Isolation of potent human Fab fragments against a novel highly immunogenic region on human muscle acetylcholine receptor which protect the receptor from myasthenic autoantibodies

Bibliographic Details
Title: Isolation of potent human Fab fragments against a novel highly immunogenic region on human muscle acetylcholine receptor which protect the receptor from myasthenic autoantibodies
Authors: Sonia Berrih-Aknin, David Beeson, Socrates J. Tzartos, Avgi Mamalaki, Efrosini Fostieri
Source: European journal of immunology. 35(2)
Publication Year: 2005
Subject Terms: Immunology, Immunology and Allergy, Monoclonal antibody, medicine.drug_class, medicine, Antigenic Modulation, Somatic hypermutation, Nicotinic acetylcholine receptor, Acetylcholine receptor, Neuromuscular junction, medicine.anatomical_structure, Immunoglobulin light chain, Antibody, biology.protein, biology, Molecular biology
Description: In the autoimmune disease myasthenia gravis (MG), antibodies against the muscle nicotinic acetylcholine receptor (AChR) cause loss of functional AChR in the neuromuscular junction. To isolate AChR-specific human antibody fragments (Fab), a phage-display library was constructed from an MG patient's thymic B lymphocytes. The first Fab isolated had a low affinity for human AChR, but two sequential antibody chain shufflings using the MG donor heavy and light chain gene repertoires resulted in isolating two new Fab with an approximately 30-fold higher binding ability. The selected Fab contained extensively mutated heavy and light chains and probably represent intraclonal variants of a common progenitor having diverged in vivo by somatic hypermutation. Interestingly, the isolated Fab bound to an extracellular highly immunogenic region located either on an alpha-subunit site affected by the gamma/epsilon-subunits or on the interface between alpha- and gamma/epsilon-subunits. This region is not the previously described "main immunogenic region" (MIR), although it seems to be close to it, as one improved Fab and an anti-MIR mAb competed for AChR binding with distinctly different subpopulations of MG sera. Furthermore, this Fab protected surface AChR in cell cultures against MG autoantibody-induced antigenic modulation, suggesting a potential therapeutic use in MG, especially in combination with a human anti-MIR Fab.
Language: English
ISSN: 1521-4141
0014-2980
Access URL: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fcb7bf0df12e42e3d829cd4a98c67f47
http://ora.ox.ac.uk/objects/uuid:615ab3fe-7305-481d-a69e-09f7225c156a
Rights: OPEN
Accession Number: edsair.doi.dedup.....fcb7bf0df12e42e3d829cd4a98c67f47
Database: OpenAIRE
Description
ISSN:15214141
00142980