The alternative pathway (AP) of complement activation is constitutively active and must be regulated by host
proteins to prevent autologous tissue injury. Dysfunction of AP regulatory
proteins has been linked to several human inflammatory disorders.
Properdin is a positive regulator of AP complement activation that has been shown to extend the half-life of cell surface–bound
C3 convertase C3bBb; it may also initiate AP complement activation. Here, we demonstrate a critical role for
properdin in autologous tissue injury mediated by AP complement activation. We identified myeloid lineage cells as the principal source of plasma
properdin by generating mice with global and tissue-specific knockout of Cfp (which encodes
properdin) and by generating BM chimeric mice.
Properdin deficiency rescued mice from AP complement–mediated embryonic lethality caused by deficiency of the membrane
complement regulator Crry and markedly reduced disease severity in the K/BxN model of
arthritis. Ab neutralization of
properdin in WT mice similarly ameliorated
arthritis development, whereas reconstitution of
properdin-null mice with exogenous
properdin restored
arthritis sensitivity. These data implicate systemic
properdin as a key contributor to AP complement–mediated injury and support its therapeutic targeting in
complement-dependent human diseases.