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

Nobuyoshi Fukushima, Hideyuki Ikematsu, Minoru Nakamura, Mieko Matsui, Shinji Shimoda, Kazuhiro Hayashida, Yoshiyuki Niho, Kichiko Koike, M. Eric Gershwin, Hiromi Ishibashi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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-VλI, V(H)IV-VλIII, 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. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)247-257
Number of pages11
JournalJournal of Autoimmunity
Volume14
Issue number3
DOIs
StatePublished - 2000

Fingerprint

Antibody-Producing Cells
Biliary Liver Cirrhosis
B-Lymphocytes
Nucleotides
Clone Cells
Genes
Autoantibodies
Immunoglobulin Variable Region
Intrahepatic Bile Ducts
Immunoglobulin Genes
Antibodies
Pyruvic Acid
Point Mutation
Granulocytes
Liver Diseases
Oxidoreductases
Chronic Disease
Monoclonal Antibodies
Maintenance
Observation

Keywords

  • Antigen-driven clonal selection
  • Antimitochondrial antibody pyruvate dehydrogenase complex
  • Immunoglobulin gene

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Fukushima, N., Ikematsu, H., Nakamura, M., Matsui, M., Shimoda, S., Hayashida, K., ... Ishibashi, H. (2000). Nucleotide variations amongst V(H) genes of AMA-producing B cell clones in primary biliary cirrhosis. Journal of Autoimmunity, 14(3), 247-257. https://doi.org/10.1006/jaut.2000.0366

Nucleotide variations amongst V(H) genes of AMA-producing B cell clones in primary biliary cirrhosis. / Fukushima, Nobuyoshi; Ikematsu, Hideyuki; Nakamura, Minoru; Matsui, Mieko; Shimoda, Shinji; Hayashida, Kazuhiro; Niho, Yoshiyuki; Koike, Kichiko; Gershwin, M. Eric; Ishibashi, Hiromi.

In: Journal of Autoimmunity, Vol. 14, No. 3, 2000, p. 247-257.

Research output: Contribution to journalArticle

Fukushima, N, Ikematsu, H, Nakamura, M, Matsui, M, Shimoda, S, Hayashida, K, Niho, Y, Koike, K, Gershwin, ME & Ishibashi, H 2000, 'Nucleotide variations amongst V(H) genes of AMA-producing B cell clones in primary biliary cirrhosis', Journal of Autoimmunity, vol. 14, no. 3, pp. 247-257. https://doi.org/10.1006/jaut.2000.0366
Fukushima, Nobuyoshi ; Ikematsu, Hideyuki ; Nakamura, Minoru ; Matsui, Mieko ; Shimoda, Shinji ; Hayashida, Kazuhiro ; Niho, Yoshiyuki ; Koike, Kichiko ; Gershwin, M. Eric ; Ishibashi, Hiromi. / Nucleotide variations amongst V(H) genes of AMA-producing B cell clones in primary biliary cirrhosis. In: Journal of Autoimmunity. 2000 ; Vol. 14, No. 3. pp. 247-257.
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abstract = "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-VλI, V(H)IV-VλIII, 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. (C) 2000 Academic Press.",
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AU - Shimoda, Shinji

AU - Hayashida, Kazuhiro

AU - Niho, Yoshiyuki

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AB - 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-VλI, V(H)IV-VλIII, 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. (C) 2000 Academic Press.

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