Complement: a key system for immune surveillance and homeostasis

Ricklin, Daniel; Hajishengallis, George; Yang, Kun; Lambris, John D.

doi:10.1038/ni.1923

Cited by 3,085 publications

(3,499 citation statements)

References 180 publications

(238 reference statements)

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“…removal of immune complexes, apoptotic materials, and necrotic debris). These reports emphasise that the removal of endogenous debris requires a highly tactful approach, in which mechanisms downstream of C3, such as the inflammatory C5a-C5aR axis and MAC assembly, should be avoided (Ricklin et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

Complement genetics, deficiencies, and disease associations

Mayilyan

2012

Protein Cell

149

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The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

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Section: Resultsmentioning

confidence: 99%

Complement genetics, deficiencies, and disease associations

Mayilyan

2012

Protein Cell

149

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“…The subsequent events lead to the formation of the C3 and C5 convertases and the formation of activation products. One of the activation products C5a is a strong chemoattractant and a potent contributor to inflammation [12]. The C3 convertase's can be established on surfaces of biomaterials further accelerating the formation of C3 to C3b.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Alginate microsphere compositions dictate different mechanisms of complement activation with consequences for cytokine release and leukocyte activation

Ørning

Hoem

Coron

et al. 2016

Journal of Controlled Release

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The inflammatory potential of 12 types of alginate-based microspheres was assessed in a human whole blood model. The inflammatory potential could be categorized from low to high based on the four main alginate microsphere types; alginate microbeads, liquefied core poly-L-ornithine (PLO)-containing microcapsules, liquefied core poly-L-lysine (PLL)-containing microcapsules, and solid core PLLcontaining microcapsules. No complement or inflammatory cytokine activation was detected for the Ca/Ba alginate microbeads. Liquefied core PLO-and PLL-containing microcapsules induced significant fluid phase complement activation (TCC), but with low complement surface deposition (anti-C3c), and a low proinflammatory cytokine secretion, with exception of an elevated MCP-1(CCL2) secretion. The solid core PLL-containing microcapsules generated lower TCC but a marked complement surface deposition and significant induction of the proinflammatory cytokines interleukin (IL-1)β, TNF, IL-6, the chemokines IL-8 (CXCL8), and MIP-1α (CCL3) and MCP-1(CCL2).Inhibition with compstatin (C3 inhibitor) completely abolished complement surface deposition, leukocyte adhesion and the proinflammatory cytokines. The C5 inhibitions partly lead to a reduction of the proinflammatory cytokines. The leukocyte adhesion was abolished by inhibitory antibodies against CD18 and partly reduced by CD11b, but not by CD11c. Anti-CD18 significantly reduced the (IL-1)β, TNF, IL-6 and MIP-1α and anti-CD11b significantly reduced the IL-6 and VEGF secretion. MCP-1 was strongly activated by anti-CD18 and anti-CD11b. In conclusion the initial proinflammatory cytokine responses are driven by the microspheres potential to trigger complement C3 (C3b/iC3b) deposition, leukocyte activation and binding through complement receptor CR3 (CD11b/CD18).MCP-1 is one exception dependent on the fluid phase complement activation mediated through CR3.

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“…Generally, certain molecular patterns on pathogens are recognized either by C1q molecule, mannose-binding proteins containing collagen-like receptor binding domains, or through the interaction with the C3 multifunctional protein (Sahu and Lambris 2001;Tenner 1999). Activated C3 recruits immune cells, amplifies antigenspecific immune responses, promotes phagocytosis, forms MAC by binding C5, C6, C7, C8 and C9 to facilitate complement-mediated cytolysis, and executes the cell death (Ricklin et al 2010). Complement proteins and receptors are mostly generated in the liver and have high concentrations in serum.…”

Section: Neuronmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

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Alzheimer's disease (AD) is a complex agerelated neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE e4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

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Complement: a key system for immune surveillance and homeostasis

Cited by 3,085 publications

References 180 publications

Complement genetics, deficiencies, and disease associations

Complement genetics, deficiencies, and disease associations

Alginate microsphere compositions dictate different mechanisms of complement activation with consequences for cytokine release and leukocyte activation

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

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