Complement biology for hematologists

Abstract

The complement system is part of the innate immunity. An increased activation or a loss of the regulation of this fine-tuned cascade is involved in a variety of hematological diseases. During the last decade, anti-C5 therapies have revolutionized the management and prognosis of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic and uremic syndrome (aHUS). The availability of a rapidly growing number of innovative complement inhibitors has opened new therapeutic perspectives for several other hematological disorders in which the complement is involved at different degrees. This review focuses on complement biology and its mechanisms of activation in hematological diseases.Recently, the first demonstration of the efficacy of C1s inhibition efficiency in cold agglutin disease (CAD) has provided an illustration of these new targets within the complement cascade for the treatment of hematological disorders.

Structural Model for Factor X Inhibition of IgM and Complement-Mediated Neutralization of Adenovirus

“…Modeling of C3b on the adenovirus facet begins with a single C4b bound to the facet ( Figure 3 A). C4b, together with C2 and the action of nearby C1 proteases, forms the C3 convertase (C4b2b) [ 12 ]. The first incoming copy of C3 interacts with the substrate interaction side of C4b ( Figure 3 B) and is cleaved by the C3 convertase to form C3b.…”

“…An initially planar IgM binds to the viral surface, where it adopts a staple-shaped or bent conformation that is recognized by complement [ 10 ]. IgM, or IgG, binding to the virus marks the beginning of the classical pathway of the complement cascade, an innate immune response that occurs immediately upon infection in order to defend the host against viruses and other pathogens [ 11 , 12 ]. The C1 complex, which is composed of complement proteins C1q, C1s, and C1r, binds to the bent conformation of IgM.…”

“…Binding of C1q to the viral surface activates the proenzymes C1s and C1r in the C1 complex. The C1 proteases in turn cleave complement component C4 into C4b and complement component C2 into C2b, forming the classical C3 convertase (C4b2b, formerly known as C4b2a) [ 12 ]. C4b has a reactive thioester that can covalently bind to the viral surface.…”

Interorgan communication with the liver: novel mechanisms and therapeutic targets

“…The lack of CD55 and CD59 on the cell surface of the hematopoietic group greatly reduces the complement regulation ability of red blood cells, and after encountering infection, complement is strongly activated, resulting in red blood cells being destroyed by MAC and causing intravascular hemolysis. The prognosis of PNH has been altered after the use of C5 inhibition, and complement inhibitors have also opened up new prospects for the treatment of hematologic diseases ( Table 2 ) ( 343 ).…”

Complement inhibition in medicine: Hematology and beyond; complement inhibition in hematology: PNH and beyond

“…This special issue aims to put together clinical processes with the biological mechanisms underlying clinical findings. Dr Duval & Fremeaux‐Bacchi in «Complement biology for hematologist» 1 nicely (and comprehensively) describe the robust and efficient proteolytic cascades resulting in opsonization and lysis of the pathogen, as well as in the generation of the inflammatory response. The authors also describe how an increased activation or a loss of the regulation of this fine‐tuned cascade is involved in a variety of hematological diseases (as well as in many others).…”