Regulating an ancient arm of our immunity
Nature Immunology
June 8, 2009
Two new studies published in Nature Immunology reveal how the ancient arm of our immune system is regulated to avoid collateral tissue damage and how staphylococcal bacteria likewise evade this response. The new findings provide insights for designing therapies for such immune-mediated diseases.
A collection of circulating blood proteins, known as complement, detects and eliminates targeted cells but can also indiscriminately attack host cells if not properly regulated. The complement system can be activated by several pathways, all centering on the generation of an enzyme called C3 convertase, the structure of which was previously unknown.
Piet Gros, John Lambris, and their colleagues teamed up to generate co-crystals of C3 convertase with SCIN, a staphylococcal protein that inhibits the complement system and may contribute to the virulence of these bacteria. The authors found that the central component of the C3 convertase is C3b, which may form a complex with its parent molecule C3. This complex formation may clarify the mechanisms behind activation and 'self-amplifcation' of the complement response. SCIN appears to 'freeze' the C3 convertase in an inactive state, preventing this enzyme from further activating the complement system and thus protecting the bacteria from the host's immune response.
This team generated another co-crystal of C3b with the human complement system inhibitor called factor H, which is known to prevent spontaneous C3b activation. They found that C3b self-amplification is prevented because factor H binds to C3b and helps to strip off C3 from the active complex, likewise preventing further activation.
doi: 10.1038/ni.1755
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