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Use & Interpretation of Laboratory Tests Books
Use & Interpretation of Laboratory Tests Books

Mitochondrial Autoantibodies
Herminio R. Reyes, Ph.D.

Concentrations of mitochondrial autoantibodies (MA), which are found in ~95% of patients with primary biliary cirrhosis (PBC), do not correlate with disease stage and prognosis, but are now known to play an important role in the immunopathogenesis of PBC.1-3 MA are directed against the E2 subunit of the pyruvate dehydrogenase enzyme complex located at the inner mitochondrial membrane (PDC-E2), the E2 subunit of the branched chain 2-oxo acid dehydrogenase complex (BCOADC-E2), the E2 subunit of the 2-oxo-glutarate dehydrogenase complex (OGDC-E2), protein X, and PDC-Ela and PDC-E113.1 Autoimmune cholangitis, which is characterized by negative MA and positive antinuclear antibodies (ANA), has virtually identical clinical and histopathologic features as PBC and is the same disease entity as MA-negative PBC.4 Molecular mimicry is postulated to play an important role in the pathogenesis of PBC.5-7

Serum IgM concentrations, which are increased in 80% of PBC,8 like MA, are commonly increased in relatives of PBC patients; an impaired IgM-to-IgG switch in response to tetanus toxoid might be due to a T-cell defect which is common in PBC.9 MA with titers of 1:40 or greater suggest PBC even in the absence of symptoms and in the presence of a normal alkaline phosphatase.10 MA in low titers are common in chronic active hepatitis and their presence does not preclude response to corticosteroids.11 MA disappear in about one month after orthotopic liver transplantation (OLT)12 and decrease with cyclosporine treatment which might be useful in PBC.13 Reliable clinical criteria for recurrence of PBC following OLT are lacking; however, studies utilizing a monoclonal antibody reactive with the immunodominant epitope of PDC-E2 suggest that apical staining of bile duct epithelium is the earliest immunohistochemical evidence of PBC recurrence after OLT.14 Immunopathogenesis studies with this monoclonal antibody reveal increased expression of either PDC-E2 or a cross-reactive molecule on the luminal surface of biliary epithelial cells of PBC patients, thereby providing insight into the tissue-specific pathology observed in PBC.15 MA are found in <1% of apparently healthy Caucasoid adults.16,17

Approximately 3% of patients with PBC have scleroderma, usually of the CREST syndrome variety.18 In addition, MA reactive with the PDC-E2 complex are found in some patients with CREST or diffuse scleroderma,19 sometimes in the absence of overt liver disease. Scleroderma typically precedes PBC in those patients with both diseases.19

Indirect immunofluorescence using HEp-2 cells or rat tissue sections,1 or mouse sperm,20 is 100% sensitive20 and specific21 for detection of MA. Use of recombinant antigens22,23 in an EIA format is promising for rapid, sensitive and specific detection of MA.

Nuclear autoantibodies specific for nuclear membrane are found in a subset of patients with PBC, including a few who are MA-negative.24-26 The nuclear autoantibody (ANA) patterns in PBC include: 1) multiple nuclear dots (MND-ANA), seen in 10-15% of PBC and mainly associated with sicca syndrome; 2) membrane-associated ANA (M-ANA), seen in 25-50% of PBC and not associated with lamin autoantibodies.24-26 Whether MND-ANA and M-ANA are sufficiently distinctive to be helpful in the evaluation of MA-negative PBC is not proved.27,28

Relevant Tests Offered by Specialty
1100 ANA with International Units & Pattern
Tests are subject to change. For additional information on these tests or to place an order, please call Specialty's Client Services at 800-421-4449.

REFERENCES

  1. Leung PSC, Coppel RL, Gershwin ME. Mitochondrial autoantibodies. In: Peter JB, Shoenfeld Y, editors. Autoantibodies. Amsterdam: Elsevier Science B.V., 1996:494-500.
  2. Van Norstrand MD, Malinchoc M, Lindor KD, et al. Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship of levels of autoantibodies to disease progression. Hepatology 1997;25:6-11.
  3. Baum H. Mitochondrial antigens, molecular mimicry and autoimmune disease. Biochim Biophys Acta 1995;1271:111-21.
  4. Goodman ZD, McNally PR, Davis DR, Ishak KG. Autoimmune cholangitis: a variant of primary biliary cirrhosis. Clinicopathologic and serologic correlations in 200 cases. Dig Dis Sci 1995;40:1232-42.
  5. Butler P, Hamilton-Miller J, Baum H, Burroughs AK. Detection of M2 antibodies in patients with recurrent urinary tract infection using and ELISA and purified PBC specific antigens. Evidence for a molecular mimicry mechanism in the pathogensis of primary biliary cirrhosis? Biochem Mol Biol Int 1995;35:473-85.
  6. Vilagut L, Vila J, Vinas O, Pares A, Gines A, Jimenez de Anta MT, Rodes J. Cross-reactivity of anti-Mycobacterium gordonae antibodies with the major mitochondrial autoantigens in primary biliary cirrhosis [see comments]. J Hepatol 1994;21:673-7.
  7. Kiechle FL, Quattrociocchi-Longe TM, Brinton DA, Gordon SC, Sukes E, Elkhalifa MY. Autoantibodies to specific enzymes: a review. Ann Clin Lab Sci 1996;26:195-207.
  8. Salaspuro MP, Laitinen OI, Lehtola J, Makkonen H, Räsä(nen JA, Sipponen P. Immunological parameters, viral antibodies, and biochemical and histological findings in relatives of patients with chronic active hepatitis and primary biliary cirrhosis. Scand J Gastroenterol 1976;11:313-20.
  9. Watmough D, French MAH, Triger DR. Antibody responses to tetanus toxoid in patients with primary biliary cirrhosis. J Clin Pathol 1987;40:683-6.
  10. Mitchison HC, Bassendine MF, Hendrick A, et al. Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis? Hepatology 1986;6:1279-84.
  11. Kenny RP, Czaja AJ, Ludwig J, Dickson ER. Frequency and significance of antimitochondrial antibodies in severe chronic active hepatitis. Dig Dis Sci 1986;31:705-11.
  12. Haagsma EB, Manns M, Klein R, et al. Subtypes of antimitochondrial antibodies in primary biliary cirrhosis before and after orthotopic liver transplantation. Hepatology 1987;7:129-33.
  13. Wiesner RH, Ludwig J, Lindor KD, et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 1990;322:1419-24.
  14. Van de Water J, Gerson LB, et al. Immunohistochemical evidence of disease recurrence after liver transplantation for primary biliary cirrhosis. Hepatology 1996;24;1079-84.
  15. Leung PS, Van de Water J, Coppel RL, Nakanuma Y, Munoz S, Gershwin ME. Molecular aspects and the pathological basis of primary biliary cirrhosis. J Autoimmun 1996;9:119-28.
  16. Triger DR, Charlton CAC, Ward AM. What does the antimitochondrial antibody mean? Gut 1982;23:814-18.
  17. Hawkins BR, O'Conner KJ, Dawkins RL, Dawkins B, Rodger B. Autoantibodies in an Australian population. I. Prevalence and persistence. J Clin Lab Immunol 1979;2:211-5.
  18. Bunn CC, McMorrow M. Anti-M4 antibodies measured by a sulphite oxidase ELISA in patients with both anti-centromere and anti-M2 antibodies. Clin Exp Immunol 1995;102;131-6.
  19. Fregeau DR, Leung PSC, Coppel RL, McNeilage LJ, Medsger TA Jr, Gershwin ME. Autoantibodies to mitochondria in systemic sclerosis. Arthritis Rheum 1988;31:386-92.
  20. Martinez S, Berrios S, Fernandez-Donoso R, Brahm J, Cuchacovich M. Antimitochondrial antibody detection by indirect immunofluorescence on mouse sperms. Eur J Histochem 1996;40:315-22.
  21. Omagari K, Rowley MJ, Whittingham S, Jois JA, Byron SL, Mackay IR. Autoantibodies to M2 mitochondrial autoantigens in normal human sera by immunofluorescence and novel assays. J Gastroenterol Hepatol 1996;11:610-6.
  22. Moteki S, Leung PS, Coppel RL, et al. Use of a designer triple expression hybrid clone for three different lipoyl domain for the detection of antimitochondrial autoantibodies. Hepatology 1996;24:97-103.
  23. Moteki S, Leung PS, Dickson ER, et al. Epitope mapping and reactivity of autoantibodies to the E2 component of 2-oxoglutarate dehydrogenase complex in primary biliary cirrhosis using recombinant 2-oxogluarate dehydrogenase complex. Hepatology 1996;23:436-44.
  24. Ruffatti A, Arslan P, Floreani A, et al. Nuclear membrane-staining antinuclear antibody in patients with primary biliary cirrhosis. J Clin Immunol 1985;5:357-61.
  25. Lassoued K, Guilly MN, Andre C, et al. Autoantibodies to 200 kd polypeptide(s) of the nuclear envelope: a new serologic marker of primary biliary cirrhosis. Clin Exp Immunol 1988;74:283-8.
  26. Courvalin JC, Lassoued K, Bartnil E, Blobel G, Wozniak RW. The 210-kD nuclear envelope polypeptide recognized by human autoantibodies in primary biliary cirrhosis is the major glycoprotein of the nuclear pore. J Clin Invest 1990;86:279-85.
  27. Fusconi M, Cassani F, Govoni M, et al. Anti-nuclear antibodies of primary biliary cirrhosis recognize 78-92-kD and 96-100-kD proteins of nuclear bodies. Clin Exp Immunol 1991;83:291-7.
  28. Evans J, Reuben A, Craft J. PBC 95K, a 95-kilodalton nuclear autoantigen in primary biliary cirrhosis. Arthritis Rheum 1991;34:731-6.





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