Frontiers in immunology
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Frontiers in immunology · Jan 2018
Clinical TrialA Novel Vaccine Strategy Employing Serologically Different Chimpanzee Adenoviral Vectors for the Prevention of HIV-1 and HCV Coinfection.
Background: Nearly 3 million people worldwide are coinfected with HIV and HCV. Affordable strategies for prevention are needed. We developed a novel vaccination regimen involving replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by modified vaccinia Ankara (MVA) boosts, for simultaneous delivery of HCV non-structural (NSmut) and HIV-1 conserved (HIVconsv) region immunogens. ⋯ Conclusions: Serologically distinct adenoviral vectors encoding HCV and HIV-1 immunogens can be safely co-administered without reducing the immunogenicity of either vaccine. This provides a novel strategy for targeting these viruses simultaneously and for other pathogens that affect the same populations. Clinical trial registration: https://clinicaltrials.gov, identifier: NCT02362217.
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Frontiers in immunology · Jan 2018
Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry.
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. ⋯ Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.
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Frontiers in immunology · Jan 2018
Analysis of Serum Interleukin (IL)-1β and IL-18 in Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by biological and clinical heterogeneity. The interleukin (IL)-1 superfamily is a group of innate cytokines that contribute to pathogenesis in many autoimmune diseases. IL-1β and IL-18 are two members that have been shown to play a role in murine lupus-like models, but their role in human SLE remains poorly understood. ⋯ High baseline serum IL-18 levels were associated with organ damage at the subsequent visit. Serum IL-1β levels were not significantly elevated in SLE patients when compared to HCs and had no association with overall or organ-specific disease activity or organ damage in cross-sectional and longitudinal analyses. Our data suggest that serum IL-18 and IL-1β have different clinical implications in SLE, with IL-18 being potentially associated with active renal disease.
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Frontiers in immunology · Jan 2018
Host Defense Peptide LL-37-Mediated Chemoattractant Properties, but Not Anti-Inflammatory Cytokine IL-1RA Production, Is Selectively Controlled by Cdc42 Rho GTPase via G Protein-Coupled Receptors and JNK Mitogen-Activated Protein Kinase.
The human host defense peptide LL-37 promotes immune activation such as induction of chemokine production and recruitment of leukocytes. Conversely, LL-37 also mediates anti-inflammatory responses such as production of anti-inflammatory cytokines, e.g., IL-1RA, and the control of pro-inflammatory cytokines, e.g., TNF. The mechanisms regulating these disparate immunomodulatory functions of LL-37 are not completely understood. ⋯ We demonstrate that LL-37 facilitates chemokine production and leukocyte recruitment engaging Cdc42/Rac1 Rho GTPase via GPCR and the JNK MAPK pathway. In contrast, LL-37-mediated anti-inflammatory cytokine IL-1RA production is independent of either Rho or Ras GTPase. The results of this study suggest that Cdc42 Rho GTPase may be the molecular switch that controls the opposing functions of LL-37 in the process of inflammation.
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Frontiers in immunology · Jan 2018
Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis.
Surfactant proteins (SP) are involved in surfactant function and innate immunity in the human lung. Both lung function and innate immunity are altered in CF, and altered SP levels and genetic association are observed in Cystic Fibrosis (CF). We hypothesized that single nucleotide polymorphisms (SNPs) within the SP genes associate with CF or severity subgroups, either through single SNP or via SNP-SNP interactions between two SNPs of a given gene (intragenic) and/or between two genes (intergenic). ⋯ The results showed (a) Two SNPs, SFTPB rs7316 (p = 0.0083) and SFTPC rs1124 (p = 0.0154), each associated with CF. (b) Three intragenic SNP-SNP interactions, SFTPB (rs2077079, rs3024798), and SFTPA1 (rs1136451, rs1059057 and rs4253527), associated with CF. (c) A total of 34 intergenic SNP-SNP interactions among the 4 SP genes to be associated with CF. (d) No SNP-SNP interaction was observed between SFTPA1 or SFTPA2 and SFTPD. (e) Equal number of SNP-SNP interactions were observed between SFTPB and SFTPA1/SFTPA2 (n = 7) and SP-B and SFTPD (n = 7). (f) SFTPC exhibited significant SNP-SNP interactions with SFTPA1/SFTPA2 (n = 11), SFTPB (n = 4) and SFTPD (n = 3). (g) A single SFTPB SNP was associated with mild CF after Bonferroni correction, and several intergenic interactions that are associated (p < 0.01) with either mild or moderate/severe CF were observed. These collectively indicate that complex SNP-SNP interactions of the SP genes may contribute to the pulmonary disease in CF patients. We speculate that SPs may serve as modifiers for the varied progression of pulmonary disease in CF and/or its severity.