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Autoimmune Disease

  • Autoimmune Diseases are those whose etiology is thought to be due a break down in Immune Tolerance leading to immune-mediated attack of host tissues. Sadly, beyond this general statement the etiology of most autoimmune diseases is poorly understood. Below we discuss some theories which explain how immune tolerance might fail; however, what the contribution of any of these mechanisms might be to any particular autoimmune disease is largely unknown.
Possible Etiologies
  • Overview
    • The following are mechanisms which have been proposed that might break immune tolerance and result in the proliferation and differentiation of effector auto-reactive lymphocytes. While clean examples of these mechanisms have been developed in laboratory animal models, their individual contributions in complex autoimmune diseases is still being understood.
  • Release of Sequestered Antigens
    • Many host antigens are sequestered in such a way that developing immune cells are not exposed to their epitopes. Consequently, there is no opportunity to negatively select lymphocytes with antigen receptors specific to these sequestered antigens during processes of tolerance. These antigens may be from "Immunologically Privileged Sites" in certain organs to which the immune system does not have access, such as the eye or testes. They may also be antigens sequestered in the intracellular space, such as DNA or chromatin. However, intense inflammatory situations or trauma may release these normally sequestered antigens and consequently allow development of auto-reactive lymphocytes. The clearest example of this is auto-immune inflammation of the eye and testes following physical trauma to these organs, causing post-traumatic uveitis or orchitis, respectively.
  • Epitope Spreading
    • It is now appreciated that during mechanisms of tolerance, only a select few epitopes within a self-proteins are exposed to developing lymphocytes while the others, termed "Cryptic Epitopes" are not. Consequently, lymphocytes specific to these "Cryptic Epitopes" may not be negatively selected and thus survive mechanisms of tolerance. However, during intense inflammatory responses Antigen Presenting Cells may begin to present these "Cryptic Epitopes", thus causing activation of auto-reactive lymphocytes to these antigens. This process of inflammation-induced activation of lymphocytes reactive to cryptic epitopes is known as "Epitope Spreading".
  • Non-specific Activation
    • Certain highly inflammatory molecules appear to non-specifically activate lymphocytes and may push tolerized lymphocytes out of anergy and into a state where they may proliferate and differentiate into effector cells. The prime example of such a molecule is bacteria-derived Lipopolysaccharide (LPS) which polyclonally activates B-cells, some of which produce auto-antibodies.
  • Defective Regulatory Mechanisms
    • A variety of regulatory mechanisms exist in the periphery which appear to dampen immune attack of self-tissues such as Regulatory T Cells discussed in Immune Tolerance. Defects in these peripheral regulatory mechanisms may be the root cause of some autoimmune diseases.
  • Molecular Mimicry
    • Certain autoimmune diseases appear to result from previous infection with certain microbes. It is thought that these microbes may possess antigens that are extremely similar to self-antigens. During the immune response to the microbe, lymphocytes specific to these microbial antigen may proliferate and differentiate into effector cells. However, once the microbe is cleared these remnant lymphocytes may begin coordinating an immune attack on tissues which possess the similar self-antigen. This process, termed "Molecular Mimicry" may be the root cause of some post-infectious autoimmune diseases.
  • Genetic Factors
    • Genetic Factors are clearly important in the pathogenesis of many autoimmune conditions. Several autoimmune diseases cluster within families and an individual which develops one disease displays a significantly increased risk of developing another. Major Histocompatibility Complex genes have shown the clearest genetic connection with autoimmunity and individuals with certain MHC alleles possess substantially higher risk of certain diseases. It is thought that these MHC alleles may possess a higher affinity for certain auto-antigens, thus increasing the probability of a self-directed immune attack.
  • Hormonal Factors
    • Undoubtedly, the female gender is an important risk factor for developing autoimmune disease and the vast majority of the burden of autoimmune disease occurs in women. While the precise reason for the increased incidence in women is not clear some have advanced a role for the presence of estrogen as a contributing factor.
Member Diseases
  • A large variety of diseases are suspected to have an autoimmune etiology. In most cases the conclusion that a disease is due to autoimmunity is one of mechanistic exclusion. Therefore, the notion that the etiopathogenesis of a disease is due to autoimmunity usually exists on a spectrum of suspicion with some diseases believed to be more likely caused by autoimmune mechanisms and others less so. Rather than list the diseases here, search for "Autoimmune" for a list of diseases in which autoimmunity is thought to play a role.