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