Name = Autoimmunity
DiseasesDB = 28805
ICD9 = ICD9|279.4
OMIM = 109100
MeshID = D001327
Autoimmunity is the failure of an organism to recognize its own constituent parts 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
Coeliac disease, diabetes mellitus type 1 (IDDM), systemic lupus erythematosus (SLE), Sjögren's syndrome, Churg-Strauss Syndrome, multiple sclerosis(MS), Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, and rheumatoid arthritis(RA). "See List of autoimmune diseases".
The misconception that an individual's immune system is totally incapable of recognizing "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. Thus, any autoimmune response 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 toleranceto self-antigens. The latter concept has been termed natural autoimmunity. Autoimmunity should not be confused with alloimmunity.
While a high level of autoimmunity is unhealthy, a low level of autoimmunity may actually be beneficial. First, low-level autoimmunity might aid in the recognition of
neoplasticcells by CD8+ T cells, and thus reduce the incidence of cancer.
Second, autoimmunity is likely to 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 pathogenspresent). In their study, Stefanova et al. (2002) injected an anti- MHC Class II antibodyinto mice expressing a single type of MHC Class II molecule (H-2b) to temporarily prevent CD4+ T cell-MHC interaction. Naive CD4+ T cells(those that have not encountered any antigens before) recovered from these mice 36 hours post-anti-MHC administration showed decreased responsiveness to the antigenpigeon cytochrome Cpeptide, as determined by Zap-70 phosphorylation, proliferation, and Interleukin-2production. 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. [cite journal |author=Stefanova I., Dorfman J. R. and Germain R. N.|title=Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes|journal=Nature|volume=420|pages=429–434|year=2002|pmid=12459785 |doi=10.1038/nature01146] This idea of autoimmunity is conceptually similar to 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.
Pioneering work by Noel Rose and Witebsky in New York, and Roitt and Doniach at
University College Londonprovided 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's 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.
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".
* 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. [cite journal |author=Pike B, Boyd A, Nossal G |title=Clonal anergy: the universally anergic B lymphocyte |journal=Proc Natl Acad Sci U S a |volume=79 |issue=6 |pages=2013–7 |year=1982 |pmid=6804951 |doi=10.1073/pnas.79.6.2013]
* Idiotype Network theory, proposed by Jerne, wherein a network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body. [cite journal |author=Jerne N |title=Towards a network theory of the immune system |journal=Ann Immunol (Paris) |volume=125C |issue=1-2 |pages=373–89 |year=1974 |pmid=4142565]
In addition, two other theories are under intense investigation:
* The so-called "Clonal Ignorance" theory, according to which host immune responses are directed to ignore self-antigens [http://pathmicro.med.sc.edu/ghaffar/tolerance2000.htm Tolerance and Autoimmunity ] ]
* 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-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.
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:
major histocompatibility complexes (MHC).
The first two, which are involved in 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.
Scientists such as H. McDevitt, G. Nepom, J. Bell and J. Todd have also provided strong evidence to suggest that certain MHC class II allotypes are strongly correlated with specific autoimmune diseases:
* HLA DR2 is strongly positively correlated with
Systemic Lupus Erythematosusand multiple sclerosis, and negatively correlated with DM Type 1.
* HLA DR3 is correlated strongly with
Sjögren's syndrome, myasthenia gravis, SLE, and DM Type 1.
* HLA DR4 is correlated with the genesis of
rheumatoid arthritis, Type 1 diabetes mellitus, and pemphigus vulgaris.
Fewer correlations exist with MHC class I molecules. The most notable and consistent is the association between HLA B27 and
ankylosing spondylitis. Correlations may exist between polymorphisms within class II MHC promoters and autoimmune disease.
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).
sexalso 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 exceptions being ankylosing spondylitis, which has a male preponderance, and Crohn's disease, which has a roughly equal prevalence in males and females. The reasons for this are unclear. Apart from inherent genetic susceptibility, several animal models suggest a role for sex steroids.
It has also been suggested that the slight exchange of cells between mothers and their children during pregnancy may induce autoimmunity. [Ainsworth, Claire (Nov. 15, 2003). [http://www.newscientist.com/article.ns?id=mg18024215.100 "The Stranger Within"] . "
New Scientist" (subscription). (reprinted [http://www.katewerk.com/chimera.html here] )] 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. [Theory: High autoimmunity in females due to imbalanced X chromosome inactivation: [http://www.abc.net.au/science/k2/moments/s1002754.htm] ]
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 hypothesisattributes 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. [cite journal |author=Saunders K, Raine T, Cooke A, Lawrence C |title=Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection |journal=Infect Immun |volume=75 |issue=1 |pages=397–407 |year=2007 |pmid=17043101 |doi=10.1128/IAI.00664-06] [ [http://www.sciencedaily.com/releases/2007/01/070117091058.htm Parasite Infection May Benefit Multiple Sclerosis Patients ] ] [cite journal |author=Wållberg M, Harris R |title=Co-infection with Trypanosoma brucei brucei prevents experimental autoimmune encephalomyelitis in DBA/1 mice through induction of suppressor APCs |journal=Int Immunol |volume=17 |issue=6 |pages=721–8 |year=2005 |pmid=15899926 |url = http://intimm.oxfordjournals.org/cgi/content/full/17/6/721 |doi=10.1093/intimm/dxh253]
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 spondylitisand DM Type 1, respectively. This has been explained by the tendency of the infecting organism to produce super-antigensthat 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 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.
Overexposure to pesticides and toxins may also induce autoimmunity. Fact|date=November 2007
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-cellsby T-cellsbefore the former can produce antibodies in large quantities. This requirement of a T-cell can be bypassed 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
antigenmay 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 -
Idiotypesare antigenic epitopesfound 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 -
Cytokineshave 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 lymphocyteactivation and consequent decline in self-tolerance. [cite journal |author=Kubach J, Becker C, Schmitt E, Steinbrink K, Huter E, Tuettenberg A, Jonuleit H |title=Dendritic cells: sentinels of immunity and tolerance |journal=Int J Hematol |volume=81 |issue=3 |pages=197–203 |year=2005 |pmid=15814330 |doi=10.1532/IJH97.04165]
*Epitope spreading or epitope drift - when the
immune reactionchanges from targeting the primary epitopeto also targeting other epitopes. [ [http://www.cancerimmunity.org/v2p8/020608.htm Induction of autoantibodies against tyrosinase-related proteins following DNA vaccination: Unexpected reactivity to a protein paralogue] Roopa Srinivasan, Alan N. Houghton, and Jedd D. Wolchok] In contrast to molecular mimicry, the other epitopes need not be structurally similar to the primary one.
The roles of specialized immunoregulatory cell types, such as
regulatory T cells, NKT cells, γδ T-cellsin 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.
Systemic autoimmune diseasesinclude SLE, Sjögren's syndrome, Scleroderma, Rheumatoid Arthritisand polymyositis.
* Local syndromes may be endocrinologic (
Diabetes Mellitus Type 1, Hashimoto's thyroiditis, Addison's diseaseetc.), dermatologic ( pemphigus vulgaris), haematologic ( autoimmune haemolytic anaemia), neural ( multiple sclerosis) or can involve virtually any circumscribed mass of body tissue.
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 autoantibodiescan be employed. Localised disorders are best diagnosed by immunofluorescenceof biopsy specimens.
Current treatments for autoimmune disease are usually immunosuppressive,
anti-inflammatory, or palliative. Non-immune therapies, such as hormone replacement in Hashimoto's thyroiditis or DM Type 1 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.Autoantibodies are used to diagnose many autoimmune diseases. The levels of autoantibodies are measured to determine the progress of the disease. Helminthic therapyhas developed based on these observations and 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.Research is available that demonstrates this approach is highly effective in treating a variety of autoimmune disorders, including Crohn's, Ulcerative Colitis, Asthma, allergies, Multiple Sclerosis, and chronic inflammatory disorders. [cite journal |author=Zaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A |title=Parasitic worms and inflammatory diseases |journal=Parasite Immunol. |volume=28 |issue=10 |pages=515–23 |year=2006 |pmid=16965287 |doi=10.1111/j.1365-3024.2006.00879.x] [cite journal |author=Dunne DW, Cooke A |title=A worm's eye view of the immune system: consequences for evolution of human autoimmune disease |journal=Nat. Rev. Immunol. |volume=5 |issue=5 |pages=420–6 |year=2005 |pmid=15864275 |doi=10.1038/nri1601] [cite journal |author=Dittrich AM, Erbacher A, Specht S, "et al" |title=Helminth Infection with Litomosoides sigmodontis Induces Regulatory T Cells and Inhibits Allergic Sensitization, Airway Inflammation, and Hyperreactivity in a Murine Asthma Model |journal=J. Immunol. |volume=180 |issue=3 |pages=1792–9 |year=2008 |pmid=18209076 |doi=] [cite journal |author=Wohlleben G, Trujillo C, Müller J, "et al" |title=Helminth infection modulates the development of allergen-induced airway inflammation |journal=Int. Immunol. |volume=16 |issue=4 |pages=585–96 |year=2004 |pmid=15039389|doi=10.1093/intimm/dxh062] [cite journal |author=Quinnell RJ, Bethony J, Pritchard DI |title=The immunoepidemiology of human hookworm infection |journal=Parasite Immunol. |volume=26 |issue=11-12 |pages=443–54 |year=2004 |pmid=15771680 |doi=10.1111/j.0141-9838.2004.00727.x] [cite journal |author=Zaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A |title=Parasitic worms and inflammatory diseases |journal=Parasite Immunol. |volume=28 |issue=10 |pages=515–23 |year=2006 |pmid=16965287 |doi=10.1111/j.1365-3024.2006.00879.x]
List of autoimmune diseases
* [http://www.aarda.org American Autoimmune Related Diseases Association: a nonprofit advocacy]
* [http://www.immunetolerance.org/ Immune Tolerance Network: a research-oriented resource]
* [http://nobelprize.org/nobel_prizes/medicine/laureates/1960/index.html Nobel Prize] The 1960 Nobel Prize in Physiology or Medicine was awarded to Frank M. Burnet and Peter B Medawar.
* [http://www.immport.org The Immunology Database and Analysis Portal] - an NIAID-funded database resource of reference and experiment data covering the entire immunology domain
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