Details

Autor(en) / Beteiligte

• Blech, Michaela
• Seeliger, Daniel
• Kistler, Barbara
• Bauer, Margit M T
• Hafner, Mathias
• Hörer, Stefan
• Zeeb, Markus
• Nar, Herbert
• Park, John E

Titel

Molecular structure of human GM-CSF in complex with a disease-associated anti-human GM-CSF autoantibody and its potential biological implications

Ist Teil von

• Biochemical journal, 2012-10, Vol.447 (2), p.205-215

Ort / Verlag

England

Erscheinungsjahr

2012

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Polyclonal autoantibodies against human GM-CSF (granulocyte/macrophage colony-stimulating factor) are a hallmark of PAP (pulmonary alveolar proteinosis) and several other reported autoimmune diseases. MB007 is a high-affinity anti-(human GM-CSF) autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine-directed human IgG1λ autoantibody-binding fragment (Fab) at 1.9 Å (1 Å=0.1 nm) resolution. Its CDR3-H substantially differs from all VH7 germline IgG1 structures reported previously. We derive a reliable model of the antigen-autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modelled complex structure with the human GM-CSF-GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode of action of the MB007 autoantibody.