The Informational Commons at Risk (Working Paper 8)

Conventional wisdom says that we are on the cusp of a Global Information Society, in which new technologies will provide citizens with unprecedented access to information. This is an appealing but flawed vision of the future. Governments are still reluctant to disclose information about core functions. At the same time, neoliberal reforms have caused a diffusion of power across sectors and borders, confounding efforts to promote governmental openness. Economic liberalization has also made it more difficult to enforce corporate disclosure requirements. Meanwhile, technological change has spurred efforts by businesses and citizens to strengthen their control over corporate and personal information. Efforts to defend the borders of the “informational commons” — the domain of publicly-accessible information — will be also be complicated by problems of policy design and political mobilization. Imposing transparency requirements was easier when authority was closely held by national and sub-national governments. The task is more difficult when power is widely diffused.

INVESTIGATING THE MECHANISM OF AUTOIMMUNE DISEASE ASSOCIATED-LQTS

The human ether-a-go-go-related gene (hERG) protein passes the rapidly activating delayed rectifier potassium channel (IKr), and malfunction of hERG protein/IKr is the primary cause of acquired long QT syndrome (LQTS). Autoimmune diseases are significantly correlated with prolonged QT intervals, for which autoantibodies have been implicated. The anti-Ro52 autoantibody is the most frequently evaluated, and importantly has been correlated with prolonged QT intervals. Pathological anti-Ro52-hERG interactions have been discussed as a mechanism for autoimmune disease-related LQTS. However, the mechanism is unclear, and it does not explain LQTS in autoimmune diseases which do not commonly express anti-Ro52. In this thesis, I investigated the effects of anti-Ro52 on hERG/IKr function. Through Western blot analysis, whole-cell patch-clamp, and immunofluorescence, I show that anti-Ro52 chronically (12 h) reduced hERG protein expression and hERG current by over 50%, but did not acutely block the channel. My work revealed a novel mechanism in which the Fc portion of anti-Ro52 interacts with the extracellular S5-pore linker of the channel to induce internalization through a tyrosine phosphorylation dependent pathway. This phenomenon extends beyond anti-Ro52 IgG, as other IgG, regardless of their antigen binding specificity, have the potential to reduce hERG expression/current. Rather, the ability of IgG to reduce hERG expression and current is dependent on the IgG subclass, as we show mouse IgG2A was the only mouse IgG subclass which reduced hERG expression. These results provide a novel explanation for autoimmune disease associated LQTS. It also has implications in the development of safe monoclonal antibody drugs.