The complexity of the immune response has increased throughout evolution. Three pathways that activate the immune response are now known to exist - the classical, lectin, and alternative pathways. Deficiencies in components of these pathways (known as "complement components") may predispose us to infections or even cause the immune response to turn against us. Lectins are molecules that circulate throughout the body and recognize and bind to sugars on the surface of pathogens, triggering the immune response by the cleavage of 2 complement components, C4 and C2, to produce an enzyme known as C4b2a. This enzyme cleaves another complement component, C3, into C3a and C3b. C3b is then deposited on the surface of the pathogen, triggering activation of the alternative pathway, and targeting the pathogen for killing.
In a study appearing in the May issue of the Journal of Clinical Investigation, Anders Sjöholm and colleagues from the University Hospital of Lund, Sweden, investigated how individuals who suffer from a genetic immunodeficiency condition in which they lack C4 or C2, are still able to mount a substantial immune response. They found that in these individuals, C2 is bypassed and lectin binding to sugars on the pathogen instead engages the alternative pathway and formation of another C3-cleaving enzyme, C3bBb. This 'bypass' pathway may be functioning in individuals with acquired or naturally occurring complement deficiencies.
In an accompanying commentary, Peter Atkinson and Michael Frank from Washington and Duke Universities, respectively, comment that these results suggest that "individuals deficient in C4 or C2 possess a 'backup' or bypass complement activation system." The authors also stress that researchers using C4-deficient animals to rule out a contribution of certain pathways of complement activation in mouse models of human disease should be aware that 'bypass' pathways such as this may still be functioning.
TITLE: Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2
AUTHOR CONTACT:
Anders G. Sjoholm
University Hospital of Lund, Sweden.
View the PDF of this article at: https://www.the-jci/article.php?id=25982
ACCOMPANYING COMMENTARY
TITLE: Bypassing complement: evolutionary lessons and future implications
AUTHOR CONTACT:
John P. Atkinson
Washington University School of Medicine, St. Louis, Missouri, USA.
View the PDF of this article at: https://www.the-jci/article.php?id=28622
Contact: Brooke Grindlinger
Journal of Clinical Investigation