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User:Jbarin/Autoimmunity draft

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For journal, see Autoimmunity (journal).
Jbarin/Autoimmunity draft

Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows 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, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, and rheumatoid arthritis (RA). See List of autoimmune diseases.


Low-level autoimmunity

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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 an integral part of vertebrate immune systems (sometimes termed 'natural autoimmunity'), normally prevented from causing disease by the phenomenon of immunological tolerance to self-antigens. 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 neoplastic cells by CD8+ T cells, and thus reduce the incidence of cancer.

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-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 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 antigens are absent.[1] 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.

Immunological tolerance

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Pioneering work by Noel Rose and Witebsky in New York, and Roitt and Doniach at University College London provided clear evidence that, at least in terms of antibody-producing B lymphocytes, diseases such as rheumatoid arthritis and thyrotoxicosis are associated with of loss of immunological tolerance, which is the ability of an individual to ignore 'self', while reacting to '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.[2]
  • Idiotype Network theory, proposed by Jerne, wherein a network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body.[3]

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[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 in the immune system.

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.

A puzzling feature of 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 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 a variety of aberrant ways [5].

Sex

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Ratio of female/male incidence
of autoimmune diseases
Hashimoto's thyroiditis 10/1[6]
Graves' disease 7/1[6]
Multiple sclerosis (MS) 2/1[6]
Myasthenia gravis 2/1[6]
Systemic lupus erythematosus (SLE) 9/1[6]
Rheumatoid arthritis 5/2[6]

A person's sex also seems to have some role in the development of autoimmunity, classifying most autoimmune diseases as sex-related diseases. Nearly 75%[6] of the more than 23.5 million Americans who suffer from autoimmune disease are women, although it is less-frequently acknowledged that millions of men also suffer from these diseases. According to the American Autoimmune Related Diseases Association (AARDA), autoimmune diseases that develop in men tend to be more severe. A few autoimmune diseases that men are just as or more likely to develop as women, include: ankylosing spondylitis, type 1 diabetes mellitus, Wegener's granulomatosis, Crohn's disease and psoriasis.

The reasons for the sex role in autoimmunity are unclear. Women appear to generally mount larger inflammatory responses than men when their immune systems are triggered, increasing the risk of autoimmunity.[6] 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.[6] A history of pregnancy also appears to leave a persistent increased risk for autoimmune disease.[6] It has been suggested that the slight exchange of cells between mothers and their children during pregnancy may induce autoimmunity.[7] 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.[8] The X-inactivation skew theory, proposed by Princeton University's Jeff Stewart, has recently been confirmed experimentally in scleroderma and autoimmune thyroiditis.[9] Other complex X-linked genetic susceptibility mechanisms are proposed and under investigation.[6]

Environmental Factors

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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.[10][11][12]

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 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 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.[citation needed] This may relate to abnormal citrullination of proteins, since the effects of smoking correlate with the presence of antibodies to citrullinated peptides.[citation needed]


See also

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References

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  1. ^ Stefanova I., Dorfman J. R. and Germain R. N. (2002). "Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes". Nature. 420 (6914): 429–434. doi:10.1038/nature01146. PMID 12459785.
  2. ^ Pike B, Boyd A, Nossal G (1982). "Clonal anergy: the universally anergic B lymphocyte". Proc Natl Acad Sci USA. 79 (6): 2013–7. doi:10.1073/pnas.79.6.2013. PMC 346112. PMID 6804951.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Jerne N (1974). "Towards a network theory of the immune system". Ann Immunol (Paris). 125C (1–2): 373–89. PMID 4142565.
  4. ^ Tolerance and Autoimmunity
  5. ^ Edwards JC, Cambridge G, Abrahams VM (1999). "Do self perpetuating B lymphocytes drive human autoimmune disease?". Immology. 97: 1868–1876.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b c d e f g h i j k Everyday Health > Women and Autoimmune Disorders By Krisha McCoy. Medically reviewed by Lindsey Marcellin, MD, MPH. Last Updated: 12/02/2009
  7. ^ Ainsworth, Claire (Nov. 15, 2003). The Stranger Within. New Scientist (subscription). (reprinted here)
  8. ^ Theory: High autoimmunity in females due to imbalanced X chromosome inactivation: [1]
  9. ^ Uz E, Loubiere LS, Gadi VK; et al. (June 2008). "Skewed X-chromosome inactivation in scleroderma". Clin Rev Allergy Immunol. 34 (3): 352–5. doi:10.1007/s12016-007-8044-z. PMC 2716291. PMID 18157513. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  10. ^ 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. doi:10.1128/IAI.00664-06. PMC 1828378. PMID 17043101.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Parasite Infection May Benefit Multiple Sclerosis Patients
  12. ^ 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. doi:10.1093/intimm/dxh253. PMID 15899926.
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