Abstract
SummaryThe complement alternative pathway is a powerful arm of the innate immune system that enhances diverse inflammatory responses in the human host. Key to the effects of the alternative pathway is properdin, a serum glycoprotein that can both initiate and positively regulate alternative pathway activity. Properdin is produced by many different leukocyte subsets and circulates as cyclic oligomers of monomeric subunits. While the formation of non‐physiological aggregates in purified properdin preparations and the presence of potential properdin inhibitors in serum have complicated studies of its function, properdin has, regardless, emerged as a key player in various inflammatory disease models. Here, we review basic properdin biology, emphasizing the major hurdles that have complicated the interpretation of results from properdin‐centered studies. In addition, we elaborate on an emerging role for properdin in thromboinflammation and discuss the potential utility of properdin inhibitors as long‐term therapeutic options to treat diseases marked by increased formation of platelet/granulocyte aggregates. Finally, we describe the interplay between properdin and the alternative pathway negative regulator, Factor H, and how aiming to understand these interactions can provide scientists with the most effective ways to manipulate alternative pathway activation in complex systems.
Highlights
While the basic principles of complement activation are well- characterized, complex interactions between complement and other cells and proteins, especially in the context of disease pathogenesis, have precluded, with few exceptions, successful use of anti-complement therapeutics in the clinic for common diseases
Factor H promoters could directly compensate for the intrinsic defect in Factor H cell-surface protection, while properdin inhibitors, which have proven to be effective at limiting thrombin receptor- activating peptide (TRAP)-mediated platelet/granulocyte aggregates (PGAs) formation[156] and complement activation on human erythrocytes[49] when Factor H regulation is impaired, could limit or prevent disease flare- ups resulting from alternative pathway activation that overwhelms the level of regulation provided by Factor H promoters
Properdin is a powerful inflammatory modulator that is tightly regulated by Factor H and has the ability to both initiate and positively regulate the alternative pathway amplification loop for all complement activity
Summary
While the basic principles of complement activation are well- characterized, complex interactions between complement and other cells and proteins, especially in the context of disease pathogenesis, have precluded, with few exceptions, successful use of anti-complement therapeutics in the clinic for common diseases.
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