Anti-topoisomerase antibodies

AutoAbBox
Autoantigen = Topoisomerase
OneIsoform = Yes
OneIsoformSpecialName = Topoisomerase I (human)
OneGene = TOP1
OneOrgan = Dermis
OneTissue =
OneCell =
OneAlso =
OneDisease = Scleroderma,

Systemic sclerosis
OneIgClass = IgG, IgA
OneIgGSubclass =
OneHLA1 = DR2
OneHLA2 = DR15
OneHLA3 = DR16
OneAssociatedProtein = lymphoid protein
tyrosine phos-
phatase type 22

OneAssociatedGene = PTPN22
OneTCellRestr =
OneTrigger =

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 is recognized as one of two major classes of autoantibodies in sclerosiscite journal | author = Catoggio LJ, Skinner RP, Maddison PJ | title = Frequency and clinical significance of anticentromere and anti Scl-70 antibodies in an English connective tissue disease population | journal = Rheumatol. Int. | volume = 3 | issue = 1 | pages = 19–21 | year = 1983 | pmid = 6412349 | doi = ] (systemic or scleroderma). The antigen of Anti Scl-70 was recognized as topoisomerase I in 1986cite journal | author = Guldner HH, Szostecki C, Vosberg HP, Lakomek HJ, Penner E, Bautz FA | title = Scl 70 autoantibodies from scleroderma patients recognize a 95 kDa protein identified as DNA topoisomerase I | journal = Chromosoma | volume = 94 | issue = 2 | pages = 132–8 | year = 1986 | pmid = 2428564 | doi = ] with anti-centromere antibodies constituting the other class. ATA is associated with more severe disease.cite journal | author = de Rooij DJ, Van de Putte LB, Habets WJ, Van Venrooij WJ | title = Marker antibodies in scleroderma and polymyositis: clinical associations | journal = Clin. Rheumatol. | volume = 8 | issue = 2 | pages = 231–7 | year = 1989 | pmid = 2547546 | doi = ]

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.cite journal | author = Hildebrandt S, Weiner E, Senécal JL, "et al" | title = The IgG, IgM, and IgA isotypes of anti-topoisomerase I and anticentromere autoantibodies | journal = Arthritis Rheum. | volume = 33 | issue = 5 | pages = 724–7 | year = 1990 | pmid = 2161233 | doi = ]

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.cite journal | author = Samuels DS, Tojo T, Homma M, Shimizu N | title = Inhibition of topoisomerase I by antibodies in sera from scleroderma patients | journal = FEBS Lett. | volume = 209 | issue = 2 | pages = 231–4 | year = 1986 | pmid = 2431927 | doi = ] 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.cite journal | author = Douvas A | title = Does Sc1-70 modulate collagen production in systemic sclerosis? | journal = Lancet | volume = 2 | issue = 8609 | pages = 475–7 | year = 1988 | pmid = 2900403 | doi = ] ATA correlates with rapid progression of disease.cite journal | author = Perera A, Fertig N, Lucas M, "et al" | title = Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti-topoisomerase I antibody | journal = Arthritis Rheum. | volume = 56 | issue = 8 | pages = 2740–6 | year = 2007 | pmid = 17665460 | doi = 10.1002/art.22747]

In systemic lupus erythematosus ATA are associated with nephritis.cite journal | author = Hamidou MA, Audrain MA, Masseau A, Agard C, Moreau A | title = Anti-topoisomerase I antibodies in systemic lupus erythematosus as a marker of severe nephritis | journal = Clin. Rheumatol. | volume = 25 | issue = 4 | pages = 542–3 | year = 2006 | pmid = 16525896 | doi = 10.1007/s10067-005-0061-9]

Increases in ATA+ in scleroderma and SLE are associated with increases in serum CTLA4.cite journal | author = Sato S, Fujimoto M, Hasegawa M, "et al" | title = Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis | journal = Rheumatology (Oxford, England) | volume = 43 | issue = 10 | pages = 1261–6 | year = 2004 | pmid = 15266059 | doi = 10.1093/rheumatology/keh303] cite journal | author = Takeuchi F, Kawasugi K, Nabeta H, Mori M, Tanimoto K | title = Association of CTLA-4 with systemic sclerosis in Japanese patients | journal = Clin. Exp. Rheumatol. | volume = 20 | issue = 6 | pages = 823–8 | year = 2002 | pmid = 12508774 | doi = ]

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,cite journal | author = Kuwana M, Kaburaki J, Mimori T, Tojo T, Homma M | title = Autoantigenic epitopes on DNA topoisomerase I. Clinical and immunogenetic associations in systemic sclerosis | journal = Arthritis Rheum. | volume = 36 | issue = 10 | pages = 1406–13 | year = 1993 | pmid = 7692859 | doi = ] , and in another population study it was found that DR-15 is associated with ATA in systemic sclerosis.cite journal | author = Joung CI, Jun JB, Chung WT, "et al" | title = Association between the HLA-DRB1 gene and clinical features of systemic sclerosis in Korea | journal = Scand. J. Rheumatol. | volume = 35 | issue = 1 | pages = 39–43 | year = 2006 | pmid = 16467040 | doi = 10.1080/03009740510026751] In addition to HLA-DR, the "protein tyrosine phosphatase, non-receptor type 22 (lymphoid)" (1p13.2 - Gene|PTPN22), "CT/TT" genotype showed significant association with anti-topo I.cite journal | author = Gourh P, Tan FK, Assassi S, "et al" | title = Association of the protein tyrosine phosphatase, non-receptor type 8 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis | journal = Arthritis Rheum. | volume = 54 | issue = 12 | pages = 3945–53 | year = 2006 | pmid = 17133608 | doi = 10.1002/art.22196] The Gene|TAP1gene(6p21.3, HLA complex) has also been found in association with ATA+ sclerosis.cite journal | author = Song YW, Lee EB, Whang DH, Kang SJ, Takeuchi F, Park MH | title = Association of TAP1 and TAP2 gene polymorphisms with systemic sclerosis in Korean patients | journal = Hum. Immunol. | volume = 66 | issue = 7 | pages = 810–7 | year = 2005 | pmid = 16112028 | doi = 10.1016/j.humimm.2005.03.006]

References