Caspase Induction by IgA Antimitochondrial Antibody: IgA-Mediated Biliary Injury in Primary Biliary Cirrhosis

Shuji Matsumura, Judith A Van de Water, Patrick S Leung, Joseph A. Odin, Kazuhide Yamamoto, Gregory J. Gores, Keith Mostov, Aftab A. Ansari, Ross L. Coppel, Yasushi Shiratori, M. Eric Gershwin

Research output: Contribution to journalArticle

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Abstract

Anti-mitochondrial antibodies (AMAs) have long been recognized as a serological hallmark of primary biliary cirrhosis (PBQ. Although high titers of immunoglobulin (1g)A AMAs are found in bile, saliva, and urine of patients, a pathogenic role for this antibody has remained elusive. Functional studies ofthis IgA in general have been impeded by low quantities ofantibody and the inability to recover antigen-specific IgA in dimeric form. Using a newly defined synthetic group A Streptecoccm derived peptide, we purified large quantities of dimeric and monomeric IgA from patient sera. The purified IgA was incubated with Madine-Darby canine kidney (MDCK) cells transfected with the human polymeric Ig receptor (pIgR)(p1gR) and the cells studied by flow cytometric analysis for binding of carboxyfluorescein conjugated VAD-fink peptide to activated caspase enzymes. A total of 87% of PBC patients that were anti-PDC-E2 positive had serum IgA that increased caspase activation in MDCK-pIgR+ cells compared to serum-derived IgA from controls with a maximum reaction 48 hours after addition of IgA. The titer of anti-PDC-E2 IgA among the PBC patients strongly correlated with caspase activation (cc = 0.88). Pre-absorption of the IgA using recombinant 2-oxo-acid dehydrogenase complex significantly diminished this activation. IgG from the same PBC patients did not induce caspase activation. These data suggest that during transcytosis through pIgR-positive cells, exposure to PDC-E2-specific dimeric IgA results in the initiation of caspase activation. In conclusion, we propose that due to an even greater concentration of dimeric IgA in biliary and mucosal secretions, constant transcytosis would render the exposed cells more susceptible to apoptosis resulting in subsequent bile duct damage.

Original languageEnglish (US)
Pages (from-to)1415-1422
Number of pages8
JournalHepatology
Volume39
Issue number5
DOIs
StatePublished - May 2004

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Biliary Liver Cirrhosis
Caspases
Immunoglobulin A
Antibodies
Wounds and Injuries
Polymeric Immunoglobulin Receptors
Transcytosis
Canidae
Anti-Idiotypic Antibodies
Serum
Keto Acids
Kidney
Peptides
Bile Ducts
Saliva
Bile
Immunoglobulins
Oxidoreductases
Immunoglobulin G
Urine

ASJC Scopus subject areas

  • Hepatology

Cite this

Caspase Induction by IgA Antimitochondrial Antibody : IgA-Mediated Biliary Injury in Primary Biliary Cirrhosis. / Matsumura, Shuji; Van de Water, Judith A; Leung, Patrick S; Odin, Joseph A.; Yamamoto, Kazuhide; Gores, Gregory J.; Mostov, Keith; Ansari, Aftab A.; Coppel, Ross L.; Shiratori, Yasushi; Gershwin, M. Eric.

In: Hepatology, Vol. 39, No. 5, 05.2004, p. 1415-1422.

Research output: Contribution to journalArticle

Matsumura, S, Van de Water, JA, Leung, PS, Odin, JA, Yamamoto, K, Gores, GJ, Mostov, K, Ansari, AA, Coppel, RL, Shiratori, Y & Gershwin, ME 2004, 'Caspase Induction by IgA Antimitochondrial Antibody: IgA-Mediated Biliary Injury in Primary Biliary Cirrhosis', Hepatology, vol. 39, no. 5, pp. 1415-1422. https://doi.org/10.1002/hep.20175
Matsumura, Shuji ; Van de Water, Judith A ; Leung, Patrick S ; Odin, Joseph A. ; Yamamoto, Kazuhide ; Gores, Gregory J. ; Mostov, Keith ; Ansari, Aftab A. ; Coppel, Ross L. ; Shiratori, Yasushi ; Gershwin, M. Eric. / Caspase Induction by IgA Antimitochondrial Antibody : IgA-Mediated Biliary Injury in Primary Biliary Cirrhosis. In: Hepatology. 2004 ; Vol. 39, No. 5. pp. 1415-1422.
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abstract = "Anti-mitochondrial antibodies (AMAs) have long been recognized as a serological hallmark of primary biliary cirrhosis (PBQ. Although high titers of immunoglobulin (1g)A AMAs are found in bile, saliva, and urine of patients, a pathogenic role for this antibody has remained elusive. Functional studies ofthis IgA in general have been impeded by low quantities ofantibody and the inability to recover antigen-specific IgA in dimeric form. Using a newly defined synthetic group A Streptecoccm derived peptide, we purified large quantities of dimeric and monomeric IgA from patient sera. The purified IgA was incubated with Madine-Darby canine kidney (MDCK) cells transfected with the human polymeric Ig receptor (pIgR)(p1gR) and the cells studied by flow cytometric analysis for binding of carboxyfluorescein conjugated VAD-fink peptide to activated caspase enzymes. A total of 87{\%} of PBC patients that were anti-PDC-E2 positive had serum IgA that increased caspase activation in MDCK-pIgR+ cells compared to serum-derived IgA from controls with a maximum reaction 48 hours after addition of IgA. The titer of anti-PDC-E2 IgA among the PBC patients strongly correlated with caspase activation (cc = 0.88). Pre-absorption of the IgA using recombinant 2-oxo-acid dehydrogenase complex significantly diminished this activation. IgG from the same PBC patients did not induce caspase activation. These data suggest that during transcytosis through pIgR-positive cells, exposure to PDC-E2-specific dimeric IgA results in the initiation of caspase activation. In conclusion, we propose that due to an even greater concentration of dimeric IgA in biliary and mucosal secretions, constant transcytosis would render the exposed cells more susceptible to apoptosis resulting in subsequent bile duct damage.",
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AU - Matsumura, Shuji

AU - Van de Water, Judith A

AU - Leung, Patrick S

AU - Odin, Joseph A.

AU - Yamamoto, Kazuhide

AU - Gores, Gregory J.

AU - Mostov, Keith

AU - Ansari, Aftab A.

AU - Coppel, Ross L.

AU - Shiratori, Yasushi

AU - Gershwin, M. Eric

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AB - Anti-mitochondrial antibodies (AMAs) have long been recognized as a serological hallmark of primary biliary cirrhosis (PBQ. Although high titers of immunoglobulin (1g)A AMAs are found in bile, saliva, and urine of patients, a pathogenic role for this antibody has remained elusive. Functional studies ofthis IgA in general have been impeded by low quantities ofantibody and the inability to recover antigen-specific IgA in dimeric form. Using a newly defined synthetic group A Streptecoccm derived peptide, we purified large quantities of dimeric and monomeric IgA from patient sera. The purified IgA was incubated with Madine-Darby canine kidney (MDCK) cells transfected with the human polymeric Ig receptor (pIgR)(p1gR) and the cells studied by flow cytometric analysis for binding of carboxyfluorescein conjugated VAD-fink peptide to activated caspase enzymes. A total of 87% of PBC patients that were anti-PDC-E2 positive had serum IgA that increased caspase activation in MDCK-pIgR+ cells compared to serum-derived IgA from controls with a maximum reaction 48 hours after addition of IgA. The titer of anti-PDC-E2 IgA among the PBC patients strongly correlated with caspase activation (cc = 0.88). Pre-absorption of the IgA using recombinant 2-oxo-acid dehydrogenase complex significantly diminished this activation. IgG from the same PBC patients did not induce caspase activation. These data suggest that during transcytosis through pIgR-positive cells, exposure to PDC-E2-specific dimeric IgA results in the initiation of caspase activation. In conclusion, we propose that due to an even greater concentration of dimeric IgA in biliary and mucosal secretions, constant transcytosis would render the exposed cells more susceptible to apoptosis resulting in subsequent bile duct damage.

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