Search

The IL‐1 family member IL‐38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL‐38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL‐38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19+ B cells from PBMC was lower, whereas cell‐associated IL‐38 expression was comparable. In vitro, IL‐38 is released from CD19+ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL‐38, compared to 100‐fold induction of IL‐6 and IL‐1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL‐38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL‐38 also correlated inversely with high sensitivity C‐reactive protein (p < 0.01), IL‐6, IL‐1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL‐38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL‐38 as an anti‐inflammatory cytokine. [ABSTRACT FROM AUTHOR]

Since Streptococcus pneumoniae transmits through droplet spread, this respiratory tract pathogen may be able to survive in saliva. Here, we show that saliva supports survival of clinically relevant S. pneumoniae strains for more than 24 h in a capsule-independent manner. Moreover, saliva induced growth of S. pneumoniae in growth-permissive conditions, suggesting that S. pneumoniae is well adapted for uptake of nutrients from this bodily fluid. By using Tn-seq, a method for genome-wide negative selection screening, we identified 147 genes potentially required for growth and survival of S. pneumoniae in saliva, among which genes predicted to be involved in cell envelope biosynthesis, cell transport, amino acid metabolism, and stress response predominated. The Tn-seq findings were validated by testing a panel of directed gene deletion mutants for their ability to survive in saliva under two testing conditions: at room temperature without CO2, representing transmission, and at 37°C with CO2, representing in-host carriage. These validation experiments confirmed that the plsX gene and the amiACDEF and aroDEBC operons, involved in respectively fatty acid metabolism, oligopeptide transport, and biosynthesis of aromatic amino acids play an important role in the growth and survival of S. pneumoniae in saliva at 37°C. In conclusion, this study shows that S. pneumoniae is well-adapted for growth and survival in human saliva and provides a genome-wide list of genes potentially involved in adaptation. This notion supports earlier evidence that S. pneumoniae can use human saliva as a vector for transmission. [ABSTRACT FROM AUTHOR]

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19 + B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19 + B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine., (© 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Objectives: To investigate ex-vivo drug-inhibited cytokine production before the start of a biological DMARD (bDMARD) as predictor of treatment response in rheumatoid arthritis (RA)., Methods: In a prospective RA cohort study [BIO-TOP], blood samples were obtained from patients before the start of a bDMARD (abatacept, adalimumab, etanercept, rituximab or tocilizumab). Peripheral blood mononuclear cells were pre-incubated for 1 hour with the therapeutic in-vivo concentration of the bDMARD and stimulated for 24 hours with heat-killed Candida albicans or Pam3Cys. Concentrations of IL-1β, IL-6, TNFα, IL-17 and IFNγ were determined by ELISA. EULAR response (good vs. moderate/no) was assessed at month 6. Area under the receiver operating characteristic curves (AUCs) were generated to evaluate the predictive value of baseline characteristics and ex-vivo cytokine production (including stimulated cytokine concentrations and absolute changes after inhibition by a bDMARD). Logistic prediction models were created to assess the added value of potential cytokine predictors., Results: 277 RA patients were included with 330 blood samples. Good response was reached in 39% of the cases. DAS28-CRP was predictive for response to adalimumab (AUC 0.70, 95%CI 0.57-0.83), etanercept (AUC 0.68, 95%CI 0.58-0.78) and rituximab (AUC 0.76, 95%CI 0.65-0.86). ACPA was modestly predictive for response to abatacept (AUC 0.63, 95%CI 0.52-0.75). In the ex-vivo analysis, 4 of 64 (6%) tests showed some predictive value but these had no added value to clinical factors routinely measured in RA, such as DAS28-CRP., Conclusions: Ex-vivo inhibition of cytokine production by bDMARDs is unable to help prediction of treatment response to bDMARDs in RA.

Objectives: Clinical data suggest that the response of rheumatoid arthritis patients to treatment with golimumab is much lower among those who switched from adalimumab than among those who switched from etanercept. To elucidate the mechanism behind this difference in response to sequential biologic treatment, we examined the effect of TNF inhibitors on ex vivo cytokine production profiling., Methods: In a prospective cohort study, blood samples were obtained from patients before the start of a biologic. Peripheral blood mononuclear cells were pre-incubated for 1 hour with the therapeutic in vivo concentration of adalimumab, etanercept or golimumab and stimulated for 24 hours with heat killed Candida albicans or Pam3Cys. Cytokine concentrations of IL-1β, IL-6 and TNFα were determined by ELISA., Results: Ex vivo cytokine profiling was performed in 71 patients. Golimumab, adalimumab and etanercept significantly (p<0.01) decreased Candida albicans-induced IL-1β and IL-6 production and Pam3Cys-induced IL-6 production. In contrast to etanercept, golimumab and adalimumab decreased the concentration of TNFα below the detection limit. Absolute changes in cytokine levels after inhibition by golimumab or adalimumab were all significantly correlated (Spearman rank rs: 0.52-0.99, p<0.001). These correlations were much lower or non-significant between etanercept and either golimumab or adalimumab., Conclusions: High similarity between ex vivo inhibited cytokine profiling by golimumab and adalimumab, compared to etanercept, may explain the previously found inferior treatment response to golimumab after adalimumab failure. This suggests that patients who are non-responsive to adalimumab should preferably not switch to golimumab and vice versa.