Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

Disease-associated amyloid deposits contain both fibrillar and nonfibrillar components. The majority of these amyloid components originate or coexist in the bloodstream. To understand the nature of the interaction between the nonfibrillar and fibrillar components, we have developed a centrifugation method to isolate fibril binding proteins from human serum. Amyloid fibrils composed of either Abeta peptide or apolipoprotein C-II (apoC-II) cosedimented with specific serum proteins. Gel electrophoresis, mass spectrometry peptide fingerprinting, and Western analysis identified the major binding species as proteins found in HDL particles, including apoA-I, apoA-II, apoE, clusterin, and serum amyloid A. Sedimentation analysis showed that purified human HDL and recombinant apoA-I lipid particles bound directly to Abeta and apoC-II amyloid fibrils. These studies reveal a novel function of HDL that may contribute to the well-established protective effect of this lipoprotein class in heart disease.

Final Analysis of the Phase 1a/b Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with Relapsed or Refractory AL Amyloidosis

Cardiac amyloidosis is a form of restrictive infiltrative cardiomyopathy that confers significant mortality. Due to the relative rarity of cardiac amyloidosis, clinical and diagnostic expertise in the recognition and evaluation of individuals with suspected amyloidosis is mostly limited to a few expert centers. Electrocardiography, echocardiography, and radionuclide imaging have been used for the evaluation of cardiac amyloidosis for over 40 years.1-3 Although cardiovascular magnetic resonance (CMR) has also been in clinical practice for several decades, it was not applied to cardiac amyloidosis until the late 1990s. Despite an abundance of diagnostic imaging options, cardiac amyloidosis remains largely underrecognized or delayed in diagnosis.4 While advanced imaging options for noninvasive evaluation have substantially expanded, the evidence is predominately confined to single-center small studies or limited multicenter larger experiences, and there continues to be no clear consensus on standardized imaging pathways in cardiac amyloidosis. This lack of guidance is particularly problematic given that there are numerous emerging therapeutic options for this morbid disease, increasing the importance of accurate recognition at earlier stages. Imaging provides non-invasive tools for follow-up of disease remission/progression complementing clinical evaluation. Additional areas not defined include appropriate clinical indications for imaging, optimal imaging utilization by clinical presentation, accepted imaging methods, accurate image interpretation, and comprehensive and clear reporting. Prospective randomized clinical trial data for the diagnosis of amyloidosis and for imaging-based strategies for treatment are not available. A consensus of expert opinion is greatly needed to guide the appropriate clinical utilization of imaging in cardiac amyloidosis.

Systemic amyloidosis is a relatively rare multisystem disease caused by the deposition of misfolded protein in various tissues and organs. It may present to almost any specialty, and diagnosis is frequently delayed.[1][1] Cardiac involvement is a leading cause of morbidity and mortality, especially

<p>Prolonged injection of casein results in Systemic amyloidosis in mice with impaired hepatic functions due to excessive serum amyloid A (SAA) fibril deposition in liver, spleen and kidney. In the present work, we have shown that Systemic amyloidosis results in accumulation of SAA fibrils in the brain. We have carried out radiolabeling studies to source the SAA fibrils and serum amyloid P component (SAP) that are present in the brain of the affected mice.<strong> </strong>Results of these experiments suggest that the systemic amyloidosis results in selective crossing of SAA and SAP proteins through blood brain barrier (BBB). Injection of <sup>125</sup>I SAA and <sup>125</sup>I SAP to casein treated mice resulted in the accumulation of these proteins in the liver to the maximum extent and to about 20% (compared to liver) localization in the brain. The Congo red stained polarizing microscopic pictures of the cerebral cortex have shown the presence of amyloid fibrils in the brain of the mice with systemic amyloidosis. Immunohistochemical studies also indicate that the abundance of SAA and SAP in the mice brain following chronic systemic amyloidosis condition. The present study provides a basis for investigation on the effect of systemic amyloidosis to the brain in chronic inflammation of mouse.</p>

Analysis of the Phase 1a/b Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with AL Amyloidosis

Background In systemic amyloidosis, disease is caused by extracellular accumulation of amyloid fibrils which, unlike other interstitial debris, are not cleared and which disrupt tissue structure and function. Direct removal of amyloid deposits is required to preserve and possibly restore tissue and organ function. We are targeting serum amyloid P component (SAP) for this purpose. SAP normal plasma protein is a normal plasma protein which binds to all amyloid fibrils and is thus always present in all human amyloid deposits. Administration of hexanoyl bis (D–proline) (CPHPC) swiftly depletes circulating SAP but leaves some SAP in amyloid deposits as an amyloidspecific antigen target. In human SAP transgenic mice with systemic AA amyloidosis, CPHPC treatment, to deplete human SAP from the plasma, followed by a single dose of anti-human SAP antibodies produced swift, almost complete, clearance of visceral amyloid (Bodin et al. Nature, 2010;468:93-7). In a mouse SAA transgenic systemic amyloidosis model, which uniquely includes cardiac amyloid, a second dose of anti–SAP antibody, after the first dose had eliminated massive liver and spleen deposits, significantly removed amyloid from the heart (Simons et al. Proc Natl Acad Sci USA. 2013;110:1611520). Amyloid clearance by anti-SAP antibody required classical complement pathway activation and macrophages. Amyloid destruction was mediated by multinucleated giant cells (MGCs), formed by macrophage fusion. MGCs have abundant surface membrane ruffles, enabling the engulfment of very large complement opsonised amyloid targets which were then swiftly destroyed within phagolysosomes. Amyloid clearance was maximal by 14 days. No ill effects were detected. After licensing this new treatment in February 2009, GlaxoSmithKline (GSK) fully humanised our optimal mouse monoclonal anti-SAP antibody and prepared for the first in human clinical study that started in June 2013. We have lately reported that a single dose of humanized monoclonal anti-SAP antibody, following depletion of circulating SAP by CPHPC, substantially reduced the amyloid load, especially from the liver, in patients with systemic AL, AA and AApoAI amyloidosis, (Richards et al, New Engl J Med, July 15 2015; DOI: 10.1056/NEJMoa1504942).

Extracellular deposition of amyloid fibrils is responsible for the pathology in the systemic amyloidoses and probably also in Alzheimer disease [Haass, C. & Selkoe, D. J. (1993) Cell 75, 1039-1042] and type II diabetes mellitus [Lorenzo, A., Razzaboni, B., Weir, G. C. & Yankner, B. A. (1994) Nature (London) 368, 756-760]. The fibrils themselves are relatively resistant to proteolysis in vitro but amyloid deposits do regress in vivo, usually with clinical benefit, if new amyloid fibril formation can be halted. Serum amyloid P component (SAP) binds to all types of amyloid fibrils and is a universal constituent of amyloid deposits, including the plaques, amorphous amyloid beta protein deposits and neurofibrillary tangles of Alzheimer disease [Coria, F., Castano, E., Prelli, F., Larrondo-Lillo, M., van Duinen, S., Shelanski, M. L. & Frangione, B. (1988) Lab. Invest. 58, 454-458; Duong, T., Pommier, E. C. & Scheibel, A. B. (1989) Acta Neuropathol. 78, 429-437]. Here we show that SAP prevents proteolysis of the amyloid fibrils of Alzheimer disease, of systemic amyloid A amyloidosis and of systemic monoclonal light chain amyloidosis and may thereby contribute to their persistence in vivo. SAP is not an enzyme inhibitor and is protective only when bound to the fibrils. Interference with binding of SAP to amyloid fibrils in vivo is thus an attractive therapeutic objective, achievement of which should promote regression of the deposits.

The Clinical Impact of Proteomics in Amyloid Typing

Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one per thousand deaths in developed countries1. Localised amyloid can also be very serious, for example cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present1. There is therefore a major unmet medical need for therapy which safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor protein can arrest amyloid accumulation1. Unfortunately control of fibril protein production is not possible in some forms of amyloidosis and in others is often slow and hazardous1. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar, plasma glycoprotein, serum amyloid P component (SAP)2, 3. Here we show that administration of anti-human SAP antibodies to mice with amyloid deposits containing human SAP, triggers a potent, complement dependent, macrophage-derived giant cell reaction which swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-D-proline compound, CPHPC4, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis.

The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XIIIth International Symposium, May 6–10, 2012, Groningen, The Netherlands, to formulate recommendations on amyloid fibril protein nomenclature and to consider newly identified candidate amyloid fibril proteins for inclusion in the ISA Amyloid Fibril Protein Nomenclature List. The need to promote utilization of consistent and up to date terminology for both fibril chemistry and clinical classification of the resultant disease syndrome was emphasized. Amyloid fibril nomenclature is based on the chemical identity of the amyloid fibril forming protein; clinical classification of the amyloidosis should be as well. Although the importance of fibril chemistry to the disease process has been recognized for more than 40 years, to this day the literature contains clinical and histochemical designations that were used when the chemical diversity of amyloid diseases was poorly understood. Thus, the continued use of disease classifications such as familial amyloid neuropathy and familial amyloid cardiomyopathy generates confusion. An amyloid fibril protein is defined as follows: the protein must occur in body tissue deposits and exhibit both affinity for Congo red and green birefringence when Congo red stained deposits are viewed by polarization microscopy. Furthermore, the chemical identity of the protein must have been unambiguously characterized by protein sequence analysis when so is practically possible. Thus, in nearly all cases, it is insufficient to demonstrate mutation in the gene of a candidate amyloid protein; the protein itself must be identified as an amyloid fibril protein. Current ISA Amyloid Fibril Protein Nomenclature Lists of 30 human and 10 animal fibril proteins are provided together with a list of inclusion bodies that, although intracellular, exhibit some or all of the properties of the mainly extracellular amyloid fibrils.

Characterization of the Binding of Serum Amyloid P to Laminin

Risk Of Progression Of Localised Amyloidosis To Systemic Disease In 606 Patients Over 30 Years

The ISA Nomenclature Committee met at the XIX International Symposium of Amyloidosis in Rochester, MN, 27 May 2024. The in-person event was followed by many electronic discussions, resulting in the current updated recommendations. The general nomenclature principles are unchanged. The total number of human amyloid fibril proteins is now 42 of which 19 are associated with systemic deposition, while 4 occur with either localised or systemic deposits. Most systemic amyloidoses are caused by the presence of protein variants which promote misfolding. However, in the cases of AA and ATTR the deposits most commonly consist of wild-type proteins and/or their fragments. One peptide drug, previously reported to create local iatrogenic amyloid deposits at its injection site, has been shown to induce rare instances of systemic deposition. The number of described animal amyloid fibril proteins is now 16, 2 of which are unknown in humans. Recognition of the importance of intracellular protein aggregates, which may have amyloid or amyloid-like properties, in many neurodegenerative diseases is rapidly increasing and their significance is discussed.