Dataset Information

The Pentraxins 1975-2018: Serendipity, Diagnostics and Drugs.

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).

SUBMITTER: Pepys MB

PROVIDER: S-EPMC6232782 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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The Pentraxins 1975-2018: Serendipity, Diagnostics and Drugs.

Pepys Mark B MB

Frontiers in immunology 20181016

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 propert ...[more]

PMID: 30459761

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Project description:Background: Neuroimmunology has impressively expanded in the past decade. Novel assays, especially cell-based assays (CBAs) can detect conformational antibodies (Abs) recognizing antigens in their native conformation. Generally, the availability of in-house and of commercial tests has improved the diagnostics, but introduced demanding laboratory tasks. Hence, standardization and quality controls represent a key step to promote accuracy. We report on the results of the 2018 external quality assessment program (EQAP) organized by the Italian Neuroimmunology Association. Methods: EQAP regarded 10 schemes, including oligoclonal bands (OCBs), intracellular-neuronal (ICN)-Abs, neuronal-surface (NS)-Abs, aquaporin-4 (AQP4)-Abs, myelin oligodendrocyte glycoprotein (MOG)-Abs, myelin-associated glycoprotein (MAG)-Abs, ganglioside-Abs, acetylcholine-receptor (AChR)-Abs, and muscle-specific-kinase (MuSK)-Abs, and 34 laboratories. Assays were classified as tissue-based assays (TBAs), solid-phase assays (SPAs), liquid-phase assays (LPAs), and CBAs. Thirty-three samples were provided. Results: Three-quarter of the tests were commercial. Median accuracy for the laboratories was 75% (range 50-100). In 8/10 schemes, at least one sample provided discrepant results. Inter-laboratory "substantial agreement" was found in 6/10 schemes (AChR, MuSK, MAG, AQP4, MOG, and NS-Abs), whereas the worst agreements regarded OCBs and ganglioside-Abs. Both commercial and in-house assays performed better in experienced laboratories. Conclusions: Assays could be divided in (a) robust commercial tests with substantial inter-laboratory agreement (MAG-Abs; AChR- and MuSK-Abs); commercial/"in-house" tests with (b) partial inter-laboratory agreement (AQP4-Abs, MOG-Abs, NS-Abs, ICN-Abs), and (c) with large inter-laboratory disagreement (OCBs, ganglioside-Abs). This real-life snapshot of the neuroimmunology test performances highlights shortcomings attributable to technician-dependent performances, assay structural limitations, and errors in test interpretations.

Project description:BackgroundAmong high-income countries, Japan has a low prevalence of obesity, but little is understood about subnational trends and variations in body mass index (BMI), largely owing to the lack of data from representative samples of prefectures. We aimed to examine long-term trends and distributions of adult BMI at the prefecture level in Japan from the late 1970s using a spatiotemporal model.MethodsWe obtained cross-sectional data for 233,988 men and 261,086 women aged 20-79 years from the 44 annual National Health and Nutrition Surveys (NHNS) conducted during 1975-2018. We applied a Bayesian spatiotemporal model to estimate the annual time series of age-standardized and age-specific mean BMI by 20-year age group and sex for each of the 47 prefectures. We assessed socioeconomic inequalities in BMI across prefectures using the concentration index, according to population density.ResultsIn men, the age-standardized prefectural mean BMI ranged from 21.7 kg/m2 (95% credible interval, 21.6-21.9) to 23.1 kg/m2 (22.9-23.4) in 1975 and from 23.5 kg/m2 (23.3-23.7) to 24.8 kg/m2 (24.6-25.1) in 2018. In women, the age-standardized prefectural mean BMI ranged from 22.0 kg/m2 (21.9-22.2) to 23.4 kg/m2 (23.2-23.6) in 1975 and from 21.7 kg/m2 (21.6-22.0) to 23.5 kg/m2 (23.2-23.8) in 2018. Mean BMI was highest in the southernmost prefecture for most of the study period, followed by northeast prefectures. The increase in mean BMI was largest in southwest prefectures, which caught up with northeast prefectures over time. The concentration index was negative, indicating higher BMI in less-populated prefectures. Absolute values of the concentration index were greater in women than in men and increased over time.ConclusionsThere were variations in adult mean BMI across prefectures, and geographic distributions changed over time. Further national and local efforts are needed to address the rising trend in mean BMI, particularly among men in rural prefectures, and socioeconomic inequalities among women. Bayesian hierarchical modeling is useful for reconstructing long-term spatiotemporal trends of mean BMI by integrating small-sized survey samples at the prefecture level in the NHNS.

Dataset Information

The Pentraxins 1975-2018: Serendipity, Diagnostics and Drugs.

Publications

The Pentraxins 1975-2018: Serendipity, Diagnostics and Drugs.

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