Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus.

The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising "universal" influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.

Abnormal regulation of the antiviral response in neurological/neurodegenerative diseases.

Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis are a few examples of debilitating neurological/neurodegenerative diseases for which there are currently no curative treatments. Recent evidence has strongly suggested a role for neuroinflammation in both the onset and progression of these diseases. However, the mechanisms that initiate neuroinflammation are presently unclear. Mounting evidence suggests that environmental factors are likely involved. One proposed mechanism linking both genetic and environmental factors is dysregulation of the antiviral response. Indeed, many mutations that have been linked to neurological conditions occur in genes related to the antiviral response. Although the products of these genes may have potent antiviral activities - they can also have deleterious effects when their expression is not appropriately regulated. For that reason, expression of antiviral genes is a tightly controlled process. Herein, we review the various antiviral genes that have been linked to neurological conditions. We focus specifically on type I interferonopathies, the symptoms of which are often evident at birth, and neurodegenerative diseases, which frequently onset later in life.