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39-507: 1UFI , 1BW6 , 1HLV 1059 12616 ENSG00000125817 ENSMUSG00000068267 P07199 P27790 NM_001810 NM_007682 NP_001801 NP_031708 Centromere protein B also known as major centromere autoantigen B is an autoantigen protein of the cell nucleus . In humans, centromere protein B is encoded by the CENPB gene . Centromere protein B is a highly conserved protein that facilitates centromere formation. It

78-461: A T cell response, and limited evidence for T cell responses implicates nucleoprotein antigens. In Celiac disease there are autoantibodies to tissue transglutaminase but the T cell response is to the foreign protein gliadin. This disparity has led to the idea that human autoimmune disease is in most cases (with probable exceptions including type I diabetes) based on a loss of B cell tolerance which makes use of normal T cell responses to foreign antigens in

117-406: A biochemical rather than a clinical discipline. By the 1950s, the modern understanding of autoantibodies and autoimmune diseases started to spread. More recently, it has become accepted that autoimmune responses are an integral part of vertebrate immune systems (sometimes termed "natural autoimmunity"). Autoimmunity should not be confused with alloimmunity . While a high level of autoimmunity

156-956: A persistent increased risk for autoimmune disease. It has been suggested that the slight, direct exchange of cells between mothers and their children during pregnancy may induce autoimmunity. This would tip the gender balance in the direction of the female. Another theory suggests the female high tendency to get autoimmunity is due to an imbalanced X-chromosome inactivation . The X-inactivation skew theory, proposed by Princeton University's Jeff Stewart, has recently been confirmed experimentally in scleroderma and autoimmune thyroiditis . Other complex X-linked genetic susceptibility mechanisms are proposed and under investigation. An interesting inverse relationship exists between infectious diseases and autoimmune diseases. In areas where multiple infectious diseases are endemic, autoimmune diseases are quite rarely seen. The reverse, to some extent, seems to hold true. The hygiene hypothesis attributes these correlations to

195-412: A process known as “ Central Tolerance ”, T-cells are exposed to cortical epithelial cells that express a variety of different major histocompatibility complexes (MHC) of both class 1 and class 2 , which have the ability to bind to T-cell receptors of CD8+ cytotoxic T-cells , and CD4+ helper T-cells , respectively. The T-cells that display affinity for these MHC are positively selected to continue to

234-619: A variety of aberrant ways. There are a large number of immunodeficiency syndromes that present clinical and laboratory characteristics of autoimmunity. The decreased ability of the immune system to clear infections in these patients may be responsible for causing autoimmunity through perpetual immune system activation. One example is common variable immunodeficiency , in which multiple autoimmune diseases are seen, e.g., inflammatory bowel disease, autoimmune thrombocytopenia and autoimmune thyroid disease. Familial hemophagocytic lymphohistiocytosis , an autosomal recessive primary immunodeficiency,

273-592: Is a DNA -binding protein that is derived from transposases of the pogo DNA transposon family. It contains a helix-loop-helix DNA binding motif at the N-terminus and a dimerization domain at the C-terminus. The DNA binding domain recognizes and binds a 17-bp sequence (CENP-B box) in the centromeric alpha satellite DNA. This protein is proposed to play an important role in the assembly of specific centromere structures in interphase nuclei and on mitotic chromosomes. It

312-630: Is also considered a major centromere autoantigen recognized by sera from patients with anti-centromere antibodies. Centromere protein B is a potential biomarker of small-cell lung cancer . This article incorporates text from the United States National Library of Medicine , which is in the public domain . This article on a gene on human chromosome 20 is a stub . You can help Misplaced Pages by expanding it . Autoantigen Autoimmunity means presence of antibodies or T cells that react with self-protein and

351-466: Is also sometimes associated with the development of autoimmune and atopic phenomena. Certain individuals are genetically susceptible to developing autoimmune diseases. This susceptibility is associated with multiple genes plus other risk factors. Genetically predisposed individuals do not always develop autoimmune diseases. Three main sets of genes are suspected in many autoimmune diseases. These genes are related to: The first two, which are involved in

390-984: Is an experimental approach that involves inoculation of the patient with specific parasitic intestinal nematodes (helminths). There are currently two closely related treatments available, inoculation with either Necator americanus, commonly known as hookworms , or Trichuris Suis Ova, commonly known as Pig Whipworm Eggs. T-cell vaccination is also being explored as a possible future therapy for autoimmune disorders. Vitamin D/Sunlight Omega-3 Fatty Acids Probiotics/Microflora Antioxidants Self-protein Self-protein refers to all proteins endogenously produced by DNA -level transcription and translation within an organism of interest. This does not include proteins synthesized due to viral infection , but may include those synthesized by commensal bacteria within

429-599: Is another example. Pancytopenia , rashes, swollen lymph nodes and enlargement of the liver and spleen are commonly seen in such individuals. Presence of multiple uncleared viral infections due to lack of perforin are thought to be responsible. In addition to chronic and/or recurrent infections many autoimmune diseases including arthritis, autoimmune hemolytic anemia, scleroderma and type 1 diabetes mellitus are also seen in X-linked agammaglobulinemia (XLA). Recurrent bacterial and fungal infections and chronic inflammation of

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468-914: Is involved in regulating the activity of immune cells, and so variations in this gene can lead to dysregulation of the immune response, making individuals more susceptible to autoimmune diseases. Most autoimmune diseases are sex-related ; a s a whole, women are much more likely to develop autoimmune disease than men. Being female is the single greatest risk factor for developing autoimmune disease than any other genetic or environmental risk factor yet discovered. Autoimmune conditions overrepresented in women include: lupus , primary biliary cholangitis , Graves' disease , Hashimoto's thyroiditis , and multiple sclerosis , among many others. A few autoimmune diseases that men are just as or more likely to develop as women include: ankylosing spondylitis , type 1 diabetes mellitus , granulomatosis with polyangiitis , primary sclerosing cholangitis , and psoriasis . The reasons for

507-508: Is present in all individuals, even in normal health state. It causes autoimmune diseases if self-reactivity can lead to tissue damage. In the later 19th century, it was believed that the immune system was unable to react against the body's own tissues. Paul Ehrlich , at the turn of the 20th century, proposed the concept of horror autotoxicus . Ehrlich later adjusted his theory to recognize the possibility of autoimmune tissue attacks, but believed certain innate protection mechanisms would prevent

546-594: Is the ability of an individual to ignore "self", while reacting to "non-self". This breakage leads to the immune system mounting an effective and specific immune response against self antigens. The exact genesis of immunological tolerance is still elusive, but several theories have been proposed since the mid-twentieth century to explain its origin. Three hypotheses have gained widespread attention among immunologists: In addition, two other theories are under intense investigation: Tolerance can also be differentiated into "central" and "peripheral" tolerance, on whether or not

585-450: Is unhealthy, a low level of autoimmunity may actually be beneficial. Taking the experience of a beneficial factor in autoimmunity further, one might hypothesize with intent to prove that autoimmunity is always a self-defense mechanism of the mammal system to survive. The system does not randomly lose the ability to distinguish between self and non-self; the attack on cells may be the consequence of cycling metabolic processes necessary to keep

624-736: The antigen pigeon cytochrome c peptide, as determined by ZAP70 phosphorylation , proliferation, and interleukin 2 production. Thus Stefanova et al. (2002) demonstrated that self-MHC recognition (which, if too strong may contribute to autoimmune disease) maintains the responsiveness of CD4+ T cells when foreign antigens are absent. Pioneering work by Noel Rose and Ernst Witebsky in New York, and Roitt and Doniach at University College London provided clear evidence that, at least in terms of antibody-producing B cells (B lymphocytes), diseases such as rheumatoid arthritis and thyrotoxicosis are associated with loss of immunological tolerance , which

663-411: The intestines . Proteins that are not created within the body of the organism of interest, but nevertheless enter through the bloodstream , a breach in the skin , or a mucous membrane , may be designated as “non-self” and subsequently targeted and attacked by the immune system . Tolerance to self-protein is crucial for overall wellbeing; when the body erroneously identifies self-proteins as “non-self”,

702-706: The MHC complex remain the subject of research, in animal models of disease (Linda Wicker's extensive genetic studies of diabetes in the NOD mouse) , and in patients (Brian Kotzin's linkage analysis of susceptibility to lupus erythematosus ). In recent studies, the gene PTPN22 has emerged as a significant factor linked to various autoimmune diseases, such as Type I diabetes, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Myasthenia Gravis, vitiligo, systemic sclerosis, juvenile idiopathic arthritis, and psoriatic arthritis. PTPN22

741-436: The above-stated checking mechanisms operate in the central lymphoid organs (thymus and bone marrow) or the peripheral lymphoid organs (lymph node, spleen, etc., where self-reactive B-cells may be destroyed). It must be emphasised that these theories are not mutually exclusive, and evidence has been mounting suggesting that all of these mechanisms may actively contribute to vertebrate immunological tolerance. A puzzling feature of

780-433: The autoimmune response from becoming pathological. In 1904, this theory was challenged by the discovery of a substance in the serum of patients with paroxysmal cold hemoglobinuria that reacted with red blood cells. During the following decades, a number of conditions could be linked to autoimmune responses. However, the authoritative status of Ehrlich's postulate hampered the understanding of these findings. Immunology became

819-642: The blood chemistry in homeostasis. Second, autoimmunity may have a role in allowing a rapid immune response in the early stages of an infection when the availability of foreign antigens limits the response (i.e., when there are few pathogens present). In their study, Stefanova et al. (2002) injected an anti- MHC class II antibody into mice expressing a single type of MHC Class II molecule (H-2 ) to temporarily prevent CD4+ T cell-MHC interaction. Naive CD4+ T cells (those that have not encountered non-self antigens before) recovered from these mice 36 hours post-anti-MHC administration showed decreased responsiveness to

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858-514: The bone marrow into the thymus , where T-cell receptors are randomly rearranged at the gene level to allow for T-cell receptor generation. These T-cells have the potential to bind to anything, including self-proteins. The immune system must differentiate the T-cells that have receptors capable of binding to self versus non-self proteins; T-cells that can bind to self-proteins must be destroyed to prevent development of an autoimmune disorder. In

897-545: The documented loss of tolerance seen in spontaneous human autoimmunity is that it is almost entirely restricted to the autoantibody responses produced by B lymphocytes. Loss of tolerance by T cells has been extremely hard to demonstrate, and where there is evidence for an abnormal T cell response it is usually not to the antigen recognised by autoantibodies. Thus, in rheumatoid arthritis there are autoantibodies to IgG Fc but apparently no corresponding T cell response. In systemic lupus there are autoantibodies to DNA, which cannot evoke

936-538: The effects of smoking correlate with the presence of antibodies to citrullinated peptides . Several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental modulation. It is beyond the scope of this article to discuss each of these mechanisms exhaustively, but a summary of some of the important mechanisms have been described: The roles of specialized immunoregulatory cell types, such as regulatory T cells , NKT cells , γδ T-cells in

975-416: The genesis of autoimmune conditions, or conditions that simulate autoimmune diseases. The most striking of these is the drug-induced lupus erythematosus . Usually, withdrawal of the offending drug cures the symptoms in a patient. Cigarette smoking is now established as a major risk factor for both incidence and severity of rheumatoid arthritis . This may relate to abnormal citrullination of proteins, since

1014-808: The gut and lungs are seen in chronic granulomatous disease (CGD) as well. CGD is a caused by decreased production of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by neutrophils. Hypomorphic RAG mutations are seen in patients with midline granulomatous disease; an autoimmune disorder that is commonly seen in patients with granulomatosis with polyangiitis and NK/T cell lymphomas. Wiskott–Aldrich syndrome (WAS) patients also present with eczema, autoimmune manifestations, recurrent bacterial infections and lymphoma. In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy also autoimmunity and infections coexist: organ-specific autoimmune manifestations (e.g., hypoparathyroidism and adrenocortical failure) and chronic mucocutaneous candidiasis. Finally, IgA deficiency

1053-653: The host immune signaling. A paradoxical observation has been the strong association of certain microbial organisms with autoimmune diseases. For example, Klebsiella pneumoniae and coxsackievirus B have been strongly correlated with ankylosing spondylitis and diabetes mellitus type 1 , respectively. This has been explained by the tendency of the infecting organism to produce super-antigens that are capable of polyclonal activation of B-lymphocytes , and production of large amounts of antibodies of varying specificities, some of which may be self-reactive (see below). Certain chemical agents and drugs can also be associated with

1092-570: The immune-manipulating strategies of pathogens. While such an observation has been variously termed as spurious and ineffective, according to some studies, parasite infection is associated with reduced activity of autoimmune disease. The putative mechanism is that the parasite attenuates the host immune response in order to protect itself. This may provide a serendipitous benefit to a host that also has autoimmune disease. The details of parasite immune modulation are not yet known, but may include secretion of anti-inflammatory agents or interference with

1131-469: The innate immune system at the other extreme. Within this scheme, the full spectrum of autoimmunity can be included. Many common human autoimmune diseases can be seen to have a substantial innate immune mediated immunopathology using this new scheme. This new classification scheme has implications for understanding disease mechanisms and for therapy development. Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of

1170-470: The medullary epithelial cells of the thymus to express proteins would normally be present in peripheral tissue rather than in an epithelial cell, such as insulin -like peptides, myelin -like peptides, and more. As these epithelial cells now present a large variety of self-proteins that could be encountered across the body, the immature T-cells are tested for affinity to self-protein and self-MHC. If any T-cell has strong affinity for self-protein and self-MHC,

1209-473: The pathogenesis of autoimmune disease are under investigation. Autoimmune diseases can be broadly divided into systemic and organ-specific or localised autoimmune disorders, depending on the principal clinico-pathologic features of each disease. Using the traditional "organ specific" and "non-organ specific" classification scheme, many diseases have been lumped together under the autoimmune disease umbrella. However, many chronic inflammatory human disorders lack

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1248-477: The patient, and high index of suspicion against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein ). In several systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens. Autoantibodies are used to diagnose many autoimmune diseases. The levels of autoantibodies are measured to determine

1287-491: The progress of the disease. Treatments for autoimmune disease have traditionally been immunosuppressive , anti-inflammatory , or palliative . Managing inflammation is critical in autoimmune diseases. Non-immunological therapies, such as hormone replacement in Hashimoto's thyroiditis or Type 1 diabetes mellitus treat outcomes of the autoaggressive response, thus these are palliative treatments. Dietary manipulation limits

1326-587: The recognition of antigens, are inherently variable and susceptible to recombination. These variations enable the immune system to respond to a very wide variety of invaders, but may also give rise to lymphocytes capable of self-reactivity. Fewer correlations exist with MHC class I molecules. The most notable and consistent is the association between HLA B27 and spondyloarthropathies like ankylosing spondylitis and reactive arthritis . Correlations may exist between polymorphisms within class II MHC promoters and autoimmune disease. The contributions of genes outside

1365-422: The second stage of development, while those that cannot bind to MHC undergo apoptosis . In the second stage, immature T-cells are exposed to a variety of macrophages , dendritic cells , and medullary epithelial cells that express self-protein on MHC class 1 and class 2 . These epithelial cells also express the transcription factor labelled autoimmune regulator (AIRE) – this crucial transcription factor allows

1404-595: The severity of celiac disease. Steroidal or NSAID treatment limits inflammatory symptoms of many diseases. IVIG is used for CIDP and GBS . Specific immunomodulatory therapies, such as the TNFα antagonists (e.g. etanercept ), the B cell depleting agent rituximab , the anti-IL-6 receptor tocilizumab and the costimulation blocker abatacept have been shown to be useful in treating RA. Some of these immunotherapies may be associated with increased risk of adverse effects, such as susceptibility to infection. Helminthic therapy

1443-448: The sex role in autoimmunity vary. Women appear to generally mount larger inflammatory responses than men when their immune systems are triggered, increasing the risk of autoimmunity. Involvement of sex steroids is indicated by that many autoimmune diseases tend to fluctuate in accordance with hormonal changes, for example: during pregnancy, in the menstrual cycle, or when using oral contraception. A history of pregnancy also appears to leave

1482-529: The subsequent immune response against endogenous proteins may lead to the development of an autoimmune disease . Of note, the list provided above is not exhaustive; the list does not mention all possible proteins targeted by the provided autoimmune diseases. Autoimmune responses and diseases are primarily instigated by T lymphocytes that are incorrectly screened for reactivity to self-protein during cell development. During T-cell development, early T-cell progenitors first move via chemokine gradients from

1521-429: The telltale associations of B and T cell driven immunopathology. In the last decade it has been firmly established that tissue "inflammation against self " does not necessarily rely on abnormal T and B cell responses. This has led to the recent proposal that the spectrum of autoimmunity should be viewed along an "immunological disease continuum", with classical autoimmune diseases at one extreme and diseases driven by

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