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Zhao, Jian,Giles, Brendan M,Taylor, Rhonda L,Yette, Gabriel A,Lough, Kara M,Ng, Han Leng,Abraham, Lawrence J,Wu, Hui,Kelly, Jennifer A,Glenn, Stuart B,Adler, Adam J,Williams, Adrienne H,Comeau, Mary E H. K. Lewis 2016 Annals of the rheumatic diseases Vol.75 No.1
<P><B>Objectives</B></P><P>Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (<I>CR2/CD21</I>) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.</P><P><B>Methods</B></P><P>Genotyped and imputed genetic variants spanning <I>CR2</I> were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.</P><P><B>Results</B></P><P>The strongest association signal was detected at rs1876453 in intron 1 of <I>CR2</I> (p<SUB>meta</SUB>=4.2×10<SUP>−4</SUP>, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control p<SUB>meta</SUB>=7.6×10<SUP>−7</SUP>, OR 0.71; case-only p<SUB>meta</SUB>=1.9×10<SUP>−4</SUP>, OR 0.75). Although allele-specific effects on B cell <I>CR2</I> mRNA or protein levels were not identified, levels of complement receptor 1 (<I>CR1/CD35)</I> mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.</P><P><B>Conclusions</B></P><P>These data suggest that rs1876453 in <I>CR2</I> has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.</P>
Neutralization Sensitivity of a Novel HIV-1 CRF01_AE Panel of Infectious Molecular Clones
Chenine, Agnes-Laurence,Merbah, Melanie,Wieczorek, Lindsay,Molnar, Sebastian,Mann, Brendan,Lee, Jenica,O’Sullivan, Anne-Marie,Bose, Meera,Sanders-Buell, Eric,Kijak, Gustavo H.,Herrera, Carolina,McLind Wolters Kluwer Health, Inc. All rights reserved. 2018 Journal of acquired immune deficiency syndromes Vol.78 No.3
<P>Conclusions: This novel panel of CRFOl_AE reporter IMC is useful for assessing vaccine-induced neutralizing antibodies in multiple assays, including those using primary cell targets. The significant differences in TZM-bl and A3R5 neutralization sensitivity, as well as the poor association when using polyclonal sera indicates the need for caution in choosing one specific platform.</P>