Protective effect of interleukin-23A (IL23A) haplotype variants on type 1A diabetes mellitus in a Brazilian population
CYTOKINE
Authors: Costa, V. S.; Santos, A. S.; Fukui, R. T.; Mattana, T. C. C.; Matioli, S. R.; Silva, M. E. R.
Abstract
The Interleukin 23 (IL-23) has a central role in autoimmunity. Allelic variants of p19 subunit of IL-23 (IL23A) and IL-23 receptor. (IL23R) genes and increased IL-23 serum concentrations were associated with autoimmune diseases. We therefore searched for variants of IL23A and IL23R that could predispose to Type 1 diabetes (T1D). The coding regions and boundary intron sequences of IL23A were sequenced. Variants of IL23A and of IL23R were also genotyped. Pancreatic and extrapancreatic autoantibodies and IL-23 serum levels were determined. The cohort involved 370 patients with T1D and 351 healthy control subjects. We observed only one coding IL23A variant (rs11171806 G > A) out of the 6 described in databases. As the G alleles of rs11171806 and rs2066808 variants of IL23A gene were in strong linkage disequilibrium (D' = 0.825 for controls, p < 2.0 x 10(-6) and D' = 0.902, p < 2.0 x 10(-17) for patients), further analyses were performed with the haplotypes. The GG haplotype was more frequent in controls (16.7%) than in T1D patients (9.5%), conferring a protection to T1D (OR = 0.53; pc = 0.0003). No association was found between IL23A allelic variants with age at diagnosis of diabetes, C-peptide levels or frequency of autoantibodies. IL23R variants (rs10889677 and rs11209026) frequency and IL-23 serum concentrations were similar between groups. The GG haplotype of IL23A variants (rs11171806 and rs2066808) was protective against T1D. IL23R variants (rs11209026 and rs10889677) were not associated with T1D. IL-23 serum concentrations did not differ between groups. (C) 2013 Elsevier Ltd. All rights reserved.
Changes in Gene Expression Pattern of Human Primary Macrophages Induced by Carbosilane Dendrimer 2G-NN16
PHARMACEUTICAL RESEARCH
Authors: Gras, Rafael; Almonacid, Luis; Ortega, Paula; Serramia, Maria J.; Gomez, Rafael; Javier de la Mata, F.; Lopez-Fernandez, Luis A.; Angeles Munoz-Fernandez, M.
Abstract
The use of dendrimers for biomedical applications has emerged with promising results. 2G-NN16 is a carbosilane dendrimer with sixteen positive charges per molecule tested to be capable to bind and release antisense oligonucleotides (ODNs) and small interference RNA (siRNA) in vitro. In spite of low cytotoxicity observed for these dendrimers, little is known about cellular changes they produce in cells in general and in immune cells in particular. Genomic technologies allow us to identify global gene expression profile changes in macrophages exposed to a non-toxic concentration (5 A mu M) of 2G-NN16, alone or complexed with a random siRNA (dendriplex). Results were confirmed by quantitative real-time RT-PCR. Exposing macrophages to this dendrimer or dendriplex causes multiple gene expression changes, but no specific action of random siRNA was detected. Pathway analysis of differentially expressed genes shows the altered functions to be immune response, proliferation and transcription regulation. Interleukin 17F (IL17F) was the most regulated gene. Global gene expression profiles are a highly sensitive method to measure the toxicity degree of a gene delivery vehicle. The strong repression of IL17F, IL23R and IL23A, all of which are involved in autoimmune disease, by this particular dendrimer suggests a potential pharmacological application.