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Background Respiratory infections, in general, and rhinovirus infection specifically are the main reason for asthma exacerbation in children and programmed cell death protein 1 ligand (PD‐L1) expression inhibits T cell responses. Objective Could the interferon (IFN) type I expression in peripheral blood mononuclear cells (PBMCs) improve disease exacerbation in pediatric asthma? Results Here we found increased level of PD‐L1 messenger RNA (mRNA) in total blood cells isolated from preschool children with virus‐induced asthma, with lower percentage of forced expiratory volume in 1 second and with high serum levels of the C‐reactive‐protein. Conclusions and Clinical Relevance These data indicate that, in the presence of infection in the airways of preschool children, worse asthma is associated with induced PD‐L1 mRNA expression in blood cells. Further, type I IFN, IFN‐β, a cytokine that is involved in the clearance of infections, was found to be associated with a better lung function in asthmatic children. These data suggest that improving peripheral blood IFN type I expression in PBMCs in pediatric asthma could improve disease exacerbation due to suppressing PD‐L1 expression in blood cells., Here we found increased level of programmed cell death protein 1 ligand (PD‐L1) messenger RNA (mRNA) in total blood cells isolated from preschool children with virus‐induced asthma, with lower percentage of forced expiratory volume in 1 second (FEV1%) and with high serum levels of the C‐reactive‐protein (CRP).Further, the activation of regulatory elements that induce interferon‐β (IFNβ), a cytokine that is involved in immunity of infections, was found to be associated with better lung function in asthmatic children.Finally, IFN‐β released by peripheral blood mononuclear cells (PBMCs) was found associated with an induced expression of PD‐L1 mRNA in control but no asthmatic children.

Here we investigated the role of NFAT-interacting protein (NIP)-45, an Interleukin (IL)-4 inducing Transcription Factor, and its impact on the differentiation of Group 2 Innate -Lymphoid -Cells (ILC2s) in the pathogenesis of asthma. NIP45, a transcription factor regulating NFATc1 activity, mRNA was found to be induced in the Peripheral Blood mononuclear cells (PMBCs) of asthmatic pre-school children with allergies and in the peripheral blood CD4+ T cells from adult asthmatic patients. In PBMCs of asthmatic and control children, NIP45 mRNA directly correlated with NFATc1 but not with T-bet. Targeted deletion of NIP45 in mice resulted in a protective phenotype in experimental asthma with reduced airway mucus production, airway hyperresponsiveness and eosinophils. This phenotype was reversed by intranasal delivery of recombinant r-IL-33. Consistently, ILC2s and not GATA3+ CD4+ T-cells were decreased in the lungs of asthmatic NIP45−/− mice. Reduced cell number spleen ILC2s could be differentiated from NIP45−/− as compared to wild-type mice after in vivo injection of a microcircle-DNA vector expressing IL-25 and decreased cytokines and ILC2 markers in ILC2 differentiated from the bone marrow of NIP45−/− mice. NIP45 thus emerges as a new therapeutic target for the resolution of the airway pathology, down-regulation of ILC2s and mucus production in asthma.

There is a significantly higher risk for type II diabetes in HIV-1 carriers, albeit the molecular mechanism for this HIV-related pathology remains enigmatic. The 52 amino acid HIV-1 p6 Gag protein is synthesized as the C-terminal part of the Gag polyprotein Pr55. In this context, p6 promotes virus release by its two late (L-) domains, and facilitates the incorporation of the viral accessory protein Vpr. However, the function of p6 in its mature form, after proteolytic release from Gag, has not been investigated yet. We found that the mature p6 represents the first known viral substrate of the ubiquitously expressed cytosolic metalloendopeptidase insulin-degrading enzyme (IDE). IDE is sufficient and required for degradation of p6, and p6 is approximately 100-fold more efficiently degraded by IDE than its eponymous substrate insulin. This observation appears to be specific for HIV-1, as p6 proteins from HIV-2 and simian immunodeficiency virus, as well as the 51 amino acid p9 from equine infectious anaemia virus were insensitive to IDE degradation. The amount of virus-associated p6, as well as the efficiency of release and maturation of progeny viruses does not depend on the presence of IDE in the host cells, as it was shown by CRISPR/Cas9 edited IDE KO cells. However, HIV-1 mutants harboring IDE-insensitive p6 variants exhibit reduced virus replication capacity, a phenomenon that seems to depend on the presence of an X4-tropic Env. Furthermore, competing for IDE by exogenous insulin or inhibiting IDE by the highly specific inhibitor 6bK, also reduced virus replication. This effect could be specifically attributed to IDE since replication of HIV-1 variants coding for an IDE-insensitive p6 were inert towards IDE-inhibition. Our cumulative data support a model in which removal of p6 during viral entry is important for virus replication, at least in the case of X4 tropic HIV-1.

Asthma bronchiale is a disease of the airways with increasing incidence, that often begins during infancy. So far, therapeutic options are mainly symptomatic and thus there is an increasing need for better treatment and/or prevention strategies. Human rhinoviruses (HRVs) are a major cause of asthma exacerbations and might cause acute wheezing associated with local production of pro-inflammatory mediators resulting in neutrophilic inflammatory response. Viral infections induce a characteristic activation of immune response, e.g., TLR3, 4, 7, 8, 9 in the endosome and their downstream targets, especially MyD88. Moreover, other cytoplasmic pattern recognition molecules (PRMs) like RIG1 and MDA5 play important roles in the activation of interferons (IFNs) of all types. Depending on the stimulation of the different PRMs, the levels of the IFNs induced might differ. Recent studies focused on Type I IFNs in samples from control and asthma patients. However, the administration of type I IFN-α was accompanied by side-effects, thus this possible therapy was abandoned. Type III IFN-λ acts more specifically, as fewer cells express the IFN-λ receptor chain 1. In addition, it has been shown that asthmatic mice treated with recombinant or adenoviral expressed IFN-λ2 (IL–28A) showed an amelioration of symptoms, indicating that treatment with IFN-λ might be beneficial for asthmatic patients.

Hintergründe und Ziele: Das Kolorektale Karzinom (CRC) stellt mit einer Inzidenz von 570.000 Fällen pro Jahr eine der häufigsten Karzinomerkrankungen dar. Patienten mit Colitis ulcerosa weisen ein deutlich höheres Risiko auf, an einem CRC zu erkranken. In dieser Studie wurden Vorstufen des Kolonkarzinoms bei Colitis-Patienten auf verschiedene molekulare Marker hin untersucht. Dabei wurden zum einen die Eigenschaften von klassischen Adenomen denen der serratierten Polypen gegenübergestellt. Zum anderen wurden sporadische Läsionen mit den entzündungs-assoziierten IEN verglichen. Hinsichtlich der molekularen Marker wurden drei inhaltliche Schwerpunkte gesetzt, Malignitätsmarker, DNA-Reparaturmechanismen und Differenzierungsmarker. Material und Methoden: 182 Läsionen von 139 Patienten mit Colitis-ulcerosa wurden immunhistochemisch analysiert und nach der prozentualen Anfärbung der Läsion und der Intensität bewertet. Statistische Auswertungen erfolgten mit T-Tests für unabhängige Stichproben sowie univariater Varianzanalysen (ANOVA) mit Posthoctests (Dunnett T3). P-Werte