Complement in the Initiation and Evolution of Rheumatoid Arthritis

Abstract

The complement system is a major component of the immune system and plays a central role in many protective immune processes, including circulating immune complex processing and clearance, recognition of foreign antigens, modulation of humoral and cellular immunity, removal of apoptotic and dead cells, and engagement of injury resolving and tissue regeneration processes. In stark contrast to these beneficial roles, however, inadequately controlled complement activation underlies the pathogenesis of human inflammatory and autoimmune diseases, including rheumatoid arthritis (RA) where the cartilage, bone, and synovium are targeted. Recent studies of this disease have demonstrated that the autoimmune response evolves over time in an asymptomatic preclinical phase that is associated with mucosal inflammation. Notably, experimental models of this disease have demonstrated that each of the three major complement activation pathways plays an important role in recognition of injured joint tissue, although the lectin and amplification pathways exhibit particularly impactful roles in the initiation and amplification of damage. Herein, we review the complement system and focus on its multi-factorial role in human patients with RA and experimental murine models. This understanding will be important to the successful integration of the emerging complement therapeutics pipeline into clinical care for patients with RA.

Decreased H19, GAS5, and linc0597 Expression and Association Analysis of Related Gene Polymorphisms in Rheumatoid Arthritis

“…Besides, complement system plays central roles in numerous protective immune processes [36]. Complement C3 and C4 are also one of the most important indicators of RA disease activity [36]. Thus, we speculate that GAS5 may play a pivotal role in the pathogenesis of RA, and its underlying mechanism is worth further exploration.…”

“…CRP is a product of inflammatory response, playing pro-inflammatory roles in RA by activating complements and inducing osteoclast differentiation, and acts as an indicator of treatment efficacy [35]. Besides, complement system plays central roles in numerous protective immune processes [36]. Complement C3 and C4 are also one of the most important indicators of RA disease activity [36].…”

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

“…In addition to inflicting damage at sites of inflammation through proteases and secreting cytokines which recruit additional immune cells, they also release neutrophil extracellular traps (NETs) comprised of intracellular proteins bound to DNA . This process may redistribute autoantigens, such as citrullinated proteins, to the extracellular environment where they may be bound by autoantibodies and drive downstream inflammatory processes such as macrophage or complement activation . These other innate effector mechanisms and cells, including dendritic and natural killer (NK) cells, are critical to RA pathogenesis as they sustain inflammation and contribute to adaptive immune cell activation …”

“…149 This process may redistribute autoantigens, such as citrullinated proteins, to the extracellular environment where they may be bound by autoantibodies and drive downstream inflammatory processes such as macrophage or complement activation. 151,152 These other innate effector mechanisms and cells, including dendritic and natural killer (NK) cells, are critical to RA pathogenesis as they sustain inflammation and contribute to adaptive immune cell activation. 153 In addition to the clear role for the innate immune system in RA pathogenesis, there is an important role of the adaptive immune system with the presence of antigen-specific T and B cells.…”

Key Components of the Complement Lectin Pathway Are Not Only Required for the Development of Inflammatory Arthritis but Also Regulate the Transcription of Factor D

“…Other cells or tissues, however, can secrete complement proteins, including epithelial and endothelial cells as well as adipocytes (26,27). The complement system is activated by three pathways, i.e., classical pathway (CP), lectin Pathway (LP) and alternative pathway (AP) (28). All three pathways of the complement system are activated by different molecules but converge at the cleavage of C3 and C5, generating C3a, C3b, C5a, and C5b, via C3 and C5 convertases, respectively.…”