MONOCLONAL-ANTIBODIES TO MITOCHONDRIAL E2 COMPONENTS DEFINE AUTOEPITOPES IN PRIMARY BILIARY-CIRRHOSIS

Primary biliary cirrhosis (PBC) is an autoimmune liver disease charact erized by the presence of antimitochondrial Abs (AMA), The autoantigen s recognized by AMA are the E2 components of the pyruvate dehydrogenas e complex (PDC-E2), the branched chain 2-oxoacid dehydrogenase complex E (BCOADC-E2), and the 2-oxoglutarate dehydrogenase complex E (OGDC-E 2), Previous studies using murine monoclonal and human combinatorial A bs to PDC-E2 have demonstrated an intense linear staining pattern in t he apical region of biliary epithelial cells (BEC) in PBC but not cont rol liver. We therefore examined whether mAbs to the other mitochondri al autoantigens BCOADC-E2 and OGDC-E2 demonstrated disease-specific pa tterns of reactivity, Using an expressed recombinant ''trihybrid'' pro tein containing the lipoyl domains of PDC-E2, OGDC-E2, and BCOADC-E2, we immunized BALB/c mice to produce 35 mAbs specific for one or more o f the above mitochondrial autoantigens. Seven of these mAbs uniquely s tained the apical region of BEC in PBC, Of these seven, one was reacti ve to PDC-E2, two recognized BCOADC-E2, three were reactive to OGDC-E2 , and one recognized all three Ags, Our current data demonstrate that, similar to our previous studies regarding PDC-E2, mAbs to BCOADC-E2 a nd OGDC-E2, or a molecule that cross-reacts with the inner lipoyl doma in of all three enzymes, also show a uniquely intense staining pattern in the apical region of BEC in patients with PBC when compared with d iseased controls. The abundance of such disease-specific determinants in the target cells of PBC raises interesting possibilities regarding the role of these autoantigens in the pathogenesis of this disease.