Title: Characterization of pathogenic human monoclonal autoantibodies against GM-CSF
Authors: Wang, YN
Thomson, CA
Allan, LL
Jackson, LM
Olson, M
Hercus, TR
Nero, TL
Turner, A
Parker, MW
Lopez, AL
Waddell, TK
Anderson, GP
Hamilton, JA
Schrader, JW
Issue Year: 2013
Publisher NATL ACAD SCIENCES
Series PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA: 110(19): 7832-7837
Abstract The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.
URI: https://publications.svi.edu.au/publications/1680
Other Identifiers 10.1073/pnas.1216011110
Publication type Article
Grant ID GNT0565217; GNT1021645
Find it online http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651501/