Complement: The Road Less Traveled

The complement field has recently experienced a strong resurgence of interest because of the unexpected discovery of new complement functions extending complement's role beyond immunity and pathogen clearance, a growing list of diseases in which complement plays a role, and the proliferation of complement therapeutics. Importantly, although the majority of complement components in the circulation are generated by the liver and activated extra-cellularly, complement activation unexpectedly also occurs intracellularly across a broad range of cells. Such cell -autonomous complement activation can engage intracellu-lar complement receptors, which then drive noncanonical cell-specific effector functions. Thus, much remains to be discovered about complement biology. In this brief review, we focus on novel noncanonical activities of complement in its "classic areas of operation " (kidney and brain biology, infection, and autoimmunity), with an outlook on the next generation of complement-targeted therapeutics.