Autoimmunity

Autoimmunity is the failure of an organism to recognise 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 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.

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-2^b) 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).

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.

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 neutralising 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.

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.

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.

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.

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.

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.

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]

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]

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).

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.

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.

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.

• Systemic syndromes include SLE, Sjögren's syndrome, Scleroderma, Rheumatoid Arthritis and polymyositis.
• Local syndromes may be endocrinologic (IDDM, Hashimoto's thyroiditis, Addison's disease etc.), dermatologic (pemphigus vulgaris), haematologic (autoimmune haemolytic anaemia), neural (multiple sclerosis) or can involve virtually any circumscribed mass of body tissue.

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.

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.

See also

• List of autoimmune diseases

References

Wikipedia information about Autoimmunity This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Autoimmunity". It may not have been reviewed by professional editors (see full disclaimer). Help contribute to Americola and edit this article.