Affinity-Purified Respiratory Syncytial Virus Antibodies from Intravenous Immunoglobulin Exert Potent Antibody-Dependent Cellular Cytotoxicity

Mixed infections are one of the major therapeutic challenges, as the current strategies have had limited success. One of the most common and widespread conditions of mixed infection is respiratory syncytial virus-mediated pathology of the respiratory tract in children. There is a dire need for the development of novel therapeutic approaches during mixed infections. Therapeutic intravenous immunoglobulin preparations, obtained from plasma pools of healthy donors have been used in immune deficiencies. This study was thus designed to characterize the functional efficacy of RSV-specific antibodies in IVIg. To explore the functional ability of these affinity-purified RSV-specific antibodies, the antibody-dependent and complement dependent cytotoxicity was determined using peripheral cells of healthy donors. This study demonstrates the existence of highly potent RSV-specific antibodies in IVIg preparations and provides the basis for the use of IVIg as broad-spectrum protective shield to RSV-infected children during mixed infections

Replication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample

A recent genomewide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case-Control Study of Schizophrenia (ICCSS) sample (N=1021 cases, 626 controls). Following consultation with the original investigators we genotyped 3 of the most promising SNPs from the Cardiff study. We replicate association with rs1344706 (trend test one tailed p=0.0113 with the previously associated A allele) in ZNF804A. We detect no evidence of association with rs6490121 in NOS1 (one tailed p=0.21), and only a trend with rs9922369 in RGRIP1L (one tailed p=0.0515). Based on these results, we completed genotyping of 11 additional LD-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass QC criteria and 4 are nominally associated, with our most significant evidence of association at rs7597593 (p=0.0013) followed by rs1344706. We observe no evidence of differential association in ZNF804A based on family history or sex of case. The associated SNP rs1344706 lies in ~30 bp of conserved mammalian sequence and the associated A allele is predicted to maintain binding sites for the brain-expressed transcription factors MYT1L and POU3F1/OCT-6. In controls, expression is significantly increased from the A allele of rs1344706 compared to the C allele. Expression is increased in schizophrenic cases compared to controls, but this difference does not achieve statistical significance. This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the the A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia

Influence of Respiratory Syncytial Virus Strain Differences on Pathogenesis and Immunity

Molecular epidemiology studies have provided convincing evidence of antigenic and sequence variability among respiratory syncytial virus (RSV) isolates. Circulating viruses have been classified into two antigenic groups (A and B) that correlate with well-delineated genetic groups. Most sequence and antigenic differences (both inter- and intra-groups) accumulate in two hypervariable segments of the G protein gene. Sequences of the G gene have been used for phylogenetic analyses. These studies have shown a worldwide distribution of RSV strains with both local and global replacement of dominant viruses with time. Although data are still limited, there is evidence that strain variation may contribute to differences in pathogenicity. In addition, there is some but limited evidence that RSV variation may be, at least partially, immune (antibody) driven. However, there is the paradox in RSV that, in contrast to other viruses (e.g., influenza viruses) the epitopes recognized by the most effective RSV-neutralizing antibodies are highly conserved. In contrast, antibodies that recognize strain-specific epitopes are poorly neutralizing. It is likely that this apparent contradiction is due to the lack of a comprehensive knowledge of the duration and specificities of the human antibody response against RSV antigens. Since there are some data supporting a group- (or clade-) specific antibody response after a primary infection in humans, it may be wise to consider the incorporation of strains representative of groups A and B (or their antigens) in future RSV vaccine development