Anti-topoisomerase antibodies

Last updated
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).

Contents

Epitopes and subtypes

Anti Scl-70 antibodies (also called anti-topoisomerase I after the type I topoisomerase target [1] ) is a type of anti-nuclear 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 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. [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]

Related Research Articles

Systemic scleroderma

Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are two major subgroups of systemic sclerosis based on the extent of skin involvement: limited and diffuse. The limited form affects areas below, but not above, the elbows and knees with or without involvement of the face. The diffuse form also affects the skin above the elbows and knees and can also spread to the torso. Visceral organs, including the kidneys, heart, lungs, and gastrointestinal tract can also be affected by the fibrotic process. Prognosis is determined by the form of the disease and the extent of visceral involvement. Patients with limited systemic sclerosis have a better prognosis than those with the diffuse form. Death is most often caused by lung, heart, and kidney involvement. There is also a slight increase in the risk of cancer.

Sjögren syndrome

Sjögren's syndrome is a long-term autoimmune disease that affects the body's moisture-producing glands, and often seriously affects other organs systems, such as the lungs, kidneys, and nervous system. Primary symptoms are dryness, pain and fatigue. Other symptoms can include dry skin, vaginal dryness, a chronic cough, numbness in the arms and legs, feeling tired, muscle and joint pains, and thyroid problems. Those affected are also at an increased risk (5%) of lymphoma.

Anti-nuclear antibody Autoantibody that binds to contents of the cell nucleus

Antinuclear antibodies are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human proteins (autoantigens). In some cases, antibodies to human antigens are produced.

Rheumatoid factor (RF) is the autoantibody that was first found in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG and different RFs can recognize different parts of the IgG-Fc. RF and IgG join to form immune complexes that contribute to the disease process.

Morphea Form of scleroderma involving isolated patches of hardened skin

Morphea, is a form of scleroderma that involves isolated patches of hardened skin on the face, hands, and feet, or anywhere else on the body, with no internal organ involvement.

Mixed connective tissue disease commonly abbreviated as MCTD, is an autoimmune disease characterized by the presence of elevated blood levels of a specific autoantibody, now called anti-U1 ribonucleoprotein (RNP) together with a mix of symptoms of systemic lupus erythematosus (SLE), scleroderma, and polymyositis. The idea behind the "mixed" disease is that this specific autoantibody is also present in other autoimmune diseases such as systemic lupus erythematosus, polymyositis, scleroderma, etc. MCTD was characterized as an individual disease in 1972 by Sharp et al., and the term was introduced by Leroy in 1980.

Anti-transglutaminase antibodies (ATA) are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substances can be foreign and also can be produced by the body. Antibodies against the body's own products are called autoantibodies. Autoantibodies can sometimes errantly be directed against healthy portions of the organism, causing autoimmune diseases.

Scleromyositis, is an autoimmune disease. People with scleromyositis have symptoms of both systemic scleroderma and either polymyositis or dermatomyositis, and is therefore considered an overlap syndrome. Although it is a rare disease, it is one of the more common overlap syndromes seen in scleroderma patients, together with MCTD and Antisynthetase syndrome. Autoantibodies often found in these patients are the anti-PM/Scl (anti-exosome) antibodies.

HLA-DR16

HLA-DR16(DR16) is a HLA-DR serotype that recognizes the DRB1*1601, *1602 and *1604 gene products. DR16 is found in the Mediterranean at modest frequencies. DR16 is part of the older HLA-DR2 serotype group which also contains the similar HLA-DR15 antigens.

HLA-DR15

HLA-DR15 (DR15) is a HLA-DR serotype that recognizes the DRB1*1501 to *1505 and *1507 gene products. DR15 is found at high levels from Ireland to Central Asia. DR15 is part of the older HLA-DR2 serotype group which also contains the similar HLA-DR16 antigens.

HLA-DR11

HLA-DR11 (DR11) is a HLA-DR serotype that recognizes the DRB1*1101 to *1110. DR11 serotype is a split antigen of the older HLA-DR5 serotype group which also contains the similar HLA-DR12 antigens.

HLA-DR5

HLA-DR5 (DR5) is a broad-antigen serotype that is further split into HLA-DR11 and HLA-DR12 antigen serotypes.

HLA-DR4

HLA-DR4 (DR4) is an HLA-DR serotype that recognizes the DRB1*04 gene products. The DR4 serogroup is large and has a number of moderate frequency alleles spread over large regions of the world.

Anti-cardiolipin antibodies

Anti-cardiolipin antibodies (ACA) are antibodies often directed against cardiolipin and found in several diseases, including syphilis, antiphospholipid syndrome, livedoid vasculitis, vertebrobasilar insufficiency, Behçet's syndrome, idiopathic spontaneous abortion, and systemic lupus erythematosus (SLE). They are a form of anti-mitochondrial antibody. In SLE, anti-DNA antibodies and anti-cardiolipin antibodies may be present individually or together; the two types of antibodies act independently. This is in contrast to rheumatoid arthritis with systemic sclerosis (scleroderma) because anti-cardiolipin antibodies are present in both conditions, and therefore may tie the two conditions together.

Anti–citrullinated protein antibody Autoantibodies

Anti-citrullinated protein antibodies (ACPAs) are autoantibodies that are directed against peptides and proteins that are citrullinated. They are present in the majority of patients with rheumatoid arthritis. Clinically, cyclic citrullinated peptides (CCP) are frequently used to detect these antibodies in patient serum or plasma.

Anti-dsDNA antibodies Group of anti-nuclear antibodies

Anti-double stranded DNA (Anti-dsDNA) antibodies are a group of anti-nuclear antibodies (ANA) the target antigen of which is double stranded DNA. Blood tests such as enzyme-linked immunosorbent assay (ELISA) and immunofluorescence are routinely performed to detect anti-dsDNA antibodies in diagnostic laboratories. They are highly diagnostic of systemic lupus erythematosus (SLE) and are implicated in the pathogenesis of lupus nephritis.

Lupus Human autoimmune disease

Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary between people and may be mild to severe. Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. Often there are periods of illness, called flares, and periods of remission during which there are few symptoms.

Scleroderma Group of autoimmune diseases resulting in abnormal growth of connective tissue

Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs as well. Symptoms may include areas of thickened skin, stiffness, feeling tired, and poor blood flow to the fingers or toes with cold exposure. One form of the condition, known as CREST syndrome, classically results in calcium deposits, Raynaud's syndrome, esophageal problems, thickening of the skin of the fingers and toes, and areas of small dilated blood vessels.

Lidia Rudnicka

Lidia Rudnicka is a Polish-American dermatologist with contributions to the field of scleroderma research, hair diseases and melanoma prevention.

Anti-Scl-70 is an anti-topoisomerase antibody-type of anti-nuclear autoantibodies, seen mainly in diffuse systemic scleroderma, but is also seen in 10–18% of cases of the more limited form of systemic scleroderma called CREST syndrome. Anti Scl-70 antibodies are associated with more severe scleroderma disease.

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.
  2. ↑ Table 5-9 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN   1-4160-2973-7. 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". Clin. Rheumatol. 8 (2): 231–7. doi:10.1007/BF02030079. PMID   2547546.
  5. ↑ 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. 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 Lett. 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?". Lancet. 2 (8609): 475–7. doi:10.1016/S0140-6736(88)90122-5. PMID   2900403.
  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 Rheum. 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". Clin. Rheumatol. 25 (4): 542–3. doi:10.1007/s10067-005-0061-9. PMID   16525896.
  10. ↑ 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.
  11. ↑ 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.
  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 Rheumatology. 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". Scand. J. Rheumatol. 35 (1): 39–43. doi:10.1080/03009740510026751. PMID   16467040.
  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 Rheum. 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". Hum. Immunol. 66 (7): 810–7. doi:10.1016/j.humimm.2005.03.006. PMID   16112028.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.