Anti-topoisomerase antibodies explained

Anti-topoisomerase antibodies (ATA) are autoantibodies directed against topoisomerase and found in several diseases, most importantly scleroderma. Diseases with ATA are autoimmune disease because they react with self-proteins. They are also referred to as anti-DNA topoisomerase I antibody (anti-topo I).

Epitopes and subtypes

Anti Scl-70 antibodies (also called anti-topoisomerase I after the type I topoisomerase target[1]) is a type of antinuclear autoantibody seen mainly in diffuse systemic scleroderma, but is also seen the more limited form of systemic scleroderma called CREST syndrome.[2] However, CREST syndrome is more closely associated with anti-centromere antibodies.[3] Scl-70 antibodies are associated with more severe scleroderma disease.[4]

Anti-topoisomerase antibodies can be classified according to their immunoglobulin class (IgM, IgG or IgA). IgG-ATA is found most frequently in scleroderma, with IgA being quite common but IgM very infrequent.[5]

Pathology

Topoisomerase I is an enzyme that relaxes the strain on DNA by nicking and ligating the DNA. ATA inhibits the activity of this enzyme.[6] Since this activity occurs in the nucleus of the cell ATA is a form of antinuclear antibody. Scleroderma results from the overproduction of collagen in affected tissues, one study claims that there is an increased density of Topoisomerase I sites in the collagen genes, and that the antibodies may be altering transcription at these loci.[7] ATA correlates with rapid progression of disease.[8]

In systemic lupus erythematosus ATA are associated with nephritis.[9]

Increases in ATA+ in scleroderma and SLE are associated with increases in serum CTLA4.[10] [11]

Genetics

HLA-DR2 (DR15 and DR16) are associated with scleroderma and systemic sclerosis. It has been found that patients with ATA that recognize the ET4 domain of topoisomerase were frequently HLA-DR2,[12] and in another population study it was found that DR-15 is associated with ATA in systemic sclerosis.[13] In addition to HLA-DR, the protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (1p13.2 -), "CT/TT" genotype showed significant association with anti-topo I.[14] The gene (6p21.3, HLA complex) has also been found in association with ATA+ sclerosis.[15]

Notes and References

  1. Guldner HH, Szostecki C, Vosberg HP, Lakomek HJ, Penner E, Bautz FA . Scl 70 autoantibodies from scleroderma patients recognize a 95 kDa protein identified as DNA topoisomerase I . Chromosoma. 94 . 2 . 132–8 . 1986 . 2428564 . 10.1007/BF00286991 . 24851422 .
  2. Table 5-9 in: Book: Mitchell, Richard Sheppard . Kumar, Vinay . Abbas, Abul K. . Fausto, Nelson . Robbins Basic Pathology. Saunders . Philadelphia . 2007. 978-1-4160-2973-1 . 8th edition.
  3. JB Imboden, DB Hellmann, JH Stone. Current Rheumatology Diagnosis & Treatment, Second Edition. McGraw-Hill, 2007.
  4. de Rooij DJ, Van de Putte LB, Habets WJ, Van Venrooij WJ . Marker antibodies in scleroderma and polymyositis: clinical associations . Clinical Rheumatology. 8 . 2 . 231–7 . 1989 . 2547546 . 10.1007/BF02030079 . 23132993 .
  5. Hildebrandt S . The IgG, IgM, and IgA isotypes of anti-topoisomerase I and anticentromere autoantibodies . Arthritis & Rheumatism. 33 . 5 . 724–7 . 1990 . 2161233 . 10.1002/art.1780330515 . vanc . Weiner E . Senécal JL . 3 . Noell . Steve . Daniels . Leslie . Earnshaw . William C . Rothfield . Naomi F .
  6. Samuels DS, Tojo T, Homma M, Shimizu N . Inhibition of topoisomerase I by antibodies in sera from scleroderma patients . FEBS Letters. 209 . 2 . 231–4 . 1986 . 2431927 . 10.1016/0014-5793(86)81117-6 . free .
  7. Douvas A . Does Sc1-70 modulate collagen production in systemic sclerosis? . The Lancet. 2 . 8609 . 475–7 . 1988 . 2900403 . 10.1016/S0140-6736(88)90122-5 . 33578122 .
  8. Perera A . Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti-topoisomerase I antibody . Arthritis & Rheumatism. 56 . 8 . 2740–6 . 2007 . 17665460 . 10.1002/art.22747 . vanc . Fertig N . Lucas M . 3 . Rodriguez-Reyna . Tatiana S. . Hu . Paul . Steen . Virginia D. . Medsger . Thomas A..
  9. Hamidou MA, Audrain MA, Masseau A, Agard C, Moreau A . Anti-topoisomerase I antibodies in systemic lupus erythematosus as a marker of severe nephritis . Clinical Rheumatology. 25 . 4 . 542–3 . 2006 . 16525896 . 10.1007/s10067-005-0061-9. 289409 .
  10. Sato S . Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis . Rheumatology. 43 . 10 . 1261–6 . 2004 . 15266059 . 10.1093/rheumatology/keh303 . vanc . Fujimoto M . Hasegawa M . 3 . Komura . K . Yanaba . K . Hayakawa . I . Matsushita . T . Takehara . K. free .
  11. Takeuchi F, Kawasugi K, Nabeta H, Mori M, Tanimoto K . Association of CTLA-4 with systemic sclerosis in Japanese patients . Clinical and Experimental Rheumatology. 20 . 6 . 823–8 . 2002 . 12508774 .
  12. Kuwana M, Kaburaki J, Mimori T, Tojo T, Homma M . Autoantigenic epitopes on DNA topoisomerase I. Clinical and immunogenetic associations in systemic sclerosis . Arthritis and Rheumatism. 36 . 10 . 1406–13 . 1993 . 7692859 . 10.1002/art.1780361013 .
  13. Joung CI . Association between the HLA-DRB1 gene and clinical features of systemic sclerosis in Korea . Scandinavian Journal of Rheumatology. 35 . 1 . 39–43 . 2006 . 16467040 . 10.1080/03009740510026751 . vanc . Jun JB . Chung WT . 3 . Song . G.‐G. . Choe . J.‐Y. . Chang . H.‐K. . Yoo . D.‐H.. 23157796 .
  14. Gourh P . Association of the protein tyrosine phosphatase, non-receptor type 8 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis . Arthritis and Rheumatism. 54 . 12 . 3945–53 . 2006 . 17133608 . 10.1002/art.22196 . vanc . Tan FK . Assassi S . 3 . Ahn . Chul W. . McNearney . Terry A. . Fischbach . Michael . Arnett . Frank C. . Mayes . Maureen D..
  15. Song YW, Lee EB, Whang DH, Kang SJ, Takeuchi F, Park MH . Association of TAP1 and TAP2 gene polymorphisms with systemic sclerosis in Korean patients . Human Immunology. 66 . 7 . 810–7 . 2005 . 16112028 . 10.1016/j.humimm.2005.03.006.

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