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The complement system consists of more than 30 plasma as well as cell surface proteins that together constitute a major arm of the immune system. The long-held belief is that most of the complement components are synthesized by hepatocytes in the liver and then secreted into the blood. However, there is also substantial evidence that several if not all of the complement proteins are synthesized extrahepatically by a wide range of cell types, including polymorphonuclear leukocytes, monocytes, macrophages, dendritic cells, lymphocytes, epithelial cells, fibroblasts, and neuronal cells. However, despite the proven evidence that complement proteins indeed could be synthesized non-hepatic cells and even found in unexpected places, the recent finding that certain complement proteins could be activated in intracellular spaces nonetheless has opened up a new debate. In fact, some in the field unfortunately seem to be in favor of rejecting this notion rather vehemently on the untenable and myopic grounds that complement proteins could not be found in intracellular compartments despite evidence to the contrary. Therefore, this opinion article is meant to remind colleagues in the field that new discoveries with the potential to shift established functional paradigms should be encouraged and celebrated even if, at first glance, they seem to defy the odds.

Complement proteins in unexpected places: why we should be excited, not concerned!