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

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

Biochemical Journal
2012 vol: 447 (2) pp: 205-215 doi: 10.1042/BJ20120884


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.

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Topics: Two-dimensional; CDR, Complementarity-determining region, GM-CSF, Granulocyte/macrophage colony-stimulating factor, GM-CSFR, GM-CSF receptor, hGM-CSF, human GM-CSF, LED, Light-emitting diode; MD, Molecular dynamics, Monolith – MicroScale Thermophoresis, MST, Proteins, Publications