Tipping the balance: intricate roles of the complement system in disease and therapy

Abstract

The ability of the complement system to rapidly and broadly react to microbial intruders, apoptotic cells and other threats by inducing forceful elimination responses is indispensable for its role as host defense and surveillance system. However, the danger sensing versatility of complement may come at a steep price for patients suffering from various immune, inflammatory, age-related, or biomaterial-induced conditions. Misguided recognition of cell debris or transplants, excessive activation by microbial or damaged host cells, autoimmune events, and dysregulation of the complement response may all induce effector functions that damage rather than protect host tissue. Although complement has long been associated with disease, the prevalence, impact and complexity of complement’s involvement in pathological processes is only now becoming fully recognized. While complement rarely constitutes the sole driver of disease, it acts as initiator, contributor, and/or exacerbator in numerous disorders. Identifying the factors that tip complement’s balance from protective to damaging effects in a particular disease continues to prove challenging. Fortunately, however, molecular insight into complement functions, improved disease models, and growing clinical experience has led to a greatly improved understanding of complement’s pathological side. The identification of novel complement-mediated indications and the clinical availability of the first therapeutic complement inhibitors has also sparked a renewed interest in developing complement-targeted drugs, which meanwhile led to new approvals and promising candidates in late-stage evaluation. More than a century after its description, complement now has truly reached the clinic and the recent developments hold great promise for diagnosis and therapy alike.

Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse

“…Several receptors mediate complement signaling and complement regulators modulate its trigger (e.g; C1inhibitor) or amplification, by down-regulating of the C3 or C5 convertases (see Figure 2 ). Since the complement system and its activation have already been presented in an article on the present research topic ( 11 ), and extensively reviewed previously, the reader may learn more functional and molecular details elsewhere ( 6 , 10 – 16 ).…”

Coagulation and complement: Key innate defense participants in a seamless web

“…A major blood-based proteolytic system, complement is orchestrated to innately respond as a first-line protector of the host from invading pathogens and damaged cells ( 52 , 53 ). Like coagulation, the complement system is delicately balanced, tightly regulated and highly versatile, integrated with other innate and adaptive response systems, and linked to physiologic systems that prevent bleeding, and effect cell proliferation, tissue regeneration and healing ( 54 ).…”

Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors

“…The human complement system contributes to various pathologies, from autoimmune, age-related, and inflammatory disorders to transplant- and biomaterial-induced complications, making it a prime target for therapeutic intervention 1 , 2 . Despite growing interest, the development of complement-targeted drugs has been slow, with two related anti-C5 antibodies (eculizumab, ravulizumab) approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and other indications long remaining the only clinical options 2 .…”

“…Complement primarily acts as a rapid host defence system that eliminates microbial intruders and apoptotic cells 1 . After initiation by various means, including immune complexes (classical pathway) or microbial signatures (lectin pathway), the cascade converges at the activation of the plasma protein C3 by convertases (Fig.…”