Mitochondrial antigens and autoantibodies: from anti-M1 to anti-M9

The specificity and clinical relevance of nine antimitochondrial antibodies (AMA) - anti-M1 to anti-M9 - are described. All nine AMA types react with antigens which are associated either with inner (M1, M2, M7) our outer mitochondrial membranes (M3, M4, M5, M6, M8, M9) derived from rat liver or beef heart mitochondria. These antigens can be clearly distinguished by their different physical and chemical properties. Anti-M1 to anti-M9 can be related to distinct clinical entities: anti-M1, anti-M5, and anti-M7 are found in nonhepatic disorders, such as syphilis (anti-M1), undefined collagen diseases (anti-M5), and some forms of cardiac diseases (anti-M7). Anti-M3 and anti-M6 are detected in drug-induced disorders, such as phenopyrazon-induced pseudolupus syndrome (PLE; anti-M3) and iproniazid-induced hepatitis (anti-M6). Anti-M2, anti-M4, anti-M8, and anti-M9 are confined to primary biliary cirrhosis (PBC). Anti-M2 is a specific marker for the diagnosis of PBC; 96% of PBC patients (n = 752) were anti-M2 positive. Anti-M4 and anti-M8 seem to reflect disease activity. Anti-M9 antibodies occur preferentially in early PBC. The clinical course of PBC was analyzed with respect to four different AMA profiles: profile A: only anti-M9 positive in the ELISA; profile B: anti-M9 and anti-M2 positive in the ELISA; profile C: anti-M2 positive in ELISA and complement fixation test (CFT), but anti-M4 and anti-M8 positive only in the ELISA; and profile D: anti-M2, anti-M4, anti-M8 positive in ELISA and CFT. Patients with profile A and B were found to have a rather benign course while those patients with profile C and D showed a rather progressive course when followed over a period of 6-15 years. Considering the similarities between bacterial and mitochondrial membranes, it is suggested that the formation of AMA of different specificities in PBC, especially of the anti-M2 type, may be induced by cross-reacting antigens.