, these data indicate that the patients' vulnerability to mucositis and inflammatory toxicity after chemotherapy varies with treatment protocol.

BACKGROUND:Increasing evidence indicates that periodontitis contributes to systemic low-grade inflammation. Porphyromonas gingivalis is strongly associated with periodontitis, and antibodies against the bacterium may be used as a serological proxy to account for periodontal status, when studying diseases associated with periodontitis. The aim of the present study is to identify an easily accessible and reliable serological biomarker for determination of periodontal status and oral carriage of the bacterium. METHODS:Saliva and serum samples were collected from periodontally healthy controls (n = 27), and patients with periodontitis stage II (n = 12) or stages III or IV (n = 44). Serum levels of immunoglobulin G (IgG) antibodies against intact and fragmented P. gingivalis, recombinant gingipains (RgpA and RgpB), and the bacteria Escherichia coli and Capnocytophaga ochracea as controls were quantified with a multiplex bead-based assay. P. gingivalis was identified in saliva using quantitative polymerase chain reaction (qPCR). RESULTS:Serum IgG antibodies against P. gingivalis whole bacteria were good indicators of periodontitis (area under the curve [AUC]: 0.75, 95% confidence interval [CI]: 0.64-0.85). The same was observed for levels of antibodies against P. gingivalis fragments (AUC: 0.78, 95% CI: 0.68-0.88). Likewise, levels of antibodies against P. gingivalis whole bacteria or P. gingivalis fragments were good indicators of oral carriage of P. gingivalis (AUC: 0.92, 95% CI: 0.86-0.98 and AUC: 0.96, 95% CI: 0.92-1, respectively). Conversely, antibodies against recombinant RgpA and RgpB were not good indicators of periodontitis or oral carriage of the bacterium. None of the antibody levels differed significantly between stage II and stage III or IV periodontitis. CONCLUSION:Serum IgG antibody levels against heat-inactivated whole P. gingivalis proved to be the preferable biomarker for periodontitis and oral carriage of the bacterium.

The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1–17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients’ plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients’ systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): −1.2 SDS (−1.9 to −0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from −0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = −0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL.

We report the 2-year end-of-study results from the phase 2 COMBI II clinical trial investigating the combination treatment of ruxolitinib and low-dose pegylated interferon alfa-2a in patients with newly diagnosed polycythemia vera (PV). The primary outcome was safety and key secondary endpoints were efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF). We used the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria. The remission criteria included remissions in symptoms, splenomegaly, peripheral blood counts, and bone marrow. We included 25 patients with PV with a median age of 70 years; 5 of those had prior thromboembolic events and 3 had computed tomography-verified splenomegaly. Two patients stopped both study drugs; 1 of these due to progression to post-PV myelofibrosis, the only one with a grade 3 infection. No events of herpes zoster infections were observed. None of the patients discontinued treatment due to psychiatric symptoms. The peripheral blood cell count remission rate was 92% at 24 months. Using the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria, 14 (56%) achieved remission at 24 months; 3 (12%) achieved complete remission and 11 (44%) achieved partial remission. The following items from the Myeloproliferative Neoplasm Symptom Total Symptom Score were significantly reduced: abdominal discomfort, night sweats, itching, and bone pain. The median JAK2V617F VAF decreased from 47% (95% confidence interval [CI], 35-59) to 7% (95% CI, 3-15), and 60% of patients achieved molecular remission. In conclusion, combination treatment improved cell counts; bone marrow cellularity, and fibrosis; and decreased JAK2V617F VAF; with acceptable toxicity in patients with PV. The trial was registered at www.clinicaltrialsregister.eu as #EudraCT2018-004150-13.

Objectives: The aim was to provide an in-depth characterization of patients hospitalized with severe odontogenic infections (SOI), especially in relation to the origin of the infection. Furthermore, the aim was to generate an overview of which kind of treatment the patients had received before hospitalization and to analyze risk factors for prolonged length of hospital stay. Material and methods: The study was a retrospective cross-sectional study, which included patients hospitalized at the University Hospital of Copenhagen, Denmark, with SOI from November 2012 through 2019. Data were extracted from medical hospital records. Analysis was performed using the χ2 test, analysis of variance, multiple correspondence analysis (MCA), and logistic regression. Results: A total of 384 eligible patients were included. The most frequent origin of infection was apical periodontitis (46.9%), infection after tooth extraction (25.8%), multiple infectious foci (8.6%), and pericoronitis (6.0%). Significant differences in concomitant diseases (p = 0.017) were found between the groups of origin of infection. The MCA model showed little to no ability to generate an in-depth characterization of the group of patients. Eleven patients (2.9%) were treated with incision and drainage before hospitalization, and 131 patients (34.3%) received no kind of antibiotic before hospitalization. Conclusion: The results indicate that clusters of variables could not be related to the origin of infection. In general, patients received insufficient treatment before hospitalization. Future studies should define risk factors for developing SOI and examine dental records of dental treatment before hospitalization. Clinical relevance: To improve prehospital treatment with patients with SOI, general dental practitioners should treat the origin of the infection, attempt drainage, and optimize the prescription of antibiotics.

Primary open-angle glaucoma (POAG) is subdivided depending on eye pressure. Patients with normal-tension glaucoma (NTG) have never had high intraocular pressure (IOP) measured while patients with ocular hypertension (OHT) have high eye pressure but no signs of glaucoma. Although IOP is considered to be a risk factor for all glaucoma patients, it is reasonable to assume that other risk factors such as inflammation play a role. We aimed to characterize the proteome and cytokine profile during hypoxia in plasma from patients with NTG (n = 10), OHT (n = 10), and controls (n = 10). Participants were exposed to hypoxia for two hours, followed by 30 min of normoxia. Samples were taken before (“baseline”), during (“hypoxia”), and after hypoxia (“recovery”). Proteomics based on liquid chromatography coupled with mass spectrometry (LC–MS) was performed. Cytokines were measured by Luminex assays. Bioinformatic analyses indicated the involvement of complement and coagulation cascades in NTG and OHT. Regulation of high-density lipoprotein 3 (HDL3) apolipoproteins suggested that changes in cholesterol metabolism are related to OHT. Hypoxia decreased the level of tumor necrosis factor-α (TNF-α) in OHT patients compared to controls. Circulating levels of interleukin-1β (IL-1β) and C-reactive protein (CRP) were decreased in NTG patients compared to controls during hypoxia. After recovery, plasma interleukin-6 (IL-6) was upregulated in patients with NTG and OHT. Current results indicate an enhanced systemic immune response in patients with NTG and OHT, which correlates with pathogenic events in glaucoma. Apolipoproteins may have anti-inflammatory effects, enabling OHT patients to withstand inflammation and development of glaucoma despite high IOP.

Aim: Periodontitis is an inflammatory disease driven by opportunistic bacteria including Porphyromonas gingivalis and Fusobacterium nucleatum, where T-cell and NKT-cell responses to these bacteria in patients with periodontitis grade B or C are not fully elucidated. The objective is to determine if exaggerated proinflammatory Th-cell responses to periodontitis-associated bacteria, but not commensal bacteria, is a characteristic of increased periodontitis grade. Methods: Mononuclear cells from patients with periodontitis grade C (n = 26) or grade B (n = 33) and healthy controls (HCs; n = 26) were stimulated with P. gingivalis, F. nucleatum or the commensal bacteria, Staphylococcus epidermidis and Cutibacterium acnes. Cytokine production by different T-cell populations and FOXP3-expression by regulatory T cells were assessed by flow cytometry. Results: Compared to HCs, grade C patients had decreased frequencies of interleukin (IL)-10-producing CD4+ T cells before stimulation (p = .02) and increased frequencies of IFN-y-producing CD4+ T cells after stimulation with P. gingivalis (p = .0019). Grade B patients had decreased frequencies of FOXP3+ CD4+ T cells before (p = .030) before and after stimulation with anti-CD2/anti-CD3/anti-CD28-loaded beads (p = .047), P. gingivalis (p = .013) and S. epidermidis (p = .018). Clinical attachment loss correlated with the frequencies of IFN-y-producing Th1 cells in P. gingivalis- and F. nucleatum-stimulated cultures in grade B patients (p = .023 and p = .048, respectively) and with the frequencies of Th17 cells in P. gingivalis-stimulated cultures (p = .0062) in grade C patients. Patients with periodontitis grade C or grade B showed lower frequencies of IL-10-producing NKT cells than HCs in unstimulated cultures (p = .0043 and p = .027 respectively). Conclusions: Both periodontitis groups showed decreased frequencies of immunoregulatory T-cell and NKT cell subsets at baseline. Clinical attachment loss correlated with P. gingivalis-induced Th17-responses in grade C patients and with Th1-responses in grade B patients when cells were stimulated with P. gingivalis, supporting that dysregulated pro-inflammatory T-cell responses to periodontitis-associated bacteria contribute to the pathogenesis of periodontitis.

ObjectiveThis study aimed to compare the prevalence and incidence of polyautoimmunity between anticyclic citrullinated peptide antibody (anti-CCP)–positive and anti-CCP–negative patients with rheumatoid arthritis (RA).MethodsIn a nationwide register-based cohort study, patients with RA (disease duration ≤ 2 yrs) in the DANBIO rheumatology register with an available anti-CCP test in the Register of Laboratory Results for Research were identified. The polyautoimmunity outcome included 21 nonrheumatic autoimmune diseases identified by linkage between the Danish Patient Registry and Prescription Registry. The age- and sex-adjusted prevalence ratio (PR) was calculated by modified Poisson regression to estimate the prevalence at diagnosis in anti-CCP–positive vs anti-CCP–negative patients. The hazard ratio (HR) of polyautoimmunity within 5 years of entry into DANBIO was estimated in cause-specific Cox regression models.ResultsThe study included 5839 anti-CCP–positive and 3799 anti-CCP–negative patients with RA. At first visit, the prevalence of prespecified polyautoimmune diseases in the Danish registers was 11.1% and 11.9% in anti-CCP–positive and anti-CCP–negative patients, respectively (PR 0.93, 95% CI 0.84-1.05). The most frequent autoimmune diseases were autoimmune thyroid disease, inflammatory bowel disease, and type 1 diabetes mellitus. During a mean follow-up of 3.5 years, only a few (n = 210) patients developed polyautoimmunity (HR 0.6, 95% CI 0.46-0.79).ConclusionPolyautoimmunity as captured through the Danish National Patient Registry occurred in approximately 1 in 10 patients with RA at time of diagnosis regardless of anti-CCP status. In the years subsequent to the RA diagnosis, only a few and mainly anti-CCP–negative patients developed autoimmune disease.

Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied. We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18-3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 x 10(6)/L, P = 0.048) and na & iuml;ve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25(high)FOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 x 10(6)/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023). These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of na & iuml;ve and regulatory T cells in combination with increased peripheral T-cell exhaustion.