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Encyclopedia > Autoimmunity
Autoimmunity
Classification & external resources
ICD-9 279.4
OMIM 109100
DiseasesDB 28805
MeSH D001327

Autoimmunity is the failure of an organism to recognize its own constituent parts (down to the sub-molecular levels) as "self", which results in an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. Prominent examples include diabetes mellitus type 1 (IDDM), systemic lupus erythematosus (SLE), Sjögren's syndrome, Hashimoto's thyroiditis, Graves' disease, and rheumatoid arthritis (RA). See List of autoimmune diseases. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Disease Bold textDatabase is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... Wikipedia does not have an article with this exact name. ... Sjögrens syndrome is an autoimmune disorder in which immune cells attack and destroy the glands that produce tears and saliva. ... This disease was discovered by Mr. ... Graves-Basedow disease is a form of thyroiditis, an autoimmune disorder that stimulates the thyroid gland, being the most common cause of hyperthyroidism (overactivity of the thyroid). ... Rheumatoid arthritis (RA) is traditionally considered a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. ... Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ...


The misconception that an individual's immune system is totally incapable of recognising "self" antigens is not new. Paul Ehrlich, at the beginning of the twentieth century, proposed the concept of horror autotoxicus, wherein a 'normal' body does not mount an immune response against its own tissues. Any autoimmune response thus was perceived to be abnormal and postulated to be connected with human disease. Now, it is accepted that autoimmune responses are vital to the development and functioning of vertebrate immune systems, and central to the development of immunological tolerance to self-antigens. The latter concept has been termed natural autoimmunity. Autoimmunity should not be confused with alloimmunity. Paul Ehrlich Paul Ehrlich in his workroom Paul Ehrlich (March 14, 1854 – August 20, 1915) was a German scientist who won the 1908 Nobel Prize in Physiology or Medicine. ... This article or section is in need of attention from an expert on the subject. ... Alloimmunity is a condition in which the body gains immunity against cells from another individual of the same species. ...

Contents

Low-level autoimmunity

Whilst a high level of autoimmunity is detrimental to the health of the organism, a low level of autoimmunity may actually be beneficial. Firstly, in the recognition by CD8+ T cells of neoplastic cells, and thus prevention of cancer. Secondly autoimmunity is likely to have a role in allowing a rapid immune response in the early stages of an infection when foreign antigen is limiting (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-2b) to temporarily prevent CD4+ T cell-MHC interaction. Naive CD4+ T cells (i.e. that have not encountered antigen before) recovered from these mice 36 hours post anti-MHC administration showed decreased responsiveness to the antigen pigeon cytochrome C peptide, as determined by Zap-70 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 antigen is absent [1]. An analogy for this concept of autoimmunity is play-fighting. The play-fighting of young cubs (TCR and self-MHC) may result in a few scratches or scars (low-level-autoimmunity) but is beneficial in the long-term as it primes the young cub for proper fights in the future, where severe injury or even death is possible (cancer, disease). Antigen presentation stimulates T cells to become either cytotoxic CD8+ cells or helper CD4+ cells. ... An antigen is a substance that stimulates an immune response, especially the production of antibodies. ... A pathogen (literally birth of pain from the Greek παθογένεια) is a biological agent that can cause disease to its host. ... The major histocompatibility complex (MHC) is a large genomic region or gene family found in most vertebrates. ... Naïve is Industrial rock group KMFDMs fourth album, released in 1990. ... T cells belong to a group of white blood cells known as lymphocytes and play a central role in cell-mediated immunity. ... An antigen is a substance that stimulates an immune response, especially the production of antibodies. ... Cytochrome c with heme c. ... ZAP-70 is an abbrevation for Zeta-chain-associated protein kinase 70 (70 is the molecular weight in kDa). ... A phosphorylated serine residue Phosphorylation is the addition of a phosphate (PO4) group to a protein or a small molecule or the introduction of a phosphate group into an organic molecule. ... Interleukin-2 (IL2) is an interleukin, a type of biological response modifier that can improve the bodys natural response to disease. ...


Immunological tolerance

Pioneering work by Noel Rose and Witebsky in New York, and Roitt and Doniach at University College London provided clear evidence that autoimmune diseases are a result of loss of tolerance. An essential prerequisite for the pathogenesis of autoimmune diseases is indeed the breakage of immunological tolerance, which is the ability of an individual to differentiate 'self' from 'non-self'. This breakage leads to the immune system mounting an effective and specific immune response against self determinants. The exact genesis of immunological tolerance is still elusive, but several theories have been proposed since the mid-twentieth century to explain its origin. Ernst Witebsky, also Ernest Witebsky (* 3 September 1901 in Frankfurt am Main; † 7 December 1969) was a German-American immunologist. ... Professor Ivan M. Roitt was born in 1927 and educated at King Edwards School, Birmingham and Balliol College, Oxford University. ... Professor Deborah Doniach M.D., F.R.C.P Distinguished clinical immunologist and pioneer in the field of Autoimmune Disease. ... University College London, commonly known as UCL, is a college of the University of London. ... This article or section is in need of attention from an expert on the subject. ...


Three hypotheses have gained widespread attention among immunologists:

  • Clonal Deletion theory, proposed by Burnet, according to which self-reactive lymphoid cells are destroyed during the development of the immune system in an individual. For their work Frank M. Burnet and Peter B. Medawar were awarded the 1960 Nobel Prize in Physiology or Medicine "for discovery of acquired immunological tolerance".
1960 Nobel Prize Winners - F. M. Burnet and P. B. Medawar
  • Clonal Anergy theory, proposed by Nossal, in which self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.[2]
  • Idiotype Network theory, proposed by Jerne, wherein a network of antibodies capable of neutralising self-reactive antibodies exists naturally within the body.[3]

In addition, two other theories are under intense investigation: Sir Frank Macfarlane Burnet (3 September 1899 – 31 August 1985), usually known as Macfarlane or Mac Burnet, was an Australian virologist best known for his contributions to immunology. ... Image File history File links Size of this preview: 493 × 600 pixel Image in higher resolution (590 × 718 pixel, file size: 94 KB, MIME type: image/jpeg) This picture is taken as a screenshot from http://nobelprize. ... Image File history File links Size of this preview: 493 × 600 pixel Image in higher resolution (590 × 718 pixel, file size: 94 KB, MIME type: image/jpeg) This picture is taken as a screenshot from http://nobelprize. ... Professor Sir Gustav Joseph Victor Nossal, AC, CBE, FRS, FAA (born June 4, 1931) is a distinguished Australian research biologist and brilliant communicator. ... Niels Kaj Jerne (December 23, 1911 - October 7, 1994) was a British-Danish-Swedish (English-born) immunologist. ...

  • the so-called "Clonal Ignorance" theory, according to which, host immune responses are directed to ignore self-antigens.[4]
  • the "Suppressor population" or "Regulatory T cell" theories, wherein regulatory T-lymphocytes (commonly CD4+FoxP3+ cells, among others) function to prevent, downregulate, or limit autoaggressive immune responses.

Tolerance can also be differentiated into 'Central' and 'Peripheral' tolerance, on whether or not the above 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. Regulatory T cells (also known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self. ...


Genetic Factors

It is now well-established that certain individuals are genetically susceptible to the development of autoimmune diseases. However, this susceptibility is not inherited in a simple Mendelian segregation, but usually tends to be associated with more than one gene. That even genetically predisposed individuals do not always develop autoimmune diseases could only mean that the pathogenesis of such disorders must also be multifactorial. Mendelian inheritance (or Mendelian genetics or Mendelism) is a set of primary tenets that underlie much of genetics developed by Gregor Mendel in the latter part of the 19th century. ...


The main genetic loci involved in the body's immune system include the genes for immunoglobulins and T-cell receptors, both of which are involved in the recognition of antigens, and the major histocompatibility complex (MHC) locus. Of these, the first two are inherently variable and susceptible to recombination, and sporadic variations may give rise to lymphoid cells which may be capable of self-reactivity. Schematic of antibody binding to an antigen An antibody is a protein complex used by the immune system to identify and neutralize foreign objects like bacteria and viruses. ... The two chains of the T cell receptor The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells) that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules. ... MHC I (1hsa) vs MHC II (1dlh) (more details. ...


However, scientists such as H. McDevitt, G. Nepom, J. Bell and J. Todd have also provided strong evidence that certain MHC class II allotypes are strongly correlated with specific autoimmune diseases:

  • HLA DR2 is strongly positively correlated with SLE and multiple sclerosis, and negatively correlated with IDDM.
  • HLA DR3 is correlated strongly with Sjögren's, myasthenia gravis, SLE and IDDM.
  • HLA DR4 is correlated with the genesis of RA, IDDM and pemphigus vulgaris.

Fewer correlations exist with MHC class I molecules, the most notable and consistent being the association between HLA B27 and ankylosing spondylitis. Scientists such as N. A. Mitchison, S. J. Ono and J. Klein have also investigated whether correlations exist between polymorphisms within class II MHC promoters and autoimmune disease. Sjögrens syndrome is an autoimmune disorder in which immune cells attack and destroy the glands that produce tears and saliva. ... Myasthenia gravis (sometimes abbreviated MG; from the Greek myastheneia, lit. ... Pemphigus is an autoimmune disorder that causes blistering and raw sores on skin and mucous membranes. ... In biology, polymorphism can be defined as the occurrence in the same habitat of two or more forms of a trait in such frequencies that the rarer cannot be maintained by recurrent mutation alone. ...


The contributions of genes outside 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 SLE).


Gender

Gender also seems to have a major role in the development of autoimmunity; most of the known autoimmune diseases tend to show a female preponderance, the most important exception being ankylosing spondylitis which has a male preponderance. The reasons for this are unclear. Apart from inherent genetic susceptibility, several animal models suggest a role for sex steroids. A sex steroid is a steroid hormone which interacts with vertebrate androgen or estrogen receptors. ...


It has also been suggested that the slight exchange of cells between mothers and their children during pregnancy may induce autoimmunity. [5] This would tip the sex 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.[6] The coloration of tortoiseshell cats is a visible manifestation of X-inactivation. ...


Environmental Factors

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 the immune manipulating strategies of pathogens. Whilst 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.[7][8][9] In medicine, the hygiene hypothesis says that an excessively hygienic environment in early childhood may predispose some people towards asthma, allergies, and other autoimmune diseases. ...


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 suffers from autoimmune disease. The details of parasite immune modulation are not yet known, but may include secretion of anti-inflammatory agents or interference with 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 IDDM, respectively. This has been explained by the tendency of the infecting organism to produce super-antigens which 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). Binomial name Klebsiella pneumoniae (Schroeter 1886) Trevisan 1887 Klebsiella pneumoniae is a Gram-negative, nonmotile, encapsulated, lactose-fermenting, facultatively anaerobic, rod-shaped bacterium found in the normal flora of the mouth, skin, and intestines. ... Coxsackie B4 virus is a virus which can trigger an autoimmune reaction which results in destruction of the insulin-producing beta cells of the pancreas, which is one of several different etiologies of diabetes. ... SEB, A typical bacterial superantigen (PDB:3SEB) The β-grasp domain is shown in red, and the β-barrel in green: The disulphide loop is shown in yellow Superantigens (SAgs) are a group of virulent toxins that indiscriminately activate T-cells of the immune system causing system-wide inflammation and other serious... Polyclonal antibodies are antibodies that are derived from different B-cell lines. ... B cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response). ...


Certain chemical agents and drugs can also be associated with the genesis of autoimmune conditions, or conditions which 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. Drug-induced lupus erythematosus (DIL or DILE) is an autoimmune disorder, similar to systemic lupus erythematosus (SLE), which is induced by chronic use of certain drugs. ...


Over exposure to pesticides and toxins may also induce autoimmunity.


Pathogenesis of autoimmunity

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:

  • T-Cell Bypass - A normal immune system requires the activation of B-cells by T-cells before the former can produce antibodies in large quantities. This requirement of a T-cell can be by-passed in rare instances, such as infection by organisms producing super-antigens, which are capable of initiating polyclonal activation of B-cells, or even of T-cells, by directly binding to the β-subunit of T-cell receptors in a non-specific fashion.
  • Molecular Mimicry - An exogenous antigen may share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens and amplify the immune response. The most striking form of molecular mimicry is observed in Group A beta-haemolytic streptococci, which shares antigens with human myocardium, and is responsible for the cardiac manifestations of Rheumatic Fever.
  • Idiotype Cross-Reaction - Idiotypes are antigenic epitopes found in the antigen-binding portion (Fab) of the immunoglobulin molecule. Plotz and Oldstone presented evidence that autoimmunity can arise as a result of a cross-reaction between the idiotype on an antiviral antibody and a host cell receptor for the virus in question. In this case, the host-cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host cells.
  • Cytokine Dysregulation - Cytokines have been recently divided into two groups according to the population of cells whose functions they promote: Helper T-cells type 1 or type 2. The second category of cytokines, which include IL-4, IL-10 and TGF-β(to name a few), seem to have a role in prevention of exaggeration of pro-inflammatory immune responses.
  • Dendritic cell apoptosis - immune system cells called dendritic cells present antigens to active lymphocytes. Dendritic cells that are defective in apoptosis can lead to inappropriate systemic lymphocyte activation and consequent decline in self-tolerance.[10]

The role of certain specific suppressor lymphocytes, and the special γδ T-cells in the genesis of autoimmunity are under investigation. SEB, A typical bacterial superantigen (PDB:3SEB) The β-grasp domain is shown in red, and the β-barrel in green: The disulphide loop is shown in yellow Superantigens (SAgs) are a group of virulent toxins that indiscriminately activate T-cells of the immune system causing system-wide inflammation and other serious... Molecular mimicry is a phenomenon associated with some pathogens, where the antigens evoking an immune response have enough similarity to the bodys own proteins to cause an autoimmune reaction, such as in rheumatoid arthritis, mediated by cross reactive T cells and/or circulating antibodies. ... An antigen is a substance that stimulates an immune response, especially the production of antibodies. ... Species S. pneumoniae S. pyogenes S. viridans Streptococcus is a genus of spherical, Gram-positive bacteria of the phylum Firmicutes. ... Myocardium is the muscular tissue of the heart. ... Rheumatic fever is an inflammatory disease which may develop after a Group A streptococcal infection (such as strep throat or scarlet fever) and can involve the heart, joints, skin, and brain. ... This article or section contains information that has not been verified and thus might not be reliable. ... An epitope is the part of a foreign organism (or its proteins) that is being recognised by the immune system and targeted by antibodies, cytotoxic T cells or both. ... Cytokines are small protein molecules that are the core of communication between immune system cells, and even between immune system cells and cells belonging to other tissue types. ... Transforming Growth Factor beta (TGF beta) is a biological protein. ... Dendritic cells (DC) are immune cells and form part of the mammal immune system. ... An antigen is a substance that stimulates an immune response, especially the production of antibodies. ... A lymphocyte is a type of white blood cell involved in the human bodys immune system. ... A scanning electron microscope (SEM) image of a single human lymphocyte. ... γδ T cells represent a small subset of T cells that possess a distinct T cell receptor (TCR) on their surface. ...


Classification

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.

Sjögrens syndrome is an autoimmune disorder in which immune cells attack and destroy the glands that produce tears and saliva. ... Scleroderma is a rare, chronic disease characterized by excessive deposits of collagen in the skin or other organs. ... Rheumatoid arthritis (RA) is traditionally considered a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. ... {{ }} Polymyositis is a type of inflammatory myopathy, related to dermatomyositis and inclusion body myositis. ... For the disease characterized by excretion of large amounts of severely diluted urine, see diabetes insipidus. ... This disease was discovered by Mr. ... Addisons disease (also known as chronic adrenal insufficiency, or hypocortisolism) is a rare endocrine disorder which results in the body not producing sufficient amounts of certain adrenal hormones. ... Pemphigus is an autoimmune disorder that causes blistering and raw sores on skin and mucous membranes. ... Autoimmune hemolytic anemia (AIHA) is a type of hemolytic anemia where the bodys immune system attacks its own red blood cells (RBCs), leading to their destruction (hemolysis). ...

Diagnosis

Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of 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. C-reactive protein (CRP) is a plasma protein, an acute phase protein produced by the liver. ... Immunofluorescence is the labeling of antibodies or antigens with fluorescent dyes. ...


Treatments

Current treatments for autoimmune disease are largely palliative, generally immunosuppressive, or anti-inflammatory.[4] Non-immune therapies, such as hormone replacement in Hashimoto's thyroiditis or T1D treat outcomes of the autoaggressive response. Dietary manipulation limits the severity of celiac disease. Steroidal or NSAID treatment limits inflammatory symptoms of many diseases. IVIG is used for CIDP and GBS. More specific immunomodulatory therapies, such as the TNFα antagonists etanercept, have been shown to be useful in treating RA. These immunotherapies may be associated with increased risk of adverse effects, such as susceptibility to infection. An immunomodulator is a drug used for its effect on the immune system: drugs may be immunosuppressants or immunostimulators. ... Etanercept (Enbrel®, co-marketed by Amgen and Wyeth) is a human recombinant, soluble tumor necrosis factor-alpha (TNFα) receptor. ...


See also

Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ...

References

  1. ^ Stefanova I., Dorfman J. R. and Germain R. N. (2002). "Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes". Nature 420: 429-434. PMID 12459785. 
  2. ^ Pike B, Boyd A, Nossal G (1982). "Clonal anergy: the universally anergic B lymphocyte". Proc Natl Acad Sci U S A 79 (6): 2013-7. PMID 6804951. 
  3. ^ Jerne N (1974). "Towards a network theory of the immune system". Ann Immunol (Paris) 125C (1-2): 373-89. PMID 4142565. 
  4. ^ a b http://pathmicro.med.sc.edu/ghaffar/tolerance2000.htm
  5. ^ Ainsworth, Claire (Nov. 15, 2003). The Stranger Within. New Scientist (subscription). (reprinted here)
  6. ^ Theory: High autoimmunity in females due to imbalanced X chromosome inactivation: [1]
  7. ^ Saunders K, Raine T, Cooke A, Lawrence C (2007). "Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection". Infect Immun 75 (1): 397-407. PMID 17043101. 
  8. ^ http://www.sciencedaily.com/releases/2007/01/070117091058.htm
  9. ^ Wållberg M, Harris R (2005). "Co-infection with Trypanosoma brucei brucei prevents experimental autoimmune encephalomyelitis in DBA/1 mice through induction of suppressor APCs". Int Immunol 17 (6): 721-8. PMID 15899926. 
  10. ^ Kubach J, Becker C, Schmitt E, Steinbrink K, Huter E, Tuettenberg A, Jonuleit H (2005). "Dendritic cells: sentinels of immunity and tolerance". Int J Hematol 81 (3): 197-203. PMID 15814330. 

New Scientist is a weekly international science magazine covering recent developments in science and technology for a general English-speaking audience. ... In those species in which sex is determined by the presence of the Y or W chromosome rather than the diploidy of the X or Z, a Barr body is the inactive X chromosome in a female cell, or the inactive Z in a male. ...

External links

  • Antibodies in autoimmune disease
  • American Autoimmune Related Diseases Association: a nonprofit advocacy
  • Association between HLA markes and selected Autoimmune diseases
  • Immune Tolerance Network: a research-oriented resource
  • Nobel Prize The 1960 Nobel Prize in Physiology or Medicine was awarded to Frank M. Burnet and Peter B Medawar.

  Results from FactBites:
 
What is Autoimmunity?: Johns Hopkins Autoimmune Disease Research Center (974 words)
Autoimmune diseases are, thus, defined when the progression from benign autoimmunity to pathogenic autoimmunity occurs.
Autoimmune diseases are among the ten leading causes of death among women in all age groups up to 65.
Autoimmune diseases of the blood, for example, are treated by hematologists, those of the nervous system by neurologists, those of the endocrine system by endocrinologists and those of the joints and muscles by rheumatologists.
Autoimmune (3383 words)
The development of an autoimmune disease may be influenced by the genes a person inherits together with the way the person's immune system responds to certain triggers or environmental influences.
Autoimmune diseases are often chronic, requiring lifelong care and monitoring, even when the person may look or feel well.
Autoimmune thyroid diseases afflict as many as 4 out of 100 women and are frequently found in families where there are other autoimmune diseases.
  More results at FactBites »

 
 

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