Immunoglobulin heavy-chain-associated amyloidosis

M. Eulitz, D. T. Weiss, Alan Solomon

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Immunoglobulin- or multiple myeloma-associated amyloidosis has been distinguished by the tissue deposition of Congophilic, fibrillar protein consisting of light chains or light-chain fragments (AL amyloidosis). We now report the isolation and characterization of another form of immunoglobulin-associated amyloid obtained from a patient who had extensive systemic amyloidosis and in whom the amyloid deposits consisted not of light chains but rather of an unusual form of heavy chain. This component, isolated from splenic amyloid extracts, represented an internally deleted IgG1 heavy chain as evidenced by immunochemical, electrophoretic, and amino acid sequence analyses. A comparable immunoglobulin-related monoclonal protein, consisting only of IgG heavy chains, was present in the patient's urine. Based on serologic reactivity with a battery of anti-immunoglobulin antisera, these two immunoglobulin-related components were antigenically identical; however, when compared to normal IgG, both were deficient in Fc-associated γ-chain determinants. The structural abnormality of the amyloid γ-chain protein was further evidenced by SDS/PAGE and immuno-blotting analyses: An unusually low molecular mass of ≃22 kDa was found for this material vs. the expected value of ≃55 kDa for a normal γ heavy chain. Despite the lack of certain Fc determinants, the amyloid and urinary heavy-chain proteins expressed the IgG1 subclass allotype marker G1m(a) located on the third constant region (C(H)3) domain of the internally deleted IgG1 heavy chains. That the amyloid protein contained an intact C(H)3 domain was established through amino acid sequence analyses of cyanogen bromide fragments and peptides generated by a lysine-specific protease. These studies also revealed that the γ-chain amyloid protein contained the complete heavy-chain variable (V(H)) domain [including the diversity (D(H)) and joining (J(H)) segments] that was contiguous with the C(H)3 domain. The low molecular mass of the protein resulted from the total absence of the first (C(H)1), hinge, and second (C(H)2) heavy-chain constant regions. Such extensive C(H) deletions and the presence of a complete V(H) distinguish this amyloid-associated heavy chain from all other heretofore characterized γ-heavy-chain disease proteins. This heavy-chain-related form of immunoglobulin-associated amyloidosis is tentatively designated AH amyloidosis.

Original languageEnglish (US)
Pages (from-to)6542-6546
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume87
Issue number17
DOIs
StatePublished - Jan 1 1990

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Immunoglobulin Heavy Chains
Amyloidosis
Immunoglobulins
Amyloidogenic Proteins
Amyloid
Immunoglobulin G
Protein Sequence Analysis
Proteins
Light
Heavy Chain Disease
Cyanogen Bromide
Peptide Fragments
Amyloid Plaques
Multiple Myeloma
Lysine
Immune Sera
Polyacrylamide Gel Electrophoresis
Peptide Hydrolases
Urine

All Science Journal Classification (ASJC) codes

  • General

Cite this

Immunoglobulin heavy-chain-associated amyloidosis. / Eulitz, M.; Weiss, D. T.; Solomon, Alan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 87, No. 17, 01.01.1990, p. 6542-6546.

Research output: Contribution to journalArticle

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N2 - Immunoglobulin- or multiple myeloma-associated amyloidosis has been distinguished by the tissue deposition of Congophilic, fibrillar protein consisting of light chains or light-chain fragments (AL amyloidosis). We now report the isolation and characterization of another form of immunoglobulin-associated amyloid obtained from a patient who had extensive systemic amyloidosis and in whom the amyloid deposits consisted not of light chains but rather of an unusual form of heavy chain. This component, isolated from splenic amyloid extracts, represented an internally deleted IgG1 heavy chain as evidenced by immunochemical, electrophoretic, and amino acid sequence analyses. A comparable immunoglobulin-related monoclonal protein, consisting only of IgG heavy chains, was present in the patient's urine. Based on serologic reactivity with a battery of anti-immunoglobulin antisera, these two immunoglobulin-related components were antigenically identical; however, when compared to normal IgG, both were deficient in Fc-associated γ-chain determinants. The structural abnormality of the amyloid γ-chain protein was further evidenced by SDS/PAGE and immuno-blotting analyses: An unusually low molecular mass of ≃22 kDa was found for this material vs. the expected value of ≃55 kDa for a normal γ heavy chain. Despite the lack of certain Fc determinants, the amyloid and urinary heavy-chain proteins expressed the IgG1 subclass allotype marker G1m(a) located on the third constant region (C(H)3) domain of the internally deleted IgG1 heavy chains. That the amyloid protein contained an intact C(H)3 domain was established through amino acid sequence analyses of cyanogen bromide fragments and peptides generated by a lysine-specific protease. These studies also revealed that the γ-chain amyloid protein contained the complete heavy-chain variable (V(H)) domain [including the diversity (D(H)) and joining (J(H)) segments] that was contiguous with the C(H)3 domain. The low molecular mass of the protein resulted from the total absence of the first (C(H)1), hinge, and second (C(H)2) heavy-chain constant regions. Such extensive C(H) deletions and the presence of a complete V(H) distinguish this amyloid-associated heavy chain from all other heretofore characterized γ-heavy-chain disease proteins. This heavy-chain-related form of immunoglobulin-associated amyloidosis is tentatively designated AH amyloidosis.

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