Anti-topoisomerase antibodies

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Autoantibody(s)
Anti-Topoisomerase
Autoantigen
Isoform
Topoisomerase I (human)
Autoantigen gene TOP1
Affected organ(s) Dermis
Associated</br>Disease(s) Scleroderma,

Systemic sclerosis

Autoantibody</br>Ig Class IgG, IgA
DR2
HLA associations DR15
DR16
Other</br>Susceptibility</br>genes lymphoid protein</br>

tyrosine phos-</br> phatase type 22</br> PTPN22


Anti-topoisomerase antibodies (ATA) are 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 is recognized as one of two major classes of autoantibodies in sclerosis[1] (systemic or scleroderma). The antigen of Anti Scl-70 was recognized as topoisomerase I in 1986[2] with anti-centromere antibodies constituting the other class. ATA is associated with more severe disease.[3]

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.[4]

Pathology

Topoisomerase I bound to a strand of DNA

Topoisomerase I is an enzyme that relaxes the strain on DNA by nicking and ligating the DNA. ATA inhibits the activity of this enzyme.[5] Since this activity occurs in the nucleus of the cell ATA is a form of anti-nuclear 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.[6] ATA correlates with rapid progression of disease.[7]

In systemic lupus erythematosus ATA are associated with nephritis.[8]

Increases in ATA+ in scleroderma and SLE are associated with increases in serum CTLA4.[9][10]

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,[11], and in another population study it was found that DR-15 is associated with ATA in systemic sclerosis.[12] 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.[13] The TAP1gene(6p21.3, HLA complex) has also been found in association with ATA+ sclerosis.[14]

References

  1. Catoggio LJ, Skinner RP, Maddison PJ (1983). "Frequency and clinical significance of anticentromere and anti Scl-70 antibodies in an English connective tissue disease population". Rheumatol. Int. 3 (1): 19–21. PMID 6412349. 
  2. 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. PMID 2428564. 
  3. de Rooij DJ, Van de Putte LB, Habets WJ, Van Venrooij WJ (1989). "Marker antibodies in scleroderma and polymyositis: clinical associations". Clin. Rheumatol. 8 (2): 231–7. PMID 2547546. 
  4. Hildebrandt S, Weiner E, Senécal JL; et al. (1990). "The IgG, IgM, and IgA isotypes of anti-topoisomerase I and anticentromere autoantibodies". Arthritis Rheum. 33 (5): 724–7. PMID 2161233. 
  5. Samuels DS, Tojo T, Homma M, Shimizu N (1986). "Inhibition of topoisomerase I by antibodies in sera from scleroderma patients". FEBS Lett. 209 (2): 231–4. PMID 2431927. 
  6. Douvas A (1988). "Does Sc1-70 modulate collagen production in systemic sclerosis?". Lancet. 2 (8609): 475–7. PMID 2900403. 
  7. 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 Rheum. 56 (8): 2740–6. PMID 17665460. doi:10.1002/art.22747. 
  8. 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". Clin. Rheumatol. 25 (4): 542–3. PMID 16525896. doi:10.1007/s10067-005-0061-9. 
  9. Sato S, Fujimoto M, Hasegawa M; et al. (2004). "Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis". Rheumatology (Oxford, England). 43 (10): 1261–6. PMID 15266059. doi:10.1093/rheumatology/keh303. 
  10. Takeuchi F, Kawasugi K, Nabeta H, Mori M, Tanimoto K (2002). "Association of CTLA-4 with systemic sclerosis in Japanese patients". Clin. Exp. Rheumatol. 20 (6): 823–8. PMID 12508774. 
  11. 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 Rheum. 36 (10): 1406–13. PMID 7692859. 
  12. Joung CI, Jun JB, Chung WT; et al. (2006). "Association between the HLA-DRB1 gene and clinical features of systemic sclerosis in Korea". Scand. J. Rheumatol. 35 (1): 39–43. PMID 16467040. doi:10.1080/03009740510026751. 
  13. 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 Rheum. 54 (12): 3945–53. PMID 17133608. doi:10.1002/art.22196. 
  14. 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". Hum. Immunol. 66 (7): 810–7. PMID 16112028. doi:10.1016/j.humimm.2005.03.006. 

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