Abstract
The phylogenetically ancient, pentraxin family of plasma proteins, comprises C-reactive protein (CRP) and serum amyloid P component (SAP) in humans and the homologous proteins in other species. They are composed of five, identical, non-covalently associated protomers arranged with cyclic pentameric symmetry in a disc-like configuration. Each protomer has a calcium dependent site that mediates the particular specific ligand binding responsible for all the rigorously established functional properties of these proteins. No genetic deficiency of either human CRP or SAP has been reported, nor even any sequence polymorphism in the proteins themselves. Although their actual functions in humans are therefore unknown, gene deletion studies in mice demonstrate that both proteins can contribute to innate immunity. CRP is the classical human acute phase protein, routinely measured in clinical practice worldwide to monitor disease activity. Human SAP, which is not an acute phase protein, is a universal constituent of all human amyloid deposits as a result of its avid specific binding to amyloid fibrils of all types. SAP thereby contributes to amyloid formation and persistence in vivo. Whole body radiolabelled SAP scintigraphy safely and non-invasively localizes and quantifies systemic amyloid deposits, and has transformed understanding of the natural history of amyloidosis and its response to treatment. Human SAP is also a therapeutic target, both in amyloidosis and Alzheimer's disease. Our drug, miridesap, depletes SAP from the blood and the brain and is currently being tested in the DESPIAD clinical trial in Alzheimer's disease. Meanwhile, the obligate therapeutic partnership of miridesap, to deplete circulating SAP, and dezamizumab, a humanized monoclonal anti-SAP antibody that targets residual SAP in amyloid deposits, produces unprecedented removal of amyloid from the tissues and improves organ function. Human CRP binds to dead and damaged cells in vivo and activates complement and this can exacerbate pre-existing tissue damage. The adverse effects of CRP are completely abrogated by compounds that block its binding to autologous ligands and we are developing CRP inhibitor drugs. The present personal and critical perspective on the pentraxins reports, for the first time, the key role of serendipity in our work since 1975. (345 words)
Highlights
Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology
We formally demonstrated that the circulating serum amyloid P component (SAP) is the precursor of amyloid P component (AP) in amyloid deposits [94]
We showed that this resulted from the instant clearance of the SAP-carboxy-pyrrolidin-1-yl]-6-oxohexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) complex by the liver [72], 3In the artefactual, non-physiological, absence of calcium, SAP inhibits the formation of Aβ amyloid fibrils in vitro [106]
Summary
When I returned to clinical training at the Royal Postgraduate Medical School in London in 1973, after my PhD discovery of the role of complement in induction of antibody formation [1,2,3,4,5], the Head of Medicine, Professor (later Sir) Christopher Booth, advised to me to start a more clinical research project He suggested that I should “crack Crohn’s disease.”. Isolated CRP had a remarkably similar appearance (Figure 1) Both these homopentameric, calcium dependent, ligand binding, plasma proteins were composed of globular subunits arranged with cyclic symmetry in a disc like configuration. We confirmed immunochemically that our protein X was serum amyloid P component (SAP) [21], and my discovery of its calcium dependent binding to unsubstituted Sepharose explained its presence in Painter’s C1 preparations, showing that it had nothing to do with C1. The early discovery of classical pathway complement activation by CRP following its binding to macromolecular ligands [22, 23] withstood the test of time and it is unequivocally crucial for the role of CRP in exacerbation of tissue damage [24]
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