Applying complement therapeutics to rare diseases

Reis, Edimara S.; Mastellos, Dimitrios C.; Yancopoulou, Despina; Risitano, Antonio M.; Ricklin, Daniel; Lambris, John D.

doi:10.1016/j.clim.2015.08.009

Cited by 57 publications

(61 citation statements)

References 137 publications

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“…For example, immune complexes present in systemic lupus erythematosus (SLE) cause consumption of complement components in the circulation and deposition of complement activation products in the kidney (lupus nephritis) and other organs 92 . Similar mechanisms are involved in antiphospholipid antibody syndrome, myasthenia gravis, and many other autoimmune diseases 3,92 . In patients with ANCA-associated vasculitis, neutrophil priming by C5a or other stimuli leads to the expression of proteins that are recognized by autoantibodies.…”

Section: Complex Involvement In Clinical Disordersmentioning

confidence: 86%

“…Although this effect was most obvious for older cellulose-based haemodialysis filters, modern synthetic filters with improved biocompatibility still induce substantial complement activation through all initiation pathways 3,147 . The generation of C5a during haemodialysis-induced complement activation is associated with neutrophil activation and an increase in TF expression as a primary initiator of coagulation.…”

Section: Complement-mediated Kidney Diseasementioning

confidence: 99%

“…The complement system is now understood to contribute to a growing list of immune, inflammatory and age-related conditions, with kidney disorders assuming a particularly prominent place 1–3 . The strong association between the complement system and disease might at first seem unexpected, given the beneficial role of complement as a first line of defence against microbial threats.…”

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confidence: 99%

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Complement in disease: a defence system turning offensive

2016

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Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris — such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways — can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

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Section: Complex Involvement In Clinical Disordersmentioning

confidence: 86%

Section: Complement-mediated Kidney Diseasementioning

confidence: 99%

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confidence: 99%

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Complement in disease: a defence system turning offensive

2016

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“…Among strategies aimed at intercepting C3, derivatives of the compstatin family and soluble CR1 displayed favorable effects in preclinical models and in patients with age-related macular degeneration or C3 glomerulopathy585960. However, targeted C3 inhibition often raised the concern that a completely shut down of C3 activity could increase susceptibility to infections.…”

Section: Discussionmentioning

confidence: 99%

A previously unrecognized role of C3a in proteinuric progressive nephropathy

Morigi

Locatelli

Rota

et al. 2016

Sci Rep

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Podocyte loss is the initial event in the development of glomerulosclerosis, the structural hallmark of progressive proteinuric nephropathies. Understanding mechanisms underlying glomerular injury is the key challenge for identifying novel therapeutic targets. In mice with protein-overload induced by bovine serum albumin (BSA), we evaluated whether the alternative pathway (AP) of complement mediated podocyte depletion and podocyte-dependent parietal epithelial cell (PEC) activation causing glomerulosclerosis. Factor H (Cfh−/−) or factor B-deficient mice were studied in comparison with wild-type (WT) littermates. WT+BSA mice showed podocyte depletion accompanied by glomerular complement C3 and C3a deposits, PEC migration to capillary tuft, proliferation, and glomerulosclerosis. These changes were more prominent in Cfh−/− +BSA mice. The pathogenic role of AP was documented by data that factor B deficiency preserved glomerular integrity. In protein-overload mice, PEC dysregulation was associated with upregulation of CXCR4 and GDNF/c-Ret axis. In vitro studies provided additional evidence of a direct action of C3a on proliferation and CXCR4-related migration of PECs. These effects were enhanced by podocyte-derived GDNF. In patients with proteinuric nephropathy, glomerular C3/C3a paralleled PEC activation, CXCR4 and GDNF upregulation. These results indicate that mechanistically uncontrolled AP complement activation is not dispensable for podocyte-dependent PEC activation resulting in glomerulosclerosis.

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“…This may be due to alternative drivers of disease pathology, or unfavourable pharmacological characteristics of antibody-based inhibition of C5. Clinical trials of another monoclonal C5 inhibitor, LFG316, has reported a similar lack of effect in the treatment of macular degeneration (Reis et al 2015). In contrast, the C5 inhibitor, Zimura, has reported benefits in clinical trials for the treatment of age-related macular degeneration, with phase II/III trials for geographic atrophy and macular degeneration ongoing (ClinicalTrials.gov identifier: NCT02686658) (Querques et al 2015).…”

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confidence: 99%

Exploring the role of C5a-C5aR1 signalling in development through pluripotent stem cell modelling

Hawksworth¹

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The complement system has been traditionally described as a powerful controller of innate immunity.With activation through the recognition of pathogenic surfaces, spontaneous hydrolysis, or extrinsic cleavage, a cleavage cascade is initiated culminating in the formation of the active complement fragments C3a, C3b, C5a, and C5b. These fragments direct immune cells to sites of inflammation, as well as tagging pathogens for destruction and directly lysing foreign cells. It is now clear however, that this complex family of proteins possesses a wide range of functions outside of immune regulation. From fertilisation and morphogenesis, to the control of foetal and adult stem cell populations, studies have described novel actions of complement factors. This thesis is focussed on the central complement receptor, C5aR1. Traditionally described as a potent activating and chemotactic receptor for immune cells, C5aR1 has been shown to function in a number of nonimmune cell populations. Of note, our laboratory has previously described a role for C5aR1 in neural tube closure, with loss of C5aR1 signalling associated with increased neural tube defects under folate deficient conditions. However, a mechanistic role of C5aR1 at this stage of development was not described.In this thesis, pluripotent stem cells were utilised as an in vitro model of human development to interrogate the expression and function of C5aR1 at a number of developmental stages. Specifically, in pluripotent stem cells representative of the blastocyst inner cell mass, in neural rosettes representative of the developing ventricular zone, and in matured post-mitotic cortical neurons. This builds on previous work by our laboratory, which had identified C5aR1 actions in the mouse ventricular zone, analogous to late neural rosette cultures, and had shown a neurotoxic effect of C5aR1 in post-mitotic mouse neurons.C5aR1 was found to be expressed in pluripotent stem cells, with a role in promoting maintenance of pluripotency in the absence of FGF2 signalling. Additionally, C5aR1 was found to be apically expressed in human neural rosettes, with signalling promoting proliferation and maintenance of cell polarity. This work correlated well with mouse studies performed outside of this thesis, to show that in vivo, loss of C5aR1 in this neural progenitor population resulted in behavioural deficits and microstructural brain changes. Lastly, we determined the mRNA expression of C5aR1 in human postmitotic cortical neurons. However, in contrast to previous mouse studies, exogenous C5a, alone or in the presence of secondary stressors, had little effect on the survival of these cells.Overall, the results presented in this thesis have further expanded our knowledge of C5a-C5aR1 signalling in development, describing novel roles for this signalling pathway. The use of pluripotent stem cells allowed for the exploration of C5aR1 actions in human development that would otherwise be limited to animal models. Additionally, it allowed for the correlation of previous animal resu...

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Applying complement therapeutics to rare diseases

Cited by 57 publications

References 137 publications

Complement in disease: a defence system turning offensive

Complement in disease: a defence system turning offensive

A previously unrecognized role of C3a in proteinuric progressive nephropathy

Exploring the role of C5a-C5aR1 signalling in development through pluripotent stem cell modelling

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