Complement activation by (auto-) antibodies

The complement system is a key part of the innate immune system and plays an important role in the clearance of pathogens and apoptotic cells upon its activation. It is well known that both IgG and IgM can activate complement via the classical pathway by binding of C1q to the Fc regions of these immunoglobulins. Recent advances have shown that also IgA is capable of activating the complement system. Besides, more insight is gained into an additional role for antibodies in the activation of both the alternative and the lectin pathways. Mouse models have shown that auto-antibodies can activate the alternative pathway and induce in cell lysis and tissue damage.Besides the role of antibodies in complement activation, complement may also be a target for recognition by antibodies directed against autologous complement components. These auto-antibodies play a role in several diseases, especially vascular diseases. Understanding how antibodies interact with the complement system will allow the manipulation of this interaction to diminish pathological consequences of auto-antibodies and optimize the effect of therapeutic antibodies.In the current review, we discuss complement activation by (auto-) antibodies by the different pathways.

► The three pathways of complement activation can be directly activated by (auto) antibodies. However, not all antibodies are capable of activating all pathways. Different antibody isotypes have different capacities to trigger activation in vitro.
► IgA activates the alternative and lectin pathway of complement but not the classical pathway. Thus IgA may provide additional support in humoral host defense. However in diseased conditions like IgA nephropathy, it may also amplify inflammation and tissue injury.
► In murine models of inflammation like experimental Reumatoid arthritis, complement activation pathways and tissue injury has been established in more detail in vivo, suggesting a major role for the alternative pathway.
► Therapeutic modulation of complement activity e.g. by antibodies that interact with the complement system are introduced in the clinic already and are being developed further.