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 language | English (US) |
|---|---|
| Pages (from-to) | 247-257 |
| Number of pages | 11 |
| Journal | Journal of Autoimmunity |
| Volume | 14 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2000 |
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Keywords
- Antigen-driven clonal selection
- Antimitochondrial antibody pyruvate dehydrogenase complex
- Immunoglobulin gene
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
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 journal › Article
}
TY - JOUR
T1 - Nucleotide variations amongst V(H) genes of AMA-producing B cell clones in primary biliary cirrhosis
AU - Fukushima, Nobuyoshi
AU - Ikematsu, Hideyuki
AU - Nakamura, Minoru
AU - Matsui, Mieko
AU - Shimoda, Shinji
AU - Hayashida, Kazuhiro
AU - Niho, Yoshiyuki
AU - Koike, Kichiko
AU - Gershwin, M. Eric
AU - Ishibashi, Hiromi
PY - 2000
Y1 - 2000
N2 - 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.
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.
KW - Antigen-driven clonal selection
KW - Antimitochondrial antibody pyruvate dehydrogenase complex
KW - Immunoglobulin gene
UR - http://www.scopus.com/inward/record.url?scp=0033850359&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033850359&partnerID=8YFLogxK
U2 - 10.1006/jaut.2000.0366
DO - 10.1006/jaut.2000.0366
M3 - Article
C2 - 10756087
AN - SCOPUS:0033850359
VL - 14
SP - 247
EP - 257
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
IS - 3
ER -