Novel mechanisms and functions of complement

Abstract

Progress in the beginning of the 21st century transformed our perception of complement from a blood-based antimicrobial system to a global regulator of immunity and tissue homeostasis. More recent years have witnessed remarkable advances regarding structure-function insights, mechanisms and locations of complement activation, thereby adding new layers of complexity in the biology of complement. This complexity is readily reflected by the multifaceted and contextual involvement of complement-driven networks in a wide range of inflammatory and neurodegenerative disorders and cancer. This Review provides an updated view of new and previously unanticipated functions of complement and how these impact immunity and disease pathogenesis.

Critical Role for a Subset of Intestinal Macrophages in Shaping Gut Microbiota in Adult Zebrafish

“…Given that our data strongly link irf8 loss with complement deficiency, and loss-of-function mutations in C1q genes are associated with immunodeficiencies and autoimmune conditions in mammals (Botto, 1998; Brown et al, 2002; Degn et al, 2011; Macedo and Isaac, 2016; Roumenina et al, 2011; Warren et al, 2002), we propose that C1q defects may underlie the susceptibility to gut microbial dysbiosis we found in zebrafish irf8 mutants and possibly also to infections known in IRF8-deficient animals and humans, but this requires further investigation (Hambleton et al, 2011; Langlais et al, 2016; Salem and Gros, 2013). In support of this, the role of complement genes in hostmicrobe interactions and modulation of cutaneous microbiota has previously been shown (Chehoud et al, 2013; Hajishengallis et al, 2013, 2017; Hasegawa et al, 2014). Consistent with the possibility that IRF8 may transcriptionally activate c1q genes in both subsets of adult zebrafish intestinal macrophages, irf8 was abundantly expressed in most, if not all, intestinal macrophages (Figure S6).…”

High complement levels in astrocyte‐derived exosomes of Alzheimer disease

“…Levels of the plasma-based factor I, which with co-factor H or CD46 constitutes a C3b/C4b inactivator, were no different in AD patients than controls. Neuronal damage by the complement pathways also could be mediated by C3a and C5a, the inflammatory anaphylatoxins generated concurrently with larger fragments, although these have not been examined in the present study 29 .…”

Anti‐HIV‐1 antibodies trigger non‐lytic complement deposition on infected cells

“…The three canonical mechanisms of complement activation, known as classical, alternative and lectin pathways, converge to the proteolytic cleavage of component 3 (C3) into C3a and C3b. Cleaved forms of complement proteins are recognized by complement receptors (CRs), expressed by numerous immune cells, such as macrophages, NK cells, or dendritic cells (DC) [4]. Covalent binding of C3b on targeted membranes promotes different events.…”