Investigating the Mechanism Of Autoimmune Disease Associated LQTS; anti‐Ro52 IgG Decreases hERG Channel Density
Bibliographic record
Abstract
Background The human ether‐a‐go‐go‐related gene (hERG) is the pore forming subunit of Kv11.1, which is responsible for the rapidly activating delayed rectifier potassium current (I Kr ). Reductions to I hERG through mutations or drug interactions can cause LQTS, which predisposes individuals to ventricular arrhythmia's and sudden cardiac death. hERG has been speculated to be involved in autoimmune disease‐associated LQTS, however the mechanism is poorly understood. In 2006, a Japanese group reported an anti‐Ro52 IgG positive patient with LQTS and accompanying torasdes de pointes. The patient's serum was found to reduce the human ether‐a‐go‐related gene (hERG) channel density in a stable cell line. The authors speculated that anti‐Ro52 underwent a cross reaction with hERG, leading the production of anti‐hERG IgG. Here we investigate in detail this proposed mechanism, and provide strong evidence that anti‐Ro52 IgG reduces hERG channel density and current. Methods Human embryonic kidney (HEK 293) cell lines stably expressing the channel of interest were treated with anti‐Ro52 IgG (Sigma, 4 μg/ml) for 24 h, while saline treated cells served as control. Western blot analysis was used to quantify changes in protein expression, and whole cell patch clamp was performed to quantify changes in current. Results We report that anti‐Ro52 IgG reduced hERG channel density and current. This was unique to hERG in that Kv1.5 and EAG channel density and current were not affected by IgG. Replacing the extracellular S5‐pore linker with that of EAGs instilled immunity to IgG treatment. Furthermore, anti‐Ro52 IgG treatment reduced IKr in rat neonatal cardiomyocytes, significantly increased the APD90, but did not affect other native currents. Our data suggest that IgG decreased hERG membrane expression through inducing channel internalization. Digestion of anti‐Ro52 and isolation of the Fab and Fc fragments revealed that the Fc region of IgG is responsible for reducing hERG. Finally, we are currently testing the effects of IgG positive and negative autoimmune patient serum on the QTc interval of rabbits. Conclusion Our findings provide strong evidence that anti‐Ro52 IgG is responsible for autoimmune disease associated‐LQTS, which mechanistically occurs through a reduction of the hERG current due to IgG‐mediated channel internalization. Support or Funding Information Funded by CIHR and Heart and Stroke
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".