Transthyretin amyloidosis: new answers but many questions

Major recent advances in understanding of systemic transthyretin (ATTR) amyloidosis include the universal recognition that cardiac wild type ATTR amyloidosis is a prevalent cause of fatal heart failure with preserved ejection fraction (HFpEF) and/or fatal arrhythmia in the elderly, predominantly in men. ATTR amyloid cardiomyopathy is strongly associated with carpal tunnel syndrome, caused by wild type ATTR amyloid deposition in the carpal ligaments. The very interesting study by Eldhagen et al in this issue sheds further light on the association between cardiac and ligament ATTR amyloid but tantalisingly leaves several crucial questions unanswered

ROLE OF COMPLEMENT IN INDUCTION OF ANTIBODY PRODUCTION IN VIVO : EFFECT OF COBRA FACTOR AND OTHER C3-REACTIVE AGENTS ON THYMUS-DEPENDENT AND THYMUS-INDEPENDENT ANTIBODY RESPONSES

In an in vivo study in mice, suppression by the C3-cleaving protein of cobra venom (CoF), and other C3-reactive agents (zymosan, aggregated IgG, anti-C3 antibodies, and type III pneumococcal polysaccharide) of the thymus-dependent antibody responses to sheep erythrocytes, ovalbumin, and human IgG was demonstrated. The thymus-independent antibody response to polyvinyl-pyrrolidone was however unaffected by CoF. These and other published observations suggest that there may be a requirement for functional C3 in induction of thymus-dependent but not thymus-independent antibody production. A model for the role of C3 in lymphocyte cooperation is proposed based on these data analyzed in the light of existing knowledge of this process. It is postulated that fixed C3 interacting with macrophage See PDF for Structure and B-cell C3 receptors might enhance or facilitate T-dependent presentation of antigen to B cells

Immunoradiometric assay of circulating C-reactive protein: age-related values in the adult general population

Background: Increased values of C-reactive protein (CRP), the classical acute phase protein, within the range below 5 mg/L, previously considered to be within the reference interval, are strongly associated with increased risk of atherothrombotic events, and are clinically significant in osteoarthritis and neonatal infection.<br/> Methods: A robust new polyclonal-monoclonal solid-phase IRMA for CRP was developed, with a range of 0.05- 10.0 mg/L.<br/> Results: Plasma CRP values in general adult populations from Augsburg, Germany (2291 males and 2203 females; ages, 25-74 years) and Glasgow, Scotland (604 males and 650 females; ages, 25-64 years) were very similar. The median CRP approximately doubled with age, from similar to 1 mg/L in the youngest decade to similar to 2 mg/L in the oldest, and tended to be higher in females. <br/>Conclusion: This extensive data set, the largest such study of CRP, provides valuable reference information for future clinical and epidemiological investigations

Misdiagnosis of hereditary amyloidosis as AL (Primary) amyloidosis

Background: Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes encoding transthyretin, fibrinogen A -chain, lysozyme, or apolipoprotein A-I, is thought to be extremely rare and is not routinely included in the differential diagnosis of systemic amyloidosis unless there is a family history. Methods: We studied 350 patients with systemic amyloidosis, in whom a diagnosis of the light-chain (AL) type of the disorder had been suggested by clinical and laboratory findings and by the absence of a family history, to assess whether they had amyloidogenic mutations. Results: Amyloidogenic mutations were present in 34 of the 350 patients (9.7 percent), most often in the genes encoding fibrinogen A -chain (18 patients) and transthyretin (13 patients). In all 34 of these patients, the diagnosis of hereditary amyloidosis was confirmed by additional investigations. A low-grade monoclonal gammopathy was detected in 8 of the 34 patients (24 percent). Conclusions: A genetic cause should be sought in all patients with amyloidosis that is not the reactive systemic amyloid A type and in whom confirmation of the AL type cannot be obtained

The Pentraxins 1975–2018: Serendipity, Diagnostics and Drugs

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

Phylogeny and expression analysis of C-reactive protein (CRP) and serum amyloid-P (SAP) like genes reveal two distinct groups in fish

This work was funded by British Society of Animal Science/Genesis Faraday to both SAM and SB Immune control of energy reallocation in fish and a BBSRC Research Experience Placements (2010).Peer reviewedPublisher PD

Inflammation and endothelial function: Direct vascular effects of human C-reactive protein on nitric oxide bioavailability

Background - Circulating concentrations of the sensitive inflammatory marker C-reactive protein (CRP) predict future cardiovascular events, and CRP is elevated during sepsis and inflammation, when vascular reactivity may be modulated. We therefore investigated the direct effect of CRP on vascular reactivity. Methods and Results - The effects of isolated, pure human CRP on vasoreactivity and protein expression were studied in vascular rings and cells in vitro, and effects on blood pressure were studied in rats in vivo. The temporal relationship between changes in CRP concentration and brachial flow-mediated dilation was also studied in humans after vaccination with Salmonella typhi capsular polysaccharide, a model of inflammatory endothelial dysfunction. In contrast to some previous reports, highly purified and well-characterized human CRP specifically induced hyporeactivity to phenylephrine in rings of human internal mammary artery and rat aorta that was mediated through physiological antagonism by nitric oxide (NO). CRP did not alter endothelial NO synthase protein expression but increased protein expression of GTP cyclohydrolase-1, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, the NO synthase cofactor. In the vaccine model of inflammatory endothelial dysfunction in humans, increased CRP concentration coincided with the resolution rather than the development of endothelial dysfunction, consistent with the vitro findings; however, administration of human CRP to rats had no effect on blood pressure. Conclusions - Pure human CRP has specific, direct effects on vascular function in vitro via increased NO production; however, further clarification of the effect, if any, of CRP on vascular reactivity in humans in vivo will require clinical studies using specific inhibitors of CRP. © 2005 American Heart Association, Inc