Anti-topoisomerase antibodies

Autoantibody
Anti-Topoisomerase
Autoantigen Isoform	Topoisomerase I (human)
Autoantigen gene	TOP1
Affected organ(s)	Dermis
Associated Disease(s)	Scleroderma, Systemic sclerosis
Autoantibody Ig Class	IgG, IgA
	DR2
HLA associations	DR15
	DR16
Other Susceptibility genes	lymphoid protein tyrosine phos- phatase type 22 PTPN22

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 - PTPN22), "CT/TT" genotype showed significant association with anti-topo I.^[14] The TAP1 gene (6p21.3, HLA complex) has also been found in association with ATA+ sclerosis.^[15]

References

1. Guldner HH, Szostecki C, Vosberg HP, Lakomek HJ, Penner E, Bautz FA (1986). "Scl 70 autoantibodies from scleroderma patients recognize a 95 kDa protein identified as DNA topoisomerase I". Chromosoma. 94 (2): 132–8. doi:10.1007/BF00286991. PMID 2428564. S2CID 24851422.
2. Table 5-9 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 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 (1989). "Marker antibodies in scleroderma and polymyositis: clinical associations". Clinical Rheumatology. 8 (2): 231–7. doi:10.1007/BF02030079. PMID 2547546. S2CID 23132993.
5. Hildebrandt S, Weiner E, Senécal JL, et al. (1990). "The IgG, IgM, and IgA isotypes of anti-topoisomerase I and anticentromere autoantibodies". Arthritis & Rheumatism. 33 (5): 724–7. doi:10.1002/art.1780330515. PMID 2161233.
6. Samuels DS, Tojo T, Homma M, Shimizu N (1986). "Inhibition of topoisomerase I by antibodies in sera from scleroderma patients". FEBS Letters. 209 (2): 231–4. doi:10.1016/0014-5793(86)81117-6. PMID 2431927.
7. Douvas A (1988). "Does Sc1-70 modulate collagen production in systemic sclerosis?". The Lancet. 2 (8609): 475–7. doi:10.1016/S0140-6736(88)90122-5. PMID 2900403. S2CID 33578122.
8. Perera A, Fertig N, Lucas M, et al. (2007). "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. doi:10.1002/art.22747. PMID 17665460.
9. Hamidou MA, Audrain MA, Masseau A, Agard C, Moreau A (2006). "Anti-topoisomerase I antibodies in systemic lupus erythematosus as a marker of severe nephritis". Clinical Rheumatology. 25 (4): 542–3. doi:10.1007/s10067-005-0061-9. PMID 16525896. S2CID 289409.
10. Sato S, Fujimoto M, Hasegawa M, et al. (2004). "Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis". Rheumatology. 43 (10): 1261–6. doi:10.1093/rheumatology/keh303. PMID 15266059.
11. Takeuchi F, Kawasugi K, Nabeta H, Mori M, Tanimoto K (2002). "Association of CTLA-4 with systemic sclerosis in Japanese patients". Clinical and Experimental Rheumatology. 20 (6): 823–8. PMID 12508774.
12. Kuwana M, Kaburaki J, Mimori T, Tojo T, Homma M (1993). "Autoantigenic epitopes on DNA topoisomerase I. Clinical and immunogenetic associations in systemic sclerosis". Arthritis and Rheumatism. 36 (10): 1406–13. doi:10.1002/art.1780361013. PMID 7692859.
13. Joung CI, Jun JB, Chung WT, et al. (2006). "Association between the HLA-DRB1 gene and clinical features of systemic sclerosis in Korea". Scandinavian Journal of Rheumatology. 35 (1): 39–43. doi:10.1080/03009740510026751. PMID 16467040. S2CID 23157796.
14. Gourh P, Tan FK, Assassi S, et al. (2006). "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. doi:10.1002/art.22196. PMID 17133608.
15. Song YW, Lee EB, Whang DH, Kang SJ, Takeuchi F, Park MH (2005). "Association of TAP1 and TAP2 gene polymorphisms with systemic sclerosis in Korean patients". Human Immunology. 66 (7): 810–7. doi:10.1016/j.humimm.2005.03.006. PMID 16112028.