Mitochondrial

Antimitochondrial antibodies (AMA) were first detected in sera from patients with primary biliary cirrhosis (PBC) using immunofluorescent staining on cryostat sections of a range of tissues. PBC is characterised by a T-cell mediated inflammation of the medium-sized bile ducts and typically affects women over the age of forty. The mitochondrial antigens of PBC have been identified as components of a functionally related enzyme family (the 2-oxo-acid dehydrogenase complexes) of which the pyruvate dehydrogenase (PDH) complex is the most prominent autoantigenic component.

Although autoantibodies to PDH are most frequently detected in the sera of patients with PBC, they have also been reported to occur in a minority of patients with rheumatic autoimmune diseases (Sjögren’s syndrome, scleroderma, SLE and rheumatoid arthritis) as well as in patients with leprosy, monoclonal gammopathies, tuberculosis or anti-glomerular basement membrane disease.

2-Oxo-acid dehydrogenase complexes catalyse key reactions in intermediary metabolism. The PDH complex oxidatively decarboxylates pyruvate to acetyl CoA; patient autoantibodies have been reported to inhibit enzyme function. Each enzyme complex consists of multiple copies of three enzymes E1, E2 and E3. E2 forms a central symmetrical core to which multiple copies of E1, E3 and protein X are attached yielding a total complex molecular weight of several thousand kDa.

As is evident from primary sequence data of the human, pig and rat 70 kDa M2 antigen (PDH E2), that the PDH autoantigen is well conserved between species. PBC patient sera have been shown to react with PDH complexes from E. coli to human.

The PDH complex from bovine heart muscle constitutes AROTEC’s mitochondrial antigen. Four of the five subunits present (E2 acetyltransferase, E3 Protein X, E1α decarboxylase and E1β decarboxylase) are known to react with AMA.

 

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