Nasal IL-13 production identifies patients with late phase allergic responses

BACKGROUND: There is limited knowledge on how local cytokine secretion patterns after nasal allergen challenge correlate with clinical symptoms especially with regards to the "late allergic response" (LAR) which occurs in approximately 40-50% of allergic patients. OBJECTIVE: In this study we aimed to characterise the immunological and clinical nasal responses to birch pollen allergen challenge with a special focus on the LAR. METHODS: In this randomised double-blinded placebo-control trial, birch pollen allergic participants were challenged with pollen extract (n=20) or placebo (n=10) on three consecutive days. On days one and three nasal secretions were collected at selected time points over a 24h time course for the measurement of 33 inflammatory mediators. Clinical responses were determined through subjective symptom scores and objective nasal airflow measurements. RESULTS: Provoked participants had significantly greater clinical responses and showed significant increases in tryptase and sST2 within minutes compared to placebo. Eight out of 20 provoked participants displayed high IL-13 levels 2-8 hours after allergen provocation. This group also showed significant changes in clinical parameters, with a secondary drop in nasal airflow measured by peak nasal inspiratory flow and increased symptoms of nasal obstruction which significantly differed from IL-13 non responders at 6 hours. CONCLUSION: IL-13 response status correlates with cytokine and clinical responses in the late phase after allergen provocation

APC/CCdh1-Mediated Degradation of the F-Box Protein NIPA Is Regulated by Its Association with Skp1

NIPA (Nuclear Interaction Partner of Alk kinase) is an F-box like protein that targets nuclear Cyclin B1 for degradation. Integrity and therefore activity of the SCFNIPA E3 ligase is regulated by cell-cycle-dependent phosphorylation of NIPA, restricting substrate ubiquitination to interphase. Here we show that phosphorylated NIPA is degraded in late mitosis in an APC/CCdh1-dependent manner. Binding of the unphosphorylated form of NIPA to Skp1 interferes with binding to the APC/C-adaptor protein Cdh1 and therefore protects unphosphorylated NIPA from degradation in interphase. Our data thus define a novel mode of regulating APC/C-mediated ubiquitination

Role of monofunctional TNF-alpha producing CD4 T cells in chronic hepatitis B.

Chronic hepatitis B is associated with an impaired HBV-specific T-cell response that is not sufficient to clear HBV, but contributes to its immunopathogenesis.  We monitored ex vivo T-cell responses in patients with chronic HBV infection under nucleos(t)ide analogue therapy using 10-color flow cytometry. Thereby we observed a yet undescribed monofunctional CD4 T-cell subpopulation producing TNF-alpha (CD4TNF-mono), but not IFN-gamma, IL-2 or MIP1-beta, in the absence of antigen restimulation ex vivo. We determined significantly lower frequencies of CD4TNF-mono T cells in healthy, HBV naϊve individuals (median 0.15%) and individuals with resolved hepatitis B (median 0.13%) compared to patients suffering from acute or chronic hepatitis B (median 0.29% and 0.25%, respectively). CD4TNF-mono T cells were also detectable in patients with HCV (median 0.35%) or HIV (median 0.52%) monoinfection and HIV/HCV (median 0.35%) or HIV/HBV (median 0.45%) coinfection. PEG-IFN-alpha treatment of chronic hepatitis B and C patients significantly increased frequency of CD4TNF-mono T cells compared to non-treatment (p=0.004 and 0.012, respectively). Phenotypic analysis of CD4TNF-mono T cells revealed an antigen-experienced CD4 memory T-cell phenotype (CD45RO+/CD45RA-) mainly secreting soluble TNF-alpha. The cells do not express activation (TNF-R2, 4-1BB, Ox40) or exhaustion (PD-1, Tim-3, CTLA-4) marker, and do not belong to the subpopulation of regulatory T cells. CD4TNF-mono T-cell lines from patients with chronic hepatitis B did not react to restimulation with HBV antigens suggesting that CD4TNF-mono T cells are not HBV-specific. Based on these results we propose that CD4TNF-mono T cells represent a not yet described bystander T-cell population in patients with chronic viral infections, which may contribute to the inflammatory response