Further Structural and Antigenic Studies of Light‐chain Amyloid Proteins

Jb, Natvig; Westermark, Per; Sletten, Knut; Husby, Gunnar; Michaelsen, T. E.

doi:10.1111/j.1365-3083.1981.tb00187.x

Cited by 25 publications

(10 citation statements)

References 13 publications

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“…Proteins SUT, GIO, MOR, WAN, AND WIN had amino acid residues within the FRI characteristic for proteins of the VAv, subgroup. Each of the proteins was homologous in sequence and closely resembled the sequences of the prototype XVI proteins AR, JAM, and YAM-L (4) and of the XVI proteins KIN-L (12), NIG-48 (13) and RS (14). The sequence of the first 6 residues of X-chain BUC (data not shown) was also consonant with that of a XVI protein.…”

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confidence: 60%

“…Four additional XVI proteins have since been identified from sequence analyses of the light chains isolated from the IgAX protein YAM (11), the IgGX protein KIN (12), the Bence Jones protein NIG-48 (13), and the protein isolated from amyloid fibrils of patient RS (14). Variable region subgroups of human K-and X-light chains have been also identified immunochemically (3,16 V region antigenic determinants when tested with antisera prepared against the alkali-denatured protein AR (14). We found that an antiserum prepared against the X-Bence Jones protein SUT from a patient with myeloma-associated amyloidosis had unique specificity for antigenic determinants associated with the V region of XVI light chains.…”

Section: Discussionmentioning

confidence: 99%

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Bence Jones proteins and light chains of immunoglobulins. Preferential association of the V lambda VI subgroup of human light chains with amyloidosis AL (lambda).

Solomon¹,

Frangione²,

Franklin³

1982

J. Clin. Invest.

236

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A B S T R A C T An antiserum prepared against a ABence Jones protein from a patient (SUT) who had multiple myeloma and amyloidosis had specificity for X-light chains of the chemically defined variable (V) region X-chain subgroup XVI. Sequence analyses of protein SUT and of five other X-light chains recognized immunologically as of the VAVI subgroup revealed that all six proteins had the N-terminal sequence characteristic for prototype XVI proteins. The isotypic nature of the VAVI subgroup was demonstrated immunochemically: XVI molecules were detected among light chains isolated from the IgG proteins of each of 12 normal individuals and XVI antigenic determinants were also detectable on the intact IgG proteins. The frequency of XVI molecules among X-type light chains is estimated to be -5% based on the finding that 5 of 91 X Bence Jones proteins were of the V,\vI subgroup.Proteins of the VAVI subgroup, in contrast to those of the other five chemically-classified X chain subgroup, appear to be preferentially associated with the amyloid process as evidenced by the fact that all six XVI proteins were obtained from patients with amyloidosis AL and, in addition, 5 of 42 X-type monoclonal immunoglobulins from patients with primary or myelomaassociated amyloidosis were classified by immunodiffusion analyses as having XVI-type light chains.

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confidence: 60%

Section: Discussionmentioning

confidence: 99%

Bence Jones proteins and light chains of immunoglobulins. Preferential association of the V lambda VI subgroup of human light chains with amyloidosis AL (lambda).

Solomon¹,

Frangione²,

Franklin³

1982

J. Clin. Invest.

236

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“…In several cases the amino acid sequences of the fibril and the monoclonal urine or serum protein have been determined and found to be identical (3,4). Many fibril proteins have been studied in detail and reported (3)(4)(5)(6)(7)(8)(9)(10). In only 5 of 17 cases have the deposits contained intact L-chains.…”

Section: Introductionmentioning

confidence: 99%

Aberrant immunoglobulin synthesis in light chain amyloidosis. Free light chain and light chain fragment production by human bone marrow cells in short-term tissue culture.

Buxbaum¹

1986

J. Clin. Invest.

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Bone marrow cells obtained from 14 patients with light chain amyloid (AL) deposition were examined by biosynthetic labeling techniques. These analyses identified free monoclonal light chain (L-chain) synthesis even in those patients whose serum or urine contained no M protein or free L-chains or only an intact M protein. The experiments also identified a subset of patients whose plasma cells synthesized polypeptides bearing constant region antigenic determinants that migrated more rapidly than intact L-chains on polyacrylamide gels. Since most AL fibrils contain L-chain fragments rather than intact L-chains, these studies suggested that the genesis of the fibril components may reflect aberrant synthesis, proteolytic processing, or both. We also noted that in some individuals the pattern of Ig synthesis normalized after several courses of cytotoxic therapy. Thus, we could use bone marrow Ig synthesis as a sensitive biochemical parameter for monitoring therapy. Finally, the presence of aberrant synthetic products in these clones raised questions about their origin with respect to the normal processes of transcription, translation, and posttranslational modification in Ig-producing cells.

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“…6 The fibrils are organized as rigid, non-branching rods which orient with a slight twist longitudinally. They are of indeterminate length, but consistently 75-100 A in diameter.7 Each fibril appears to contain two or more filamentous subunits (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) A diameter). This distinct ultrastructure of the fibrils has been reported in all types of amyloid, both of human and animal origin?…”

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confidence: 99%

The pathogenesis and biochemistry of amyloidosis

Cohen

Connors

1987

The Journal of Pathology

133

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The transformation of serum proteins into Congo red-sensitive fibrillar material is requisite for the onset and progression of amyloid disease. All the mechanisms which lead to the disease itself have not been elucidated, but our knowledge has increased significantly. It is apparent that in all types of amyloid fibrils, three common features are displayed by the major protein constituents. These are that the fibril protein has a serum precursor, a high degree of anti-parallel beta-sheet conformation and a distinctive ultrastructure on electron microscopy. In the AL and AA forms of amyloidosis, the putative precursors appear to undergo limited degradation to form the protein component of amyloid fibrils. It has been suggested that there may be certain primary structural characteristics inherent in precursor molecules which make them amyloidogenic, thus predisposing them to amyloid fibril formation. This would include certain subtypes of immunoglobulin light chains, possibly kappa I and lambda VI, in the AL type of amyloidosis and one of the polymorphic SAA species, SAA2, which has been identified as the predominating isotype found in AA amyloid fibrils. In AH amyloidosis, the mechanism of amyloid fibril formation appears to be simply a concentration phenomenon where elevated concentrations of B2-M are not handled normally and amyloid deposition is the result. Amyloidogenesis in the hereditary form of systemic amyloidosis may involve other factors in addition to the presence of a variant precursor prealbumin as indicated by the delayed onset of the disease. It is evident that the elucidation of the mechanism(s) which governs the onset and progression of the amyloidoses will allow future regulation and treatment of these all too often complex disorders.

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Further Structural and Antigenic Studies of Light‐chain Amyloid Proteins

Cited by 25 publications

References 13 publications

Bence Jones proteins and light chains of immunoglobulins. Preferential association of the V lambda VI subgroup of human light chains with amyloidosis AL (lambda).

Bence Jones proteins and light chains of immunoglobulins. Preferential association of the V lambda VI subgroup of human light chains with amyloidosis AL (lambda).

Aberrant immunoglobulin synthesis in light chain amyloidosis. Free light chain and light chain fragment production by human bone marrow cells in short-term tissue culture.

The pathogenesis and biochemistry of amyloidosis

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