Nucleotide sequence analysis of natural and combinatorial anti-PDC-E2 antibodies in patients with primary biliary cirrhosis: Recapitulating immune selection with molecular biology

Virginia Pascual, Sanghoon Cha, M. Eric Gershwin, J. Donald Capra, Patrick S Leung

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Abstract

We have analyzed at the nucleotide level the variable region gene sequences of five human mAbs and five recombinant Fab fragments derived from the mesenteric lymph nodes of patients with primary biliary cirrhosis. Both mAbs and Fabs were monospecific for dihydrolipoamide acetyltransferase, the E2 subunit of the pyruvate dehydrogenase complex, which has been shown to be the major autoantigen of primary biliary cirrhosis. We found that although the mAbs, mainly of the IgM isotype, were encoded by a diverse array of V(H) and V(L) gene segments either as direct copies of germline genes or somatically mutated, the recombinant IgG Fabs expressed clonally related heavy chains displaying a high number of somatic mutations that very likely occurred in the context of Ag selection. Combinatorial pairing of clonally related heavy chains with highly homologous light chains suggests that the IgG anti-pyruvate dehydrogenase complex repertoire of primary biliary cirrhosis patients is the result of the clonal expansion of a restricted set of B cells.

Original languageEnglish (US)
Pages (from-to)2577-2585
Number of pages9
JournalJournal of Immunology
Volume152
Issue number5
StatePublished - Mar 1 1994

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Biliary Liver Cirrhosis
Dihydrolipoyllysine-Residue Acetyltransferase
Sequence Analysis
Molecular Biology
Antibodies
Pyruvate Dehydrogenase Complex
Genes
Immunoglobulin Fab Fragments
Autoantigens
Immunoglobulin M
B-Lymphocytes
Nucleotides
Immunoglobulin G
Lymph Nodes
Light
Mutation

ASJC Scopus subject areas

  • Immunology

Cite this

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abstract = "We have analyzed at the nucleotide level the variable region gene sequences of five human mAbs and five recombinant Fab fragments derived from the mesenteric lymph nodes of patients with primary biliary cirrhosis. Both mAbs and Fabs were monospecific for dihydrolipoamide acetyltransferase, the E2 subunit of the pyruvate dehydrogenase complex, which has been shown to be the major autoantigen of primary biliary cirrhosis. We found that although the mAbs, mainly of the IgM isotype, were encoded by a diverse array of V(H) and V(L) gene segments either as direct copies of germline genes or somatically mutated, the recombinant IgG Fabs expressed clonally related heavy chains displaying a high number of somatic mutations that very likely occurred in the context of Ag selection. Combinatorial pairing of clonally related heavy chains with highly homologous light chains suggests that the IgG anti-pyruvate dehydrogenase complex repertoire of primary biliary cirrhosis patients is the result of the clonal expansion of a restricted set of B cells.",
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AU - Cha, Sanghoon

AU - Gershwin, M. Eric

AU - Capra, J. Donald

AU - Leung, Patrick S

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