The Interplay of Complements and their Regulators in the Human Body

An infection can be viewed as a battle between invading pathogen and the host. The complement system represents an evolutionarily conserved component of innate immunity designed to manage this ongoing conflict. It functions by labeling bacteria with opsonins, facilitating phagocytosis through chemo attractants, inducing bacterial lysis via pore formation, and promoting antibody production by bridging innate and adaptive immunity. However, the complement system is not entirely foolproof. Its non-specific nature, overactivation, polymorphisms, genetic mutations, and alterations in self-cells (such as those occurring in cancer) can lead to complement-mediated damage to host tissues. Deficiencies in complement proteins increase susceptibility to recurrent infections. Beyond its defensive roles, the complement system is essential for maintaining homeostasis by coordinating inflammation, eliminating and recycling cellular debris, and regulating apoptosis. Tight regulation of complement activity is crucial to prevent self-damage. One regulatory strategy involves synthesizing most complement proteins as inactive precursors, each acting as a protease that sequentially activates the next component in the cascade. Another mechanism involves a group of specialized proteins known as Regulators of Complement Activation (RCA), which exist in both soluble and membrane-bound forms. The development of therapeutics for complement-mediated diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) requires a deep understanding of this complex system and its regulatory mechanisms. In this review, we describe the complement pathways and their interplay with soluble and membrane-bound regulators in the human body.