Complement System Entry Suspense: A Hero or Villain in Rare and Genetic Diseases

Dear Colleagues,

A complement is a group of about fifty liquid and cell membrane-associated proteins, which are mainly produced in the liver; however, there are several other sources, (e.g., monocytes, macrophages, dendritic cells, lymphocytes, adipocyte, fibroblasts, and epithelial cells) which are also involved in the direct synthesis of complement proteins. Complement activation is a complex process largely materializing in three different ways, i.e., through classical, alternative, and lectin pathways. Complement activation using the classical pathway occurs due to the ligation of IgG/IgM immune complexes (ICs) to their receptors and/or C1q, as well as the binding of C1q to certain molecules released from injured cells. The lectin pathway is activated through the binding of the mannan-binding lectin, a serum protein, to mannose-containing carbohydrates or related ficolins to certain carbohydrates or acetylated structures. The alternative pathway can be initiated when a spontaneously activated complement component binds to the surface of a pathogen. Each of the complement activation pathways follow a series of reactions for the generation of common key components termed C3 and C5. The downstream cleavage of C3 by the C3 convertases causes the formation of C3a and C3b; similarly, the downstream cleavage of C5 by C5 convertases triggers the formation of C5a and C5b. C3a binds with the C3aR receptor, and C5a binds with C5aR1 and C5aR2 receptors. C3b is a major opsonin capable of inducing the tagging and phagocytic uptake of pathogens, and C5b initiates the terminal complement pathway, resulting in the formation of the membrane attack complex (MAC) composed of C5b, C6, C7, C8, and multiple C9 molecules.

Complement activation and the production of several of its downstream molecules are essential for controlling cellular and metabolic functions. However, an abnormal complement activation and the resultant effector functions contribute to the development of visceral and brain tissue damage, organ failure, and death in many rare and genetic diseases (e.g., Gaucher disease, hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, Guillain–Barré syndrome hereditary angioedema, systemic lupus erythematosus, lupus-like disease with rash, glomerulonephritis, recurrent meningococcal infection, and leukocyte adhesion deficiency type I diseases). The activity of complement components is also modulated by a set of regulatory proteins, which bind to the activated complement components to host cells or the spontaneous activation of complement components in plasma to protect complement-induced disease processing. This Special Issue invites original research articles, reviews, and opinions describing the molecular mechanism through which the complement system activates/suppresses and modifies the disease processing of rare and genetic illnesses.

Dr. Manoj Kumar Pandey
Guest Editor

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• complement activation