What Is AutoImmunity

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Autoimmunity

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 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).

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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 auto toxicus, 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 tolerance to self-antigens.

The latter concept has been termed natural autoimmunity. Autoimmunity should not be confused with alloimmunity.

Low-level autoimmunity

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 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 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.

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

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 a 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 the 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.

Idiotype Network theory, proposed by Jerne, wherein a network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body.

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 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 emphasized 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.

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