Review: The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases

Abstract

The complement system is increasingly understood to play major roles in the pathogenesis of human inflammatory and autoimmune diseases. Because of this situation, there are rapidly expanding commercial efforts to develop novel complement inhibitors and effector pathway–modulating drugs. This review provides insights into the evolving understanding of the complement system components, mechanisms of activation within and across the 3 pathways (classical, alternative, and lectin), how the pathways are normally controlled and then dysregulated in target tissues, and what diseases are known to be, in large part, complement‐dependent through the successful development and approval of complement therapeutics in patients. Mechanisms of complement activation in rheumatoid arthritis, lupus, and thrombotic microangiopathies are also illustrated. In addition, the specific therapeutic drugs that are both approved and under development are discussed in the context of both nonrheumatic and rheumatic diseases. Finally, the methods by which the complement system can be assessed in humans through biomarker studies are outlined, with the goal of understanding, in specific patients, how the system is functioning.

Inflammation, immunity, and vascular remodeling in pulmonary hypertension; Evidence for complement involvement?

“…This system consists of a network of nearly 50 circulating, membrane-bound, and intracellular proteins and protein fragments activated by limited proteolysis in a cascade-like fashion (much like the coagulation cascade). Complement activation occurs via 3 major interconnected pathways (Figure 1): (1) the classical, involving antibody-mediated activation via the C1 complex (comprising C1q as the main component), resulting in cleavage of C2 and C4 components; (2) the lectin, triggered by carbohydrates (such as, for example, mannose-binding lectin) on cell surfaces, and resulting in cleavage of C2 and C4 components; and (3) the alternative, which involves cleavage of C3 facilitated by complement factors B, D, and and stabilized by properdin [20][21][22][23] . These pathways all converge onto formation of C3 convertases, which catalyze proteolysis of complement component C3 into the smaller C3a (anaphylatoxin) and the larger C3b fragment.…”

Serine proteinases in the turnover of the cartilage extracellular matrix in the joint: implications for therapeutics

“…The complement cascade is an important component of innate immunity which upon activation has essential roles in pathogen clearance (Thurman et al, 2017). Key components of this pathway are the serine proteinases C1s, C1r, C2, Factor B, Factor I and Factor D. A cascade of proteolytic events triggered by the detection of a foreign antigen results in the formation of a membrane attack complex (MAC) and cell lysis (for review, see Harris, 2018).…”

“…Indeed, C1s has been shown to degrade collagen types I and II (Yamaguchi et al, 1990), although it does not generate the 'three quarter and one quarter' fragments (Woolley et al, 1975) following classical collagenase cleavage, suggesting that it is unlikely to be a major collagenase in arthritis. Cartilage matrix components released by proteolytic degradation can initiate complement activation (Happonen et al, 2012), and targeting of the different factors within the complement cascade is now viewed as having therapeutic potential for RA (for an excellent review, see Thurman et al, 2017).…”

Expression of C1q in the serum of patients with non‑severe aplastic anemia, and its association with disease severity

“…When the complement system is in equilibrium it protects the organism from pathogens. When the balance is disrupted, the complement system may attack cells and tissues, causing multiple inflammatory reactions and autoimmune diseases (11). The complement system is activated via the classical pathway, alternative pathway, or mannose-binding lectin pathway.…”

“…Under physiological conditions, complement activation and the regulation of the system are in equilibrium, and the system protects the organism from pathogens. When the balance is altered, the disorganized complement system attacks its own cells and tissues, causing multiple inflammatory reactions and autoimmune diseases (11). The complement system has a biological role in phagocytosis, clearing senescent cells, the immune response and mediating inflammatory reactions (12).…”