User:Simoncaulton/Anti dsDNA

Discovery

The first evidence for antinuclear antibodies arose in 1948 when Hargraves, Richmond and Morton discovered the LE cell. These abnormal cells found in the bone marrow of systemic lupus erythematosus (SLE) patients are categorised as polymorphonuclear leukocytes with phagocytosed whole nuclei. Subsequently in 1957, antibodies to dsDNA were the first autoantibodies to be identified in patients with SLE.

Antibody production

Although the exact mechanism of the generation of dsDNA antibodies is still unkown, it is likely that extracellular DNA is one cause of an immune response against dsDNA. There is a great deal of evidence supporting the idea that dead or dying cells are one major source of this extracellular DNA.The Role of Extracellular DNA in Autoimmunity in SLE. Apoptosis is the highly organised process of programmed cell death in which the cell degrades the nuclear DNA and signals for phagocytosis. In patients with SLE and other autoimmune disorders this process is thought to be defective, causing either an increase in cell death and/or a decrease in the rate of dead cell clearance.

There is a higher rate of apoptosis in patients with SLE and various changes in genes and proteins have been implicated in the defects in apoptosis. These include increased levels of soluble Fas and bcl-2 and polymorphisms in the programmed cell death 1 and run-related transcription factor X1.Deranged removal of apoptotic cells:its role in the genesis of lupus.

Blebs on apoptotic cells contain nearly all the autoantigens found in SLE, and phagocytes bind these apoptotic cells and phagocytose them. If this process is defective, these autoantigens can be released into the circulation allowing an immune response. Serum amyloid P component is a protein that is thought to aid in the cleaance of chromatin produced by apoptotic cells and deficiencies in this protein have been shown (in mice) to cause spontaneous formation of ANA. Autoantigens present on the blebs of apoptotic cells are also prone to modification, which can increase their immunogenicity.antinuclear antibodies:cause of disease or caused by disease Deranged removal of apoptotic cells:its role in the genesis of lupus.

Upon release of nuclear proteins and chromatin, antigen presenting cells, such as dendritic cells and macrophages, display these antigens to T helper cells. Although the details of this process are still contraversial, evidence is emerging that to activate an antigen presenting cell, it must act via the pattern recognition receptor, toll-like receptor 9 (TLR9). Plasmacytoid dentritic cells are the major target immune cells for dsDNA as they express high levels of toll-like receptor 9. Upon binding of TLR9 and dsDNA, the dentritic cell activates and produces type 1 interferons. The T helper cells then activate B cells which are also in the presence of these antigens. This causes the production of auto antibodies. The Role of Extracellular DNA in Autoimmunity in SLE Toll-like receptors in systemic autoimmune disease

Anti-dsDNA antibodies can also be produced through infection via a mechansim known as molecular mimicry. Upon exposure to pneumococcal polysaccharide, cross reactive antibodies between dsDNA and pneumococcal polysaccharide are produced in lupus. molecular mimicry and autoimmunity. Epstein-Barr virus is also known to induce dsDNA antibodies, as seen after immunisation of animals with EBNA-1 epitopes.

Anti-dsDNA antibodies may also be created secondary to the production of antibodies to other proteins within the nucleosome. Mice that have T cells directed towards the nucleosome can illicit a response to other antigens such as dsDNA and histone via a mechansim known as antigen spreading. This effect can also occur after an infection causes the production of autoantibodies to other structures within the nucleus. lupus nephritis. consequence of disturbed removal of apoptosis cells epstein barr virus and molecular mimicry in sytemic lupus erythematosus

Detection and quantitation

Farr assay

The Farr assay is used to quantify the amount of dsDNA antibodies in a patient's serum. Ammonium sulphate is used to precipitate antigen-antibody complexes that form if the sera contains antibodies to dsDNA. The quantity of these antibodies is determined by using radiolabelled dsDNA. Although this test is very specific, it is of little use in routine diagnostic laboratories due to its laboriousness and use of radioactive materials.

EIA

Poole BD, Scofield RH, Harley JB, James JA (2006). "Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus". Autoimmunity. 39 (1): 63–70. doi:10.1080/08916930500484849. PMID 16455583. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)