Induction of autoimmune response to the extracellular loop of the HERG channel pore induces QTc prolongation in guinea-pigs.
Channelopathies of autoimmune origin are novel and are associated with corrected QT (QTc) prolongation and complex ventricular arrhythmias. We have recently demonstrated that anti-SSA/Ro antibodies from patients with autoimmune diseases and with QTc prolongation on the ECG target the human ether-à-go-go-related gene (HERG) K+channel by inhibiting the corresponding current, IKr, at the pore region. Immunization of guinea-pigs with a peptide (E-pore peptide) corresponding to the extracellular loop region connecting the S5 and S6 segments of the HERG channel induces high titres of antibodies that inhibit IKr, lengthen the action potential and cause QTc prolongation on the surface ECG. In addition, anti-SSA/Ro-positive sera from patients with connective tissue diseases showed high reactivity to the E-pore peptide. The translational impact is the development of a peptide-based approach for the diagnosis and treatment of autoimmune-associated long QT syndrome.



We recently demonstrated that anti-SSA/52 kDa Ro antibodies (Abs) from patients with autoimmune diseases and corrected QT (QTc) prolongation directly target and inhibit the human ether-à-go-go-related gene (HERG) K+channel at the extracellular pore (E-pore) region, where homology with SSA/52 kDa Ro antigen was demonstrated. We tested the hypothesis that immunization of guinea-pigs with a peptide corresponding to the E-pore region (E-pore peptide) will generate pathogenic inhibitory Abs and cause QTc prolongation. Guinea-pigs were immunized with a 31-amino-acid peptide corresponding to the E-pore region of HERG. On days 10-62 after immunization, ECGs were recorded and blood was sampled for the detection of E-pore peptide Abs. Serum samples from patients with autoimmune diseases were evaluated for reactivity to E-pore peptide by enzyme-linked immunosorbent assay (ELISA), and histology was performed on hearts using Masson's Trichrome. Inhibition of the HERG channel was assessed by electrophysiology and by computational modelling of the human ventricular action potential. The ELISA results revealed the presence of high titres of E-pore peptide Abs and significant QTc prolongation after immunization. High reactivity to E-pore peptide was found using anti-SSA/Ro Ab-positive sera from patients with QTc prolongation. Histological data showed no evidence of fibrosis in immunized hearts. Simulations of simultaneous inhibition of repolarizing currents by anti-SSA/Ro Ab-positive sera showed the predominance of the HERG channel in controlling action potential duration and the QT interval. These results are the first to demonstrate that inhibitory Abs to the HERG E-pore region induce QTc prolongation in immunized guinea-pigs by targeting the HERG channel independently from fibrosis. The reactivity of anti-SSA/Ro Ab-positive sera from patients with connective tissue diseases with the E-pore peptide opens novel pharmacotherapeutic avenues in the diagnosis and management of autoimmune-associated QTc prolongation.
Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, NY, USA.|Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
Frank
F
Fabris
Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, NY, USA.
Yuankun
Y
Yue
Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, NY, USA.|Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
Yongxia
Y
Qu
Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Laval University, Quebec City, QC, Canada.
Mohamed
M
Chahine
Department of Pharmacology & Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Eric
E
Sobie
Pathology Department, VA New York Harbor Healthcare System, New York, NY, USA.|Department of Pathology, New York University School of Medicine, New York, NY, USA.
Peng
P
Lee
Pathology Department, VA New York Harbor Healthcare System, New York, NY, USA.
Rosemary
R
Wieczorek
Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, NY, USA.|Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
Xian-Cheng
XC
Jiang
Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.
Pier-Leopoldo
PL
Capecchi
Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.
Franco
F
Laghi-Pasini
Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.
Pietro-Enea
PE
Lazzerini
Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, NY, USA. mohamed.boutjdir@va.gov.|Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA. mohamed.boutjdir@va.gov.|Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA. mohamed.boutjdir@va.gov.|Department of Pharmacology, State University of New York Downstate Medical Center, Brooklyn, NY, USA. mohamed.boutjdir@va.gov.|Department of Medicine, New York University School of Medicine, New York, NY, USA. mohamed.boutjdir@va.gov.
Mohamed
M
Boutjdir
D000818:Animals; D000906:Antibodies / Q000276:immunology; D015551:Autoimmunity; D002478:Cells, Cultured; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000276:immunology*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008133:Long QT Syndrome / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology
D000906:Antibodies; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D010446:Peptide Fragments
HERG channel; Immunization; Long QT syndrome; autoimmune diseases