Anti-topoisomerase antibodies

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Autoantibody(s)
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 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. doi:10.1002/art.22747. PMID 17665460.
  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. doi:10.1007/s10067-005-0061-9. PMID 16525896.
  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. doi:10.1093/rheumatology/keh303. PMID 15266059.
  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. doi:10.1080/03009740510026751. PMID 16467040.
  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. doi:10.1002/art.22196. PMID 17133608.
  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. doi:10.1016/j.humimm.2005.03.006. PMID 16112028.



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