Self‐nonself discrimination by the complement system

Meri, Seppo

doi:10.1002/1873-3468.12284

Cited by 72 publications

(64 citation statements)

References 136 publications

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“…Furthermore, this study allowed the identification of key amino acid residues in FH CCP20 that bind the glycerol side chain and carboxyl group of Neu5Ac (i.e., the predominant form of sialic acid found in mammalian cells). Interestingly, CCP20 acts as a hot spot for HUS-associated mutations, which indeed modify the Neu5Ac-binding pocket and alter the overall affinity of FH for sialic acid [13], ultimately leading to the defective complement regulation observed in this pathology (see [25, 51]); see further details below.…”

Section: Interaction Of Factor H With Glycans—discriminating Self Fromentioning

confidence: 99%

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Complement factor H in host defense and immune evasion

Parente

Clark

Inforzato

et al. 2016

Cell. Mol. Life Sci.

152

147

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Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.

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Section: Interaction Of Factor H With Glycans—discriminating Self Fromentioning

confidence: 99%

“…by RPE cells, as well as by the liver [21, 23]. Thus, systemic and locally secreted FH, most likely, both contribute to the regulation of complement activation in the context of immune surveillance [21, 24, 25]. …”

Section: Introductionmentioning

confidence: 99%

Complement factor H in host defense and immune evasion

Parente

Clark

Inforzato

et al. 2016

Cell. Mol. Life Sci.

152

147

View full text Add to dashboard Cite

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“…Specifically, the classical and the lectin pathways can recognize targets with specific pattern recognition molecules C1q, mannan-binding-lectin (MBL), and ficolins 1–3 (FCN1–3) (1–3). In contrast, the alternative pathway is continuously active and can amplify efficiently complement activation against non-self targets (2–4). All three pathways merge to activate the complement component C3, the most abundant complement factor in human blood plasma.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity

et al. 2017

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Inflammation is an important mediator of obesity-related complications such as the metabolic syndrome but its causes and mechanisms are unknown. As the complement system is a key mediator of inflammation, we studied whether it is activated in acquired obesity in subcutaneous adipose tissue (AT) and isolated adipocytes. We used a special study design of genetically matched controls of lean and heavy groups, rare monozygotic twin pairs discordant for body mass index (BMI) [n = 26, within-pair difference (Δ) in body mass index, BMI >3 kg/m2] with as much as 18 kg mean Δweight. Additionally, 14 BMI-concordant (BMI <3 kg/m2) served as a reference group. The detailed measurements included body composition (DEXA), fat distribution (MRI), glucose, insulin, adipokines, C3a and SC5b-9 levels, and the expression of complement and insulin signaling pathway-related genes in AT and adipocytes. In both AT and isolated adipocytes, the classical and alternative pathway genes were upregulated, and the terminal pathway genes downregulated in the heavier co-twins of the BMI-discordant pairs. The upregulated genes included C1q, C1s, C2, ficolin-1, factor H, receptors for C3a and C5a (C5aR1), and the iC3b receptor (CR3). While the terminal pathway components C5 and C6 were downregulated, its inhibitor clusterin was upregulated. Complement gene upregulation in AT and adipocytes correlated positively with adiposity and hyperinsulinemia and negatively with the expression of insulin signaling-related genes. Plasma C3a, but not SC5b-9, levels were elevated in the heavier co-twins. There were no differences between the co-twins in BMI-concordant pairs. Obesity is associated with increased expression of the early, but not late, complement pathway components and of key receptors. The twins with acquired obesity have therefore an inflated inflammatory activity in the AT. The results suggest that complement is likely involved in orchestrating clearance of apoptotic debris and inflammation in the AT.

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“…All these data point to a delicate balance of complement activation and inhibition necessary for homeostasis and prevention of harmful inflammation. The C-terminal domains of FH, especially the CCP20, are important for the interaction of the regulator with cell surface glycosaminoglycans and sialic acid as well as with C3b deposited during complement activation (30,(53)(54)(55)(56)(57)(58). These domains are conserved among FHR proteins, including FHR-B.…”

Section: Discussionmentioning

confidence: 99%