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

^ 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.
^ 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.
^ JB Imboden, DB Hellmann, JH Stone. Current Rheumatology Diagnosis & Treatment, Second Edition. McGraw-Hill, 2007.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.