Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse

Motoko Sasaki, Judith A Van de Water, Thomas P. Kenny, Michael L. Gallo, Patrick S Leung, Yasuni Nakanuma, Aftab A. Ansari, Ross L. Coppel, James Neuberger, M. Eric Gershwin

Research output: Contribution to journalArticle

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Abstract

The immunodominant antimitochondrial antibody (AMA) response in primary biliary cirrhosis (PBC) is directed against the E2 component of pyruvate dehydrogenase (PDC-E2). The nature of the clonal selection process is unclear, and to address this issue, we took advantage of a transgenic technology, XenoMouse, that contains 80% of the human immunoglobulin (Ig) variable gene repertoire and can produce high-affinity human antibodies to virtually any immunogen without evidence of clonal bias. We immunized mice with PDC-E2 to obtain 13 HmAbs, including 4 IgG2 and 9 IgM isotypes. Immunoglobulin gene analysis was unique and demonstrated a clonal bias; the immunoglobulin gene usage was considerably different from other antibody responses analyzed in XenoMouse systems. Four of the 13 mAbs recognized the inner lipoyl domain of PDC-E2, 2 of 13 recognized the entire PDC-E2 molecule, 4 of 13 recognized PDC-E2 and OGDC-E2, 1 of 13 recognized OGDC only, 1 recognized BCOADC-E2 only, and 1 recognized an unidentified 100-kd mitochondrial protein. Immunohistochemical staining using these HmAbs produced mitochondrial staining of septal bile ducts in both PBC and control livers. Ig gene analysis showed that 7 of 13 HmAbs used the VH3 and 4 of 13 used VH4 gene repertoire, respectively. Three of 7 VH3 antibodies used the same Ig VH3-21 gene family found in human AMA from patients with PBC. The CDRs of these autoantibodies were slightly mutated when compared with the sequences present within the Ig germline genes. In conclusion, the XenoMouse not only recapitulates the unique specificity and restriction of PBC patients, but indicates that the autoantibodies are derived from a restricted clonal selection process. Such data suggest that the original immunogen leads to somatic mutation without subsequent development of determinant spreading.

Original languageEnglish (US)
Pages (from-to)631-637
Number of pages7
JournalHepatology
Volume34
Issue number4 I
DOIs
StatePublished - 2001

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Immunoglobulin Genes
Biliary Liver Cirrhosis
Monoclonal Antibodies
dihydrolipoamide succinyltransferase
Autoantibodies
Antibody Formation
Staining and Labeling
Antibody Affinity
Antibodies
Mitochondrial Proteins
Bile Ducts
Pyruvic Acid
Genes
Immunoglobulin M
Immunoglobulins
Oxidoreductases
Immunoglobulin G
To autoantigen
Technology
Mutation

ASJC Scopus subject areas

  • Hepatology

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Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse. / Sasaki, Motoko; Van de Water, Judith A; Kenny, Thomas P.; Gallo, Michael L.; Leung, Patrick S; Nakanuma, Yasuni; Ansari, Aftab A.; Coppel, Ross L.; Neuberger, James; Gershwin, M. Eric.

In: Hepatology, Vol. 34, No. 4 I, 2001, p. 631-637.

Research output: Contribution to journalArticle

Sasaki, Motoko ; Van de Water, Judith A ; Kenny, Thomas P. ; Gallo, Michael L. ; Leung, Patrick S ; Nakanuma, Yasuni ; Ansari, Aftab A. ; Coppel, Ross L. ; Neuberger, James ; Gershwin, M. Eric. / Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse. In: Hepatology. 2001 ; Vol. 34, No. 4 I. pp. 631-637.
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abstract = "The immunodominant antimitochondrial antibody (AMA) response in primary biliary cirrhosis (PBC) is directed against the E2 component of pyruvate dehydrogenase (PDC-E2). The nature of the clonal selection process is unclear, and to address this issue, we took advantage of a transgenic technology, XenoMouse, that contains 80{\%} of the human immunoglobulin (Ig) variable gene repertoire and can produce high-affinity human antibodies to virtually any immunogen without evidence of clonal bias. We immunized mice with PDC-E2 to obtain 13 HmAbs, including 4 IgG2 and 9 IgM isotypes. Immunoglobulin gene analysis was unique and demonstrated a clonal bias; the immunoglobulin gene usage was considerably different from other antibody responses analyzed in XenoMouse systems. Four of the 13 mAbs recognized the inner lipoyl domain of PDC-E2, 2 of 13 recognized the entire PDC-E2 molecule, 4 of 13 recognized PDC-E2 and OGDC-E2, 1 of 13 recognized OGDC only, 1 recognized BCOADC-E2 only, and 1 recognized an unidentified 100-kd mitochondrial protein. Immunohistochemical staining using these HmAbs produced mitochondrial staining of septal bile ducts in both PBC and control livers. Ig gene analysis showed that 7 of 13 HmAbs used the VH3 and 4 of 13 used VH4 gene repertoire, respectively. Three of 7 VH3 antibodies used the same Ig VH3-21 gene family found in human AMA from patients with PBC. The CDRs of these autoantibodies were slightly mutated when compared with the sequences present within the Ig germline genes. In conclusion, the XenoMouse not only recapitulates the unique specificity and restriction of PBC patients, but indicates that the autoantibodies are derived from a restricted clonal selection process. Such data suggest that the original immunogen leads to somatic mutation without subsequent development of determinant spreading.",
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T1 - Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse

AU - Sasaki, Motoko

AU - Van de Water, Judith A

AU - Kenny, Thomas P.

AU - Gallo, Michael L.

AU - Leung, Patrick S

AU - Nakanuma, Yasuni

AU - Ansari, Aftab A.

AU - Coppel, Ross L.

AU - Neuberger, James

AU - Gershwin, M. Eric

PY - 2001

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AB - The immunodominant antimitochondrial antibody (AMA) response in primary biliary cirrhosis (PBC) is directed against the E2 component of pyruvate dehydrogenase (PDC-E2). The nature of the clonal selection process is unclear, and to address this issue, we took advantage of a transgenic technology, XenoMouse, that contains 80% of the human immunoglobulin (Ig) variable gene repertoire and can produce high-affinity human antibodies to virtually any immunogen without evidence of clonal bias. We immunized mice with PDC-E2 to obtain 13 HmAbs, including 4 IgG2 and 9 IgM isotypes. Immunoglobulin gene analysis was unique and demonstrated a clonal bias; the immunoglobulin gene usage was considerably different from other antibody responses analyzed in XenoMouse systems. Four of the 13 mAbs recognized the inner lipoyl domain of PDC-E2, 2 of 13 recognized the entire PDC-E2 molecule, 4 of 13 recognized PDC-E2 and OGDC-E2, 1 of 13 recognized OGDC only, 1 recognized BCOADC-E2 only, and 1 recognized an unidentified 100-kd mitochondrial protein. Immunohistochemical staining using these HmAbs produced mitochondrial staining of septal bile ducts in both PBC and control livers. Ig gene analysis showed that 7 of 13 HmAbs used the VH3 and 4 of 13 used VH4 gene repertoire, respectively. Three of 7 VH3 antibodies used the same Ig VH3-21 gene family found in human AMA from patients with PBC. The CDRs of these autoantibodies were slightly mutated when compared with the sequences present within the Ig germline genes. In conclusion, the XenoMouse not only recapitulates the unique specificity and restriction of PBC patients, but indicates that the autoantibodies are derived from a restricted clonal selection process. Such data suggest that the original immunogen leads to somatic mutation without subsequent development of determinant spreading.

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