The complement system historically has been recognized as a component of immune defense against foreign invaders (e.g. bacteria, viruses, and fungi) by opsonization and cytolysis. Recent studies showed that its versatile functions extend far beyond the elimination of microbes. The complement has verified as a surveillance system to discriminate healthy and altered host cells (e.g. apoptotic and necrotic cells and their fragments), because of the capacity to recognize and dispel the damaged “self” components.
By sending “danger” signals and orchestrating immune responses, complement system contributes substantially to homeostasis, but it may damage healthy host cells and tissues if not properly controlled. With a major functional linkage with other systems, including coagulation, adaptive immunity, Fc receptors, TLRs, and noninflammatory disposal mechanisms, the intricate complement network requires rigorous regulation to maintain appropriate homeostasis. Excessive or insufficient activation will break the delicate balance between complement activation and regulation, leading a variety of disease, including:
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Complement therapeutics for autoimmune disease
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Complement therapeutics for nephropathy
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Osteology
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Genetic disease
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Infection
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Neurology
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Inflammatory disease
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Ophthalmology
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Complement therapeutics for cardiovascular disease
Fig. 1 Complement associated diseases.
Complement Deficiency and Diseases
Nearly 50% of all complement proteins serve as regulators or inhibitors in the amplification cascade, so any absence or suboptimal function of the proteins gives rise to severe clinical disease.
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Classical Pathway Deficiency
C1q, C2, C3 are basic components of the classical pathway, any deficiency of them will correspondingly present clinical symptoms. C1q deficiency is associated with an increased susceptibility to systemic lupus erythematosus (SLE) or SLE-like syndrome with fever, rash, arthritis, and glomerulonephritis. The investigation revealed that C1q deficiency contributes to the encapsulated bacteria induced infection and high morbidity in childhood from recurrent bacterial/viral infections. C2 deficiency is the most common homozygous complement deficiency, which also relates to SLE-like illness, infections, rheumatic disorders, and atherosclerosis. C3 deficiency may be a reason for recurrent pyogenic infections and membrano-proliferative glomerulonephritis.
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Alternative Pathway Deficiency
In the alternative pathway, properdin binds to C3b and stabilizes C3 and C5 convertase. Patients with properdin deficiency present hypersensitivity to Neisseria infections (meningococcus and gonococcus) which can be fulminant and life-threatening. Factor D is essential in catalyzing the cleavage of factor B to Bb, allowing the formation of C3bBb. Factor D deficiency shows an insufficiency of alternative pathway hemolytic activity, and it can greatly reduce opsonization of encapsulated bacteria, Streptococcus pneumoniae. While there is no evidence for the association between factor D deficiency and autoimmunity. Factor B deficiency has the analogous role in clinical disease compared with factor D deficiency.
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Lectin Pathway Deficiency
As the initiation factor of lectin pathway, mannose-binding lectin (MBL) plays an irreplaceable role. Children with MBL deficiency are high-risk group for infection, especially in the period that the passive immunity (acquired from maternal IgG) has been lost, while the protective antibody has not formed yet. MBL deficiency has a very high prevalence with increased susceptibility and clinical severity of fungal, protozoal, and viral infections as well as community-acquired pneumonia and Neisseria meningitis.
Excessive Activation and Disease
Clinical studies reveal that excessive activation of complement system causes massive accumulation of complement components in the serum of rheumatoid arthritis (RA). In addition, age-related macular degeneration (AMD) and coagulation disorders are related to the excessive accumulation of complement.
Fig 2. Simplified scheme of the complement system with currently exploited targets of complement-directed therapeutic intervention. (Ricklin, et al. 2013)
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Reference
1. Ricklin, Daniel, and John D. Lambris. "Complement in immune and inflammatory disorders: therapeutic interventions." The Journal of Immunology 190.8 (2013): 3839-3847.
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