Nucleotide variations amongst V(H)Genes of AMA-producing B cell clones in primary biliary cirrhosis

Primary biliary cirrhosis, a chronic liver disease characterized by progressive inflammatory destruction of intrahepatic bile ducts, is also characterized by the presence of antimitochondrial antibodies (AMA). The predominant autoantibody is directed at the E2 component of pyruvate dehydrogenase (PD...

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Veröffentlicht in:Journal of autoimmunity 2000-05, Vol.14 (3), p.247-257
Hauptverfasser: Fukushima, N, Ikematsu, H, Nakamura, M, Matsui, M, Shimoda, S, Hayashida, K, Niho, Y, Koike, K, Gershwin, M E, Ishibashi, H
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container_issue 3
container_start_page 247
container_title Journal of autoimmunity
container_volume 14
creator Fukushima, N
Ikematsu, H
Nakamura, M
Matsui, M
Shimoda, S
Hayashida, K
Niho, Y
Koike, K
Gershwin, M E
Ishibashi, H
description Primary biliary cirrhosis, a chronic liver disease characterized by progressive inflammatory destruction of intrahepatic bile ducts, is also characterized by the presence of antimitochondrial antibodies (AMA). The predominant autoantibody is directed at the E2 component of pyruvate dehydrogenase (PDC-E2). Recent studies of this autoantibody response have analysed immunoglobulin-variable regions of human monoclonal antibodies and provided evidence for antigen-driven clonal selection. However, the number of clones analysed has been very limited and the presence of somatic mutations not formally proven. In this study, we took advantage of three stable B cell lines producing human IgG anti-PDC-E2 mAbs from a patient with PBC. We analysed the V(H)and V(L)gene structure of these reagents and, in addition, analysed 10 V(H)-D and D-J(H)sequences over a period of nearly 3 years. The expressed Ig V regions of the heavy chain (V(H)) and the light chain (V(L)) genes of mAb18, mAb37, and mAb82 utilized the V(H)III-VlambdaI, V(H)IV-VlambdaIII, and V(H)IV-V(k)IV gene families, respectively. The utilized gene elements were Ig gene elements that were found frequently in other antibodies with different specificity and affinity. Presence of somatic point-mutations was confirmed in mAb82 by comparison of the expressed V(H)gene sequence with that of corresponding germline V(H)gene obtained from the granulocyte genomic DNA of the same patient. Interestingly, clonally related B cells were consistently found throughout the observation period and nucleotide variations among the V(H)genes were very few, ranging from 0.19 to 0.72% per base. These findings suggest that long-lived B cell clones can exist and may contribute, at least in part, to maintenance of autoantibodies in humans.
doi_str_mv 10.1006/jaut.2000.0366
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The predominant autoantibody is directed at the E2 component of pyruvate dehydrogenase (PDC-E2). Recent studies of this autoantibody response have analysed immunoglobulin-variable regions of human monoclonal antibodies and provided evidence for antigen-driven clonal selection. However, the number of clones analysed has been very limited and the presence of somatic mutations not formally proven. In this study, we took advantage of three stable B cell lines producing human IgG anti-PDC-E2 mAbs from a patient with PBC. We analysed the V(H)and V(L)gene structure of these reagents and, in addition, analysed 10 V(H)-D and D-J(H)sequences over a period of nearly 3 years. The expressed Ig V regions of the heavy chain (V(H)) and the light chain (V(L)) genes of mAb18, mAb37, and mAb82 utilized the V(H)III-VlambdaI, V(H)IV-VlambdaIII, and V(H)IV-V(k)IV gene families, respectively. The utilized gene elements were Ig gene elements that were found frequently in other antibodies with different specificity and affinity. Presence of somatic point-mutations was confirmed in mAb82 by comparison of the expressed V(H)gene sequence with that of corresponding germline V(H)gene obtained from the granulocyte genomic DNA of the same patient. Interestingly, clonally related B cells were consistently found throughout the observation period and nucleotide variations among the V(H)genes were very few, ranging from 0.19 to 0.72% per base. 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subjects Amino Acid Sequence
Antibodies, Monoclonal - immunology
B-Lymphocytes - immunology
Base Sequence
Dihydrolipoyllysine-Residue Acetyltransferase
Female
Genetic Variation
Germ Cells
Humans
Immunoglobulin G - immunology
Immunoglobulin Heavy Chains - genetics
Immunoglobulin Heavy Chains - immunology
Immunoglobulin Light Chains - genetics
Immunoglobulin Light Chains - immunology
Immunoglobulin Variable Region - genetics
Immunoglobulin Variable Region - immunology
Molecular Sequence Data
Nucleotides
Polymerase Chain Reaction
Pyruvate Dehydrogenase Complex - immunology
title Nucleotide variations amongst V(H)Genes of AMA-producing B cell clones in primary biliary cirrhosis
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