Proteinuria in amyloidosis correlates with epithelial detachment and distortion of amyloid fibrils

To obtain a better understanding of the mechanism of proteinuria in amyloidosis we investigated the ultrastructural distribution and pattern of arrangement of glomerular amyloid fibrils in 15 patients. Clinical data were correlated with the ultrastructural features and with the morphometric indices obtained from composite electron micrographs of whole glomeruli. The epithelial side of amyloid deposits showed spicules (discrete pointed bundles of fibrils) and apparent fraying which we termed tufts (ill-defined and diffuse expansion of fibrils). The extent of mesangial amyloid deposition and total GBM deposition did not correlate with proteinuria. Current data suggest the importance of partial detachment of epithelial cells in pathogenesis of proteinuria, which in turn correlates with distortion of amyloid fibrils, spicules and tufts.     

Vascular involvement and cell damage in experimental AA and clinical beta(2)-microglobulin amyloidosis.

BACKGROUND: Amyloidosis is a highly prevalent disease characterized by the deposition of amyloid fibrils. Although several types of amyloidosis can be identified according to their protein constituents and suggest putative aetiological factors, the causes of amyloidosis remain unknown. Furthermore, the cellular participation and the ultrastructural particularities of amyloidosis have received little attention. The aim of our study was to evaluate the vascular participation in amyloidosis and the cellular consequences of this disease. METHODS: Two forms of amyloidosis were studied: experimental amyloid A (AA) and clinical beta(2)-microglobulin amyloidosis. We studied kidney, liver, and spleen in a mouse model, and examined surgically obtained carpal deposits from dialysis patients. We used light and electron microscopy with immunogold labelling for anti-beta(2)-microglobulin and anti-AA protein antibodies. RESULTS: AA amyloid fibril accumulation was associated with membrane lesions in basal, cytoplasmic organelle (endoplasmic reticulum, mitochondria), and nuclear membranes. Amyloid fibrils from beta(2)-microglobulin amyloidosis were also closely associated with elastic fibres and endothelial basement membrane. We observed proliferation of endothelial cells as well as basement membrane enlargement and disruption. CONCLUSIONS: Vascular abnormalities, including endothelial enlargement, basement membrane modifications, and vascular proliferation were associated with amyloidosis. Amyloid fibrils have a high avidity for elastic fibres and are able to contact and damage the basement membrane, the cell and intracellular organelle membranes, as well as the nuclear envelope, suggesting a toxic effect of amyloid fibrils on cells.     

Impaired lysosomal processing of beta2-microglobulin by infiltrating macrophages in dialysis amyloidosis

BACKGROUND: Macrophages may participate in amyloid fibril formation by processing the protein precursor. Although this theory seems to apply for amyloidosis, in which proteolytic cleavage is a prerequisite for amyloid fibril formation, it has not been demonstrated for beta2-microglobulin (beta2m) amyloidosis. We aimed to establish the role played by macrophages in beta2m amyloidosis. METHODS: We used a double immunogold electron microscopy technique, including mouse antihuman CD68, rabbit antihuman beta2m, amyloid P component, and lysosome-associated membrane protein (LAMP-1) antibodies. Differential density labeling studies of beta2m and amyloid P component were performed extra- and intracellularly to assess protein processing by macrophages. RESULTS: The cells surrounding amyloid fibrils were found to be mostly CD68 positive, suggesting that they were of monocyte-macrophage lineage. Intracellular accumulation of amyloid fibrils was also observed; these fibrils were constantly surrounded by LAMP-1-linked gold particles, demonstrating that intracellular beta2m was almost exclusively lysosomal. The rough-surface endoplasmic reticulum was not labeled by beta2m antibody, suggesting that there was no active synthesis of beta2m by the cells. As a marker of endocytosis, protruded cytoplasmic processes in close relation with the intracellular accumulations of beta2m amyloid fibrils were observed. No difference in density labeling (extracellular vs. intracellular) was observed for beta2m, whereas intracellular P component labeling was significantly decreased. CONCLUSIONS: All of these data are strongly suggestive of phagocytosis and not synthesis of amyloid fibrils by macrophages. Further, they demonstrate an impaired lysosomal processing specific for beta2m, as other compounds of the amyloid fibrils (P component) are significantly cleared.     

Glycosaminoglycan and proteoglycan inhibit the depolymerization of beta2-microglobulin amyloid fibrils in vitro

BACKGROUND: Although several kinds of evidence suggest that glycosaminoglycans (GAGs) and proteoglycans (PGs) may contribute to the development of beta2-microglobulin-related (Abeta2m) amyloidosis, the precise roles of these molecules for the development of Abeta2m amyloidosis are poorly understood. METHODS: We investigated the effects of GAGs and PGs on the depolymerization of Abeta2m amyloid fibrils at a neutral pH, as well as on the formation of the fibrils at an acidic pH in vitro, using fluorescence spectroscopy with thioflavin T and electron microscopy. RESULTS: Depolymerization of Abeta2m amyloid fibrils at pH 7.5 at 37 degrees C was inhibited dose-dependently by the presence of some GAGs (heparin, dermatan sulfate, or heparan sulfate) or PGs (biglycan, decorin, or keratan sulfate proteoglycan). Electron microscopy revealed that a significant amount of Abeta2m amyloid fibrils remained in the reaction mixture with some lateral aggregation. Second, when monomeric beta2m was incubated with aggrecan, biglycan, decorin, or heparin at pH 2.5 at 37 degrees C for up to 21 days, the thioflavin T fluorescence increased depending on dose and time. Electron microscopy revealed the formation of rigid and straight fibrils similar to Abeta2m amyloid fibrils in beta2m incubated with biglycan for 21 days. CONCLUSION: These results suggest that some GAGs and PGs could enhance the deposition of Abeta2m amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of beta2m in the fibrils, as well as by acting as a scaffold for the polymerization of beta2m into the fibrils.     

Specific glycosaminoglycans promote unseeded amyloid formation from beta2-microglobulin under physiological conditions

Dialysis-related amyloidosis (DRA) is a complication of hemodialysis where beta2-microglobulin (beta2m) forms plaques mainly in cartilaginous tissues. The tissue-specific deposition, along with a known intransigence of pure beta2m to form fibrils in vitro at neutral pH in the absence of preformed fibrillar seeds, suggests a role for factors within cartilage in enhancing amyloid formation from this protein. To identify these factors, we determined the ability of a derivative lacking the N-terminal six amino acids found in ex vivo beta2m amyloid deposits to form amyloid fibrils at pH 7.4 in the absence of fibrillar seeds. We show that the addition of the glycosaminoglycans (GAGs) chrondroitin-4 or 6-sulfate to fibril growth assays results in the spontaneous generation of amyloid-like fibrils. By contrast, no fibrils are observed over the same time course in the presence of hyaluronic acid, a nonsulfated GAG that is abundant in cartilaginous joints. Based on the observation that hyaluronic acid has no effect on fibril stability, while chrondroitin-6-sulfate decreases the rate of fibril disassembly, we propose that the latter GAG enhances amyloid formation by stabilizing the rare fibrils that form spontaneously. This leads to the accumulation of beta2m in fibrillar deposits. Our data rationalize the joint-specific deposition of beta2m amyloid in DRA, suggesting mechanisms by which amyloid formation may be promoted.     

Inflammatory cell infiltration around beta 2-microglobulin amyloid deposition: histologic comparison of beta 2-microglobulin amyloidosis with AA or AL amyloidosis]

Thirty-one autopsy cases of beta 2-microglobulin (beta 2M) amyloidosis were pathologically investigated in comparison with 17 autopsy cases of AA or AL amyloidosis. In 20 cases (65%, 20/31) of beta 2M amyloidosis, inflammatory cells, mainly macrophages were seen infiltrating around beta 2M amyloid in intervertebral disks. The more beta 2M amyloidosis advances, the more macrophage infiltration tends to be prominent. In cases of severe beta 2M amyloidosis, the cytoplasm of macrophages around amyloid deposition were swollen with engulfed amyloid substance and were often transforming to foreign body multinucleated giant cells. In addition, granulation tissue was formed with infiltrating macrophages, foreign body multinucleated giant cells, capillary proliferation and fibrosis around beta 2M amyloid deposition. On the other hand, inflammatory cell infiltration around amyloid deposition was scarcely seen in AA or AL amyloidosis. Ultrastructurally, macrophages were abundant in phagocytic vacuoles containing amyloid fibrils. These macrophages were immunohistochemically positive for CD68, IL-1 beta and TNF-alpha. Thus, macrophage infiltration around beta 2M amyloid is thought to be responsible for local pain and tissue destruction of dialysis patients.     

Monomeric and dimeric {beta}2-microglobulin may be extracted from amyloid deposits in vitro

Background. There is a controversy as to whether {beta}2-microglobulin ({beta}2M amyloid deposits may be degraded resulting in regression and cure of amyloidosis. We have recently reported a long-term clinical study involving transplanted patients suggesting that there is no resorption of amyloid deposits in vivo, even after correction of the primary cause of amyloidosis. To progress in the study of the solubility of amyloid fibrils we performed an in vitro study with the intent to remove protein constituents from amyloid fibrils and amyloid deposits. Methods. Amyloid fibrils were prepurified from four amyloid deposits surgically obtained from carpal tunnel. They were incubated for 2 h with a phosphate-buffered saline (PBS) solution containing trypsin, collagenase, kallikrein, the three of them, or PBS alone. The experiments were repeated in the presence of the antiprotease &agr;2M). Results. Several bands were observed when the supernatants were run through SDS-PAGE. Western blotting identified in these bands the presence of &agr;2M, light chains of immunoglobulins and {beta}2M in mono- and dimeric form. The same proteins were solubilized with PBS alone. Equivalent results were obtained with crude amyloid deposits; however, {beta}2M presented almost exclusively in monomeric form. Conclusions. These results show that the protein constituents may be recovered from the amyloid fibrils in vitro. They also show that even the more insoluble {beta}2M dimers are resuspended by the action of PBS, with no need for proteases to cleave their attachment to the amyloid deposits.     

Nodular Amyloidosis Treated with a Pulsed Dye Laser

BACKGROUND: Nodular amyloidosis is a rare form of primary localized cutaneous amyloidosis which is characterized by single or multiple nodules located on the extremities, trunk, genitalia, or face. OBJECTIVE: To determine the clinical and histologic response of nodular amyloidosis to pulsed dye laser treatment. METHODS: Biopsy-proven amyloid nodules were treated with a 585-nm pulsed dye laser (average fluence 5.25 J/cm2; 10 mm spot) at 6- to 8-week time intervals. Clinical and histologic examination of laser-irradiated nodules were performed before and 6 weeks after the final laser treatment. RESULTS: Clinical improvement in the color, size, and pliability of nodules was noted and maintained for 6 months. Histologic examination revealed decreased inflammation and improvement in dermal collagen after laser irradiation. CONCLUSIONS: Since amyloid fibrils may be formed in association with dermatan sulfate-an essential matrix component in collagen fiber formation, it is postulated that the improvement seen in amyloid nodules after pulsed dye laser treatment may be attributed to a mechanism similar to that seen with hypertrophic scars.     

Immunohistochemical Identification of Amyloid,Using an Anti‐human Serum Amyloid P Component (SAP) Antibody,is Possible in Ruminants but not in Dogs and Cats

Amyloidosis represents a heterogenous group of diseases that have in common the deposition of fibrils composed of proteins of beta‐pleated sheet structure, a structure which can be specifically identified by histochemistry using the Congo red or similar stains. Amyloid consists primarily of the amyloid fibrils but also of the amyloid P component (AP). This component, which is identical with the serum counterpart (SAP), is found in all types of human amyloid, and immunohistochemical identification of AP has been proposed as an adjunct to the universal, type‐independent diagnosis of human amyloidosis. In the present study of animal amyloidosis, we compared the amyloid‐specific Congo red stain with an immunohistochemical protocol using an anti‐human SAP antibody for the identification of amyloid in formalin fixed tissue samples. The species and types of amyloidoses investigated were: (i) seven cows, one yak (Bos grunniens), and one sheep affected with amyloidosis of presumed AA type, (ii) one dog with a pancreatic endocrine tumour producing amyloid of presumed AIAPP type, (iii) two cats with presumed AIAPP‐amyloidosis of the islets of Langerhans, one cat with presumed AA‐amyloidosis, and one cat with an amyloid‐producing odontogenic tumour. Intense immunostaining co‐localized with amyloid, identified by its congophilia and green birefringence, using a protocol without any antigen retrieval in each of the seven cows, the yak and the sheep. The method seemed more sensitive in the ruminants than the Congo red stain, but was unable to detect amyloid in the dog and the cats regardless of the application of various antigen retrieval protocols. However, specific identification of amyloid still rests on the Congo red method or similar histochemical techniques.     

Ultrastructural localization of advanced glycation end products and beta2-microglobulin in dialysis amyloidosis

BACKGROUND: beta2-microglobulin (beta2m) is considered to be the amyloidogenic precursor in dialysis-related amyloidosis (DRA, Abeta2M amyloidosis). beta2m modified with advanced glycation end products (AGE) may be an important factor in the pathogenesis of DRA. The presence of AGE in beta2m-positive amyloid deposits and surrounding macrophages has been demonstrated by immunohistochemical techniques in light microscopy. METHODS: In order to better define the localization of beta2m and AGE in amyloid deposits and in cells, carpal tunnel connective tissues obtained from surgical specimens in six patients with DRA were studied by immunohistochemistry and electron microscopy, using the avidine-biotine complex and immunogold staining procedures, respectively. A polyclonal rabbit anti-human beta2m and two monoclonal mouse anti-AGE antibodies [AG-1 anti-imidazolone and AG-10 anti-N(epsilon)-carboxymethyl-lysine] enabled us to label their respective antigens at the optical and ultrastructural level. RESULTS: with both techniques, extracellular amyloid deposits strongly reacted with anti-beta2m and anti-AGE antibodies, although the immunoreactivity of beta2m was more intense. Macrophage-like synovial cells (CD-68 positive) surrounding amyloid deposits were also immunoreactive for beta2m and AGE, which were detected in lysosomes and in intracellular fibrillar material. Anti-AGE reactivity was also evident in collagenous structures in the absence of beta2m or amyloid deposits, supporting the proposal that AGE modification of collagen might have pathogenic relevance in the development of DRA. CONCLUSIONS: The co-localization of AGE and beta2m, both intra- and extra-cellularly, in amyloid fibrils was confirmed by immunoelectron microscopy; however, the positivity of collagen to anti-AGE antibodies and a different pattern of intracellular localization suggest that molecules other than beta2m may also be modified by AGE and may be involved in the pathogenesis of DRA.     

Glycosaminoglycans enhance the trifluoroethanol-induced extension of beta 2-microglobulin-related amyloid fibrils at a neutral pH

beta(2)-Microglobulin-related (A beta 2M) amyloidosis is a frequent and serious complication in patients on long-term dialysis, and beta(2)-microglobulin is a major structural component of A beta 2M amyloid fibrils. Several biologic molecules inhibiting the depolymerization of A beta 2M amyloid fibrils at a neutral pH were found recently. The effect of trifluoroethanol and glycosaminoglycans (GAG) on the extension of the fibrils at a neutral pH was investigated with the use of fluorescence spectroscopy with thioflavin T, circular dichroism spectroscopy, and electron microscopy. Trifluoroethanol at concentrations of up to 20% (vol/vol) caused fibril extension of heparin-stabilized seeds, inducing a subtle change in the tertiary structure of beta(2)-microglobulin and stabilizing the fibrils at a neutral pH. This extension reaction followed a first-order kinetic model. In addition, some GAG, especially heparin, dose-dependently enhanced the fibril extension. These results suggest that some GAG, especially heparin, may bind to the fibrils and enhance their deposition in vivo. Thus, the experimental system described here should be useful to search for the factors that accelerate A beta 2M amyloid deposition in vivo. In addition, the interference of the binding of GAG to A beta 2M amyloid fibrils may be an attractive therapeutic modality.     

Clinical, radiological and serum amyloid P component scintigraphic features of beta2-microglobulin amyloidosis associated with continuous ambulatory peritoneal dialysis.

BACKGROUND: Beta2-Microglobulin (beta2M) amyloidosis occurs in patients with end-stage renal failure (ESRF) who undergo long-term continuous ambulatory peritoneal dialysis (CAPD), but its prevalence in patients treated exclusively by CAPD is unknown. In addition, its features may differ from those of haemodialysis-associated beta2M amyloidosis because CAPD is more biocompatible. METHODS: We performed serum amyloid P component (SAP) scintigraphy, a specific technique for imaging amyloid deposits, in 13 consecutive patients with ESRF who had been dialysed for >5 years, at least 80% of the time by CAPD. Clinical and radiological features of beta2M amyloidosis were sought and compared with the results of SAP scintigraphy. RESULTS: SAP scans showed articular amyloid deposits in seven patients, all of whom had evidence of carpal tunnel syndrome and four of whom had arthralgia characteristic of dialysis amyloidosis. Typical radiographic bone cysts were present in only one case who had been dialysed for >17 years. The remaining six patients had no clinical, radiological or scintigraphic evidence of beta2M amyloidosis. CONCLUSIONS: The prevalence of beta2M amyloidosis in this study was comparable with that in reported haemodialysis populations. Many of the amyloid deposits demonstrated by SAP scintigraphy were not associated with symptoms, but larger and longer term studies are required to determine whether CAPD favourably influences their clinical expression.     

Dialysis-related amyloidosis: history and clinical manifestations

Dialysis-related amyloidosis (DRA) or beta(2)-microglobulin amyloidosis (A beta(2)M) is a unique type of amyloidosis that has been described in individuals with both long-standing chronic renal disease and end-stage renal disease (ESRD). It has been associated with serious complications that significantly add to the morbidity of long-term dialysis patients. The deposition of beta(2)M in amyloid fibrils in various joint and osteoarticular surfaces leads to the clinical complaints and findings typical of this disorder. However, a visceral form with systemic organ involvement has also been described. Despite advances in the understanding of this disorder and in the delivery of dialysis, the ability to alter the incidence of DRA and its course remains uncertain.     

Renal Amyloidosis

Amyloidosis is an uncommon group of diseases in which soluble proteins aggregate and deposit extracellularly in tissue as insoluble fibrils, leading to tissue destruction and progressive organ dysfunction. More than 25 proteins have been identified as amyloid precursor proteins. Amyloid fibrils have a characteristic appearance on ultrastructural examination and generate anomalous colors under polarized light. Amyloidosis can be systemic or localized. The kidney is a prime site for amyloid deposition. Immunofluorescence, immunoperoxidase, and more recently laser microdissection and mass spectrometry are important tools used in the typing of renal amyloidosis.     

Tissue distribution of dialysis amyloidosis

Twenty-three uremic patients on intermittent hemodialysis for eight to eighteen years provided the material for the present pathological study. In all of them, there was evidence for dialysis related amyloidosis based on previous clinical or histological findings or both. The material examined consisted of nine skin biopsies, five abdominal fat aspirates, eight trans-iliac bone biopsies and numerous post-mortem specimens of various visceral organs from eight cases. None of the skin biopsies or fat aspirates showed amyloid deposits. In only one bone biopsy could a small Congo red positive area be recognized that showed characteristic birefringence under polarizing light. Autopsy material findings were negative except for one case: this patient had been dialyzed for 18 years. Very minute amyloid deposits with a positive immunofluorescence staining for beta 2-microglobulin (beta 2-M) were found in the walls of small vessels from her lung, heart, liver and intestine. Thus, in chronic hemodialysis patients the accumulation of beta 2-M amyloid fibrils in tissues other than joints and juxta-articular structures appears to have a low incidence, to occur lately and to be of limited size. Although extra-articular amyloid deposits may progressively occur and extend with increasing survival time on dialysis, tiny deposits such as those observed in only two of our patients will hardly lead to serious complications.     

Systemic light chain deposition disease presenting as multiple pulmonary nodules. A case report and review of the literature

This case report describes the primary manifestation of systemic light chain deposition disease as bilateral nodules on chest radiographs. Although this case was initially classified as amyloidosis, a subsequent renal biopsy and ultrastructural, histochemical, and immunohistochemical studies allowed its distinction from amyloidosis. Kappa light chains were expressed with immunoperoxidase studies on paraffin-embedded tissue, and ultrastructural studies showed the dense, granular deposits characteristic of systemic light chain deposition disease. Serum and urine electrophoresis showed a monoclonal spike, but no plasmacytosis was identified at bone marrow biopsy and autopsy. The literature on this subject is also herein reviewed, with particular attention to the extrarenal manifestations of systemic light chain deposition disease.     

Demonstration of plasma proteinase inhibitors in beta 2-microglobulin amyloid deposits.

beta 2-microglobulin-related amyloidosis (A beta 2M) represents a frequent complication in long-term dialysis patients. Although the pathogenetic mechanism has yet to be fully understood, it is known that amyloid fibrils usually consist of intact molecules of beta 2-microglobulin (beta 2m). Plasma proteinase inhibitors (PPI) are a broad family of glycoproteins with the function of eliminating unwanted proteolysis of serine proteases. Their role in amyloidogenesis has become a subject of intense discussion, especially since the recent identification of alpha 1-antichymotrypsin in the beta-protein amyloid deposits of Alzheimer's disease. We evaluated immunohistochemically and biochemically the presence and distribution of several PPIs (alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, antithrombin III, alpha 2-macroglobulin and tissue inhibitor metalloproteinase) and amyloid P component in A beta 2M deposits in osteo-articular and visceral tissues from dialysis patients with amyloidosis, as well as two carpal tunnel synovia from non-dialysis patients and one Alzheimer's brain as controls. The immunohistochemical study demonstrated that all but one (anti-alpha 1-antichymotrypsin) of the PPI antibodies tested showed varying degrees of positive reaction against A beta 2M deposits. All the antibodies (including anti-alpha 1-antichymotrypsin) also reacted to some extent with other non-amyloid visceral and connective tissue elements diffusely and/or selectively. Among them, only the reaction of anti-amyloid P component had significantly distinctive localization to A beta 2M deposits, which were identified in adjacent serial sections by Congo red staining and immunohistochemical reaction against anti-beta 2m.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal amyloidosis in children

Renal amyloidosis is a detrimental disease caused by the deposition of amyloid fibrils. A child with renal amyloidosis may present with proteinuria or nephrotic syndrome. Chronic renal failure may follow. Amyloid fibrils may deposit in other organs as well. The diagnosis is through the typical appearance on histopathology. Although chronic infections and chronic inflammatory diseases used to be the causes of secondary amyloidosis in children, the most frequent cause is now autoinflammatory diseases. Among this group of diseases, the most frequent one throughout the world is familial Mediterranean fever (FMF). FMF is typically characterized by attacks of clinical inflammation in the form of fever and serositis and high acute-phase reactants. Persisting inflammation in inadequately treated disease is associated with the development of secondary amyloidosis. The main treatment is colchicine. A number of other monogenic autoinflammatory diseases have also been identified. Among them cryopyrin-associated periodic syndrome (CAPS) is outstanding with its clinical features and the predilection to develop secondary amyloidosis in untreated cases. The treatment of secondary amyloidosis mainly depends on the treatment of the disease. However, a number of new treatments for amyloid per se are in the pipeline.     

Nodular macroglossia with combined light chain and beta-2 microglobulin deposition in a long-term dialysis patient.

We describe a case in which nodular macroglossia, a very rare type of tongue involvement, was associated with the co-deposition of lambda light chain and beta-2 microglobulin fibrils in the tongue. The combined presence of two different amyloid fibrils did not lead to a more unfavourable clinical outcome. We believe that both these features often remain underdiagnosed and are in fact more frequent than reported. A careful clinical examination of the tongue together with serum immunofixation should be routine in all patients with dialysis-related amyloidosis in order to investigate the prevalence and type of tongue involvement and to rule out other types of amyloidosis. In all cases of suspected mixed amyloidosis, immunohistochemical characterization of fibrils should be carried out by electron microscopy.     

UNRESOLVED ISSUES IN DIALYSIS: Dialysis‐Related Amyloidosis: Late Finding or Hidden Epidemic?

Dialysis-related amyloidosis is a complication of end-stage renal disease (ESRD) that results from retention of beta2-microglobulin (beta2M) and its deposition as amyloid fibrils into osteoarticular tissue. The clinical manifestations usually develop after several years of dialysis dependence and include carpal tunnel syndrome, destructive arthropathy, and bone cysts and fractures. High-flux membranes, daily dialysis, and hemofiltration all would be expected to delay the onset of dialysis-related amyloidosis because, to varying degrees, each increases the clearance of beta2M from the plasma. Thus what is currently a late complication of ESRD might become an even later complication as dialysis practices change. The significance of histologically evident but clinically silent beta2M amyloid, detectable not only in osteoarticular tissue but also in blood vessels, is unclear. Accumulating evidence that amyloidogenic proteins have direct and specific effects on cell processes irrespective of the extent of amyloid deposition raises the possibility that early, clinically silent beta2M amyloid deposits have unrecognized importance.