Characterization of pathogenic human monoclonal autoantibodies against GM-CSF.

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.

• Authors: Yanni Wang, Christy A Thomson, Lenka L Allan, Linda M Jackson, Melanie Olson, Timothy R Hercus, Tracy L Nero, Amanda Turner, Michael W Parker, Angel L Lopez, Thomas K Waddell, Gary P Anderson, John A Hamilton, John W Schrader
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 19 Pg. 7832-7 (May 07 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23620516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Autoantibodies
• CD11b Antigen
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Antibodies, Monoclonal (immunology)
• Autoantibodies (immunology)
• B-Lymphocytes (cytology)
• CD11b Antigen (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Epitope Mapping (methods)
• Granulocyte-Macrophage Colony-Stimulating Factor (immunology, metabolism)
• Humans
• Immunologic Memory
• Inhibitory Concentration 50
• Kinetics
• Mutation
• Neutrophils (metabolism)
• Point Mutation
• Pulmonary Alveolar Proteinosis (immunology, metabolism)
• Surface Plasmon Resonance
• T-Lymphocytes (cytology)