Immunoglobulin light chain (AL)-amyloidosis was one of the first types of amyloidosis discovered and still little is known about its pathogenic mechanisms. One major obstacle is the very heterogeneous condition; in fact, every patient could be considered to have their own disease since symptoms and outcome vary enormously. The reason for this is not known but intrinsic factors of the immunoglobulin light chain (LC) and the fact that every LC is unique seem to be important. Post-translational modifications such as glycosylation and proteolysis are most certainly involved. By using western blotting, we studied in detail the proteolytic pattern in six patients with AL-amyloidosis of kappa type with the aid of three peptide antisera against two domains in the constant segment and one conserved domain in framework 3 of the variable region. Materials from one to five organs were analysed. The result clearly demonstrates that the fragmentation pattern was similar in amyloid of different organs in one patient but differed greatly between patients. Full-length, N-, and C-terminal fragments were detected with the three antisera. The results strongly support the hypothesis that proteolytic cleavage occurs after fibril formation.
Antiserum specific for human prealbumin (HPA) was studied by indirect immunofluorescence on tissue sections of cardiac ventricles containing senile cardiac amyloid. The pattern of reactivity was identical to that previously reported for an antiserum specific for protein ASc1 (formerly designated ASCA present in these tissues. Anti-HPA failed to react with isolated atrial amyloid (IAA), primary amyloid (A lambda I, A lambda IV, A lambda VI), secondary amyloid (AA), amyloid associated with medullary carcinoma of the thyroid (AEt), pancreatic amyloid associated with adult onset diabetes, cerebral amyloid present in Alzheimer's disease or lichen amyloid. THe reaction of anti-HPA was completely blocked by purified human prealbumin but was not influenced by absorption with purified human albumin or proteins extracted from any amyloid types tested. The anti-HPA reaction was also completely blocked by purified protein ASc1, and the reaction of anti-ASc1 was similarly blocked by purified HPA. These studies suggest that senile cardiac amyloid of the ASc1 type contains prealbumin or a protein antigenically closely related to this molecule.
Islet amyloid polypeptide (IAPP, "amylin") has been proposed as having important roles in the pathogenesis of type 2 diabetes mellitus via its biological activity and by forming islet amyloid. The domestic cat develops a type of diabetes that closely resembles type 2 diabetes in humans, including the frequent formation of islet amyloid deposits in the impaired glucose tolerant (IGT) and diabetic state. With the aid of computerized image analysis and immuno-histochemistry, we examined the IAPP and insulin content inpancreatic islets of normal, IGT and diabetic cats. IAPP immunoreactivity in beta cells from IGT cats was significantly stronger (p < 0.01) as compared with cells from normal cats, while the insulin labelling strength was unchanged. Overtly diabetic cats were usually almost devoid of beta cells. As in humans, cellular IAPP but not IAPP in islet amyloid deposits was labelled by the newly developed monoclonal antibody to IAPP 4A5, thus providing further evidence that IAPP is modified by a yet unknown mechanism during the amyloidogenic process. The study provides evidence that an increased beta cell storage of IAPP independent of insulin may be an important factor in the early phase of the development of islet amyloid in this form of diabetes.
Twelve patients with primary amyloidosis (AL) were investigated with magnetic resonance imaging (MRI). In 9 patients an abnormal thickening of the heart walls was present and in 2 macroglossia was found at MRI. T1 was significantly increased in liver (p less than 0.05) and subcutaneous fat (p less than 0.01) while it was decreased in the spleen (p less than 0.05). T2 was significantly decreased (p less than 0.01) in the spleen in patients with amyloidosis, while it was not significantly altered in the liver or subcutaneous fat. After therapy T1 of the liver was reduced towards normal values in 4 patients. It is concluded that MRI might be a method to quantitate the amount of amyloid deposits in the tissue, and that the effect of therapy may be monitored with this technique.
The ISA Nomenclature Committee met electronically before and directly after the XVII ISA International Symposium on Amyloidosis, which, unfortunately, had to be virtual in September 2020 due to the ongoing COVID-19 pandemic instead of a planned meeting in Tarragona in March. In addition to confirmation of basic nomenclature, several additional concepts were discussed, which are used in scientific amyloid literature. Among such concepts are cytotoxic oligomers, protofibrils, primary and secondary nucleation, seeding and cross-seeding, amyloid signature proteins, and amyloid plaques. Recommendations for their use are given. Definitions of amyloid and amyloidosis are confirmed. Possible novel human amyloid fibril proteins, appearing as 'classical' in vivo amyloid, were discussed. It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins. There are several possible amyloid proteins under investigation, and these are included in a new Table.
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