Immunopathogenesis of Primary Biliary Cirrhosis

Akiyoshi Nishio; Emmet B. Keeffe; M. Eric Gershwin

doi:10.1055/s-2002-34506

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2002; 22(3): 291-302
DOI: 10.1055/s-2002-34506

Immunopathogenesis of Primary Biliary Cirrhosis

Akiyoshi Nishio¹ , Emmet B. Keeffe² , M. Eric Gershwin³

¹Department of Gastroenterology, Tenri Hospital, Nara, Japan
²Liver Transplant Program,Stanford University Medical Center, Palo Alto, California
³Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California at Davis, Davis, California

Abstract

ABSTRACT

Although the autoantigens of antimitochondrial antibodies (AMA) have been defined and epitope mapped for both autoreactive B and T cells, the pathogenesis of primary biliary cirrhosis (PBC) still remains a mystery. The data gathered so far address several important aspects of this intriguing puzzle. First, biliary epithelial cells (BECs) seem to be immunologically active because they express molecules such as major histocompatibility complex (MHC) antigens, and adhesion and costimulatory molecules. Second, although pyruvate dehydrogenase complex (PDC)-E2, the major autoantigen in PBC, is upregulated in BECs when examined immunohistochemically, this abnormal staining seems to be secondary to immune complexes of AMA bound to PDC-E2 present in the BECs. Third, in addition to CD4⁺ T cells, CD8⁺ T cells also recognize the inner lipoyl domain of PDC-E2. Fourth, modification of mitochondrial antigens by xenobiotics may lead to the induction of the disease. These findings help to clarify the pathogenic mechanism of PBC and suggest that (l) induction may be secondary to a primary response to a xenobiotic that is normally metabolized in an estrogen-dependent pathway and (2) pathology is mediated by and orchestrated by a highly directed and specific CD4, CD8 and autoantibody response to the lipoyl domain of the mitochondrial autoantigens, with tissue destruction based on the immunoglobulin A (IgA) receptor, apoptosis, and the mucosal organization of biliary and salivary duct cells.

KEYWORDS

Primary biliary cirrhosis - T cells - molecular mimicry - xenobiotics

Full Text

References

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