TY - JOUR
T1 - Contactin-1 links autoimmune neuropathy and membranous glomerulonephritis
AU - Fehmi, Janev
AU - Davies, Alexander J.
AU - Antonelou, Marilina
AU - Keddie, Stephen
AU - Pikkupeura, Sonja
AU - Querol, Luis
AU - Delmont, Emilien
AU - Cortese, Andrea
AU - Franciotta, Diego
AU - Persson, Staffan
AU - Barratt, Jonathan
AU - Pepper, Ruth
AU - Farinha, Filipa
AU - Rahman, Anisur
AU - Canetti, Diana
AU - Gilbertson, Janet A.
AU - Rendell, Nigel B.
AU - Radunovic, Aleksandar
AU - Minton, Thomas
AU - Fuller, Geraint
AU - Murphy, Sinead M.
AU - Carr, Aisling S.
AU - Reilly, Mary R.
AU - Eftimov, Filip
AU - Wieske, Luuk
AU - Teunissen, Charlotte E.
AU - Roberts, Ian S. D.
AU - Ashman, Neil
AU - Salama, Alan D.
AU - Rinaldi, Simon
N1 - Publisher Copyright: Copyright: © 2023 Fehmi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2023/3/1
Y1 - 2023/3/1
N2 - Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment.
AB - Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment.
UR - http://www.scopus.com/inward/record.url?scp=85149719443&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85149719443&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/36893151
U2 - https://doi.org/10.1371/journal.pone.0281156
DO - https://doi.org/10.1371/journal.pone.0281156
M3 - Article
C2 - 36893151
SN - 1932-6203
VL - 18
JO - PLOS ONE
JF - PLOS ONE
IS - 3 March
M1 - e0281156
ER -