Glycosaminoglycans are part of amyloid fibrils: Ultrastructural evidence in avian AA amyloid stained with cuprolinic blue and labeled with immunogold

Gruys, E.; Ultée, A. J.; Upragarin, Narin

doi:10.1080/13506120500535768

Cited by 19 publications

(15 citation statements)

References 42 publications

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“…Previously, Cuprolinic blue or sulfated Alcian blue have been used to show the association of sulfated GAGs with collagen fibrils (23,24). Our images on tissue confirm those studies performed previously with Cuprolinic blue or sulfated Alcian blue on tissue with amyloid-associated amyloid (36,37). In other reports, Jiang et al (38) showed that the interaction of heparin and AL LC depended on concentration and mass.…”

Section: Discussionsupporting

confidence: 80%

Role of Glycosaminoglycan Sulfation in the Formation of Immunoglobulin Light Chain Amyloid Oligomers and Fibrils

Ren

Hong

Gong³

et al. 2010

Journal of Biological Chemistry

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Primary amyloidosis (AL) results from overproduction of unstable monoclonal immunoglobulin light chains (LCs) and the deposition of insoluble fibrils in tissues, leading to fatal organ disease. Glycosaminoglycans (GAGs) are associated with AL fibrils and have been successfully targeted in the treatment of other forms of amyloidosis. We investigated the role of GAGs in LC fibrillogenesis. Ex vivo tissue amyloid fibrils were extracted and examined for structure and associated GAGs. The GAGs were detected along the length of the fibril strand, and the periodicity of heparan sulfate (HS) along the LC fibrils generated in vitro was similar to that of the ex vivo fibrils. To examine the role of sulfated GAGs on AL oligomer and fibril formation in vitro, a 1 LC purified from urine of a patient with AL amyloidosis was incubated in the presence or absence of GAGs. The fibrils generated in vitro at physiologic concentration, temperature, and pH shared morphologic characteristics with the ex vivo 1 amyloid fibrils. The presence of HS and over-O-sulfatedheparin enhanced the formation of oligomers and fibrils with HS promoting the most rapid transition. In contrast, GAGs did not enhance fibril formation of a non-amyloidogenic 1 LC purified from urine of a patient with multiple myeloma. The data indicate that the characteristics of the full-length 1 amyloidogenic LC, containing post-translational modifications, possess key elements that influence interactions of the LC with HS. These findings highlight the importance of the variable and constant LC regions in GAG interaction and suggest potential therapeutic targets for treatment.Amyloid deposition is hypothesized to play a role in many diseases including rheumatoid arthritis and diabetes, as well as the amyloidoses themselves (1). The amyloidoses are a group of systemic and localized diseases that exhibit deposition of insoluble fibrillar proteins in organs and tissues. Primary amyloidosis (AL) 2 is the most common systemic form in the UnitedStates. It results from a plasma cell dyscrasia in which clonal B cells produce an excess of amyloidogenic immunoglobulin light chains (LCs), which circulate and deposit as insoluble fibrils throughout the body (2). A structural rearrangement from nonfibril-prone oligomers to more fibril-prone conformers is required for protofilament formation (3). Nascent protofilaments can nucleate and elongate through the addition of partially folded oligomeric intermediates to the ends of the growing protofilaments. Protofilaments can further intertwine to form protofibrils and fibrils (4, 5). Glycosaminoglycans (GAGs) are one of the major components of the extracellular matrix. They consist of disaccharide repeating units that are unbranched and attached to a serine residue of a core protein through a trisaccharide linker. Each GAG has a unique sequence, and post-assembly modifications, which can be induced by a number of factors, lead to alterations in sulfation, acetylation, or length of chain (6). Recently, Staples et al. (7) showed that the fu...

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Section: Discussionsupporting

confidence: 80%

Role of Glycosaminoglycan Sulfation in the Formation of Immunoglobulin Light Chain Amyloid Oligomers and Fibrils

Ren

Hong

Gong³

et al. 2010

Journal of Biological Chemistry

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“…If a patient has a visceral amyloid syndrome, even if an Ig abnormality is present, it is important to address the possibility that the amyloidosis may be secondary or familial with an incidental monoclonal gammopathy of undetermined significance . The light chain origin of an amyloid deposit can be confirmed with immunohistochemistry or an immunogold assay . Mass spectrometry can confirm the amyloid protein composition, and it is considered the standard for typing the protein subunit in amyloid deposits .…”

Section: Disease Overviewmentioning

confidence: 99%

Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatment

Gertz

2014

American J Hematol

129

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Disease Overview: Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. Diagnosis: Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple‐green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. Prognosis: N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. Therapy: All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include NT‐proBNP <5,000 ng/mL, troponin T <0.06 ng/mL, age <70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan–dexamethasone or cyclophosphamide–bortezomib–dexamethasone. Other combinations of chemotherapy with agents such as cyclophosphamide–thalidomide (or lenalidomide)–dexamethasone, bortezomib–dexamethasone, and melphalan–prednisone–lenalidomide have documented activity. Future Challenges: Late diagnosis remains a major obstacle to initiating effective therapy. Recognizing the presenting syndromes is necessary for improving survival.Am. J. Hematol. 89:1133–1140, 2014. © 2014 Wiley Periodicals, Inc.

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“…If a patient has a visceral amyloid syndrome, even if an Ig abnormality is present, it is important to address the possibility that the amyloidosis may be secondary or familial with an incidental monoclonal gammopathy of undetermined significance . The light chain origin of an amyloid deposit can be confirmed with immunohistochemistry or immunogold assay . Mass spectrometry can confirm the amyloid protein composition and is considered the standard for typing the protein subunit in amyloid deposits (CME question 2).…”

Section: Disease Overviewmentioning

confidence: 99%

Immunoglobulin light chain amyloidosis: 2013 update on diagnosis, prognosis, and treatment

Gertz

2013

American J Hematol

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Disease Overview Immunoglobulin (Ig) light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of Ig light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. Diagnosis Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple‐green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is of immunoglobulin origin is mandatory. Prognosis N‐terminal pro–brain natriuretic peptide (NT‐proBNP), serum troponin T, and immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. Therapy All patients with a visceral amyloid syndrome require therapy to prevent deposition of amyloid in other viscera and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include NT‐proBNP <5,000 ng/mL, troponin T < 0.06 ng/mL, age <70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan‐dexamethasone. Pomalidomide appears to have activity, as do other combinations of chemotherapy with agents such as cyclophosphamide‐thalidomide (or lenalidomide or bortezomib)‐dexamethasone, bortezomib‐dexamethasone, and melphalan‐prednisone‐lenalidomide. Future Challenges Late diagnosis remains a major obstacle to initiating effective therapy when organ dysfunction is still recoverable. Recognizing the presenting syndromes is necessary for improving survival. Am. J. Hematol. 88:417–425, 2013. © 2013 Wiley Periodicals, Inc.

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Glycosaminoglycans are part of amyloid fibrils: Ultrastructural evidence in avian AA amyloid stained with cuprolinic blue and labeled with immunogold

Cited by 19 publications

References 42 publications

Role of Glycosaminoglycan Sulfation in the Formation of Immunoglobulin Light Chain Amyloid Oligomers and Fibrils

Role of Glycosaminoglycan Sulfation in the Formation of Immunoglobulin Light Chain Amyloid Oligomers and Fibrils

Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatment

Immunoglobulin light chain amyloidosis: 2013 update on diagnosis, prognosis, and treatment

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