It might contribute to disease development via several pathways. By interacting with the HLA haplotype 96 and changing gene expression in the joint 97 , smoking may promote the development of RA. Environmental factors have also been found to induce changes in apoptosis Autoantigens have been demonstrated within apoptotic bodies and apoptotic cells and appear critical for the presentation of antigens, activation of innate immunity and regulation of macrophage cytokine secretion A classical experimental model that illustrates these principles is lymphoproliferation Lpr and generalized lymphoproliferative disease gld , in which mice develop an autoimmune disease that resembles human SLE Tissue destruction can be divided into a variety of effector pathways depending on the autoimmune disease.
Of note, the immune system is promiscuous and there is often an orchestrated response that involves a multitude of diverse cell populations. The effector mechanisms for a number of autoimmune diseases are illustrated in Fig.
Explorations in the Science of Illness and Extraordinary Healing
The presence of autoantibodies is a common feature of autoimmune diseases , and a large number of serum antibodies are directed against functional structures of the cell nucleic acids, nuclear molecules, receptors or other functional cell components. They not only play a central role in diagnosis and classification, but may also be involved in tissue damage. Classical ADCC is mediated by natural killer cells that carry the receptor for the Fc portion of IgG; binding stimulates the release of hydrogen peroxide and hydroxyl radicals.
Other cells, that is monocytes and eosinophils, can also mediate ADCC. The diagnostic and clinical classifications of a variety of autoimmune diseases have been reviewed recently - However, with the development of proteomic, genomic and metabolomics, far more sensitive and specific methodologies will be developed in the future Fig.
PBC has long been considered a model example of human autoimmunity because of its serological hallmarks antimitochondrial antibodies , specific pathology within small and medium intrahepatic bile ducts, the female predominance and the similarity of clinical outcomes across multiple regions and ethnic groups 56 , , First, as with other autoimmune diseases, there are specific diagnostic criteria based upon i biochemical evidence of cholestasis, that is alkaline phosphatase elevation; ii the presence of the signature antimitochondrial antibodies; and iii histological evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts.
Secondly, there is considerable recent evidence to show that PBC also displays features that are generically similar to those of other human autoimmune diseases. For example, the hallmark serological feature of PBC, antimitochondrial antibodies AMA , can be detected in asymptomatic patients and are often found in serum samples for many years before clinical onset Once again, as noted previously, this is similar to other autoimmune diseases in which multiple cytopathic pathways are involved Again, this is similar to other autoimmune diseases in which the frequency of autoreactive cells is significantly higher in the target tissue than the blood.
This is of particular importance because it means that mechanistic studies must depend on obtaining target tissue, therefore often requiring invasive technology. Fourthly, it should be noted that PBC is a good example for understanding the importance of genetic and environmental interactions.
Autoantibodies key to early diagnosis of autoimmune diseases
Fifthly, although there are multiple mouse models of PBC, as with the many experimental models of SLE, they do not faithfully represent the disease and so far have proven inadequate for the development of novel therapeutic agents. At present, ursodeoxycholic acid is the only agent approved to treat PBC; the mechanism of action is not entirely understood, but it may reduce the bystander inflammatory response.
Finally, as with many other autoimmune diseases, there is considerable ongoing research to identify specific activation pathways, the blockade of which might reduce the inflammatory and therefore cytopathic response. It is clear that the goal for treating patients with autoimmunity is a specific agent that will completely reverse if not cure the disease. At present, this does not exist for any autoimmune disease. By contrast, it is hoped that it would also be possible to modify the host immune system to restore tolerance. Although this is possible in selected mouse models of autoimmunity, it has not proven effective as yet in humans despite many attempts using immunotherapy, including stem cell therapies.
However, our understanding of human autoimmune disease has and continues to be developed through a huge number of molecular studies investigating not only genetic factors, but also the role of epigenetics , the environment, infection and the microbiota. In addition, there have been improvements in laboratory testing methods, including standardization of serology and development of new autoantibody tests. Further, improved understanding of geoepidemiology has led to a much better appreciation of what is happening to individual patients during a breach of tolerance.
Autoimmunity is a challenge for all clinicians; nevertheless, the prognosis for patients with these diseases has dramatically improved in the past decade and we anticipate further improvements in the future. We thank Lei Jin and all other persons who contributed to this work.
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Search for more papers by this author. Tools Request permission Export citation Add to favorites Track citation. Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Abstract There have been significant advances in our understanding of human autoimmunity that have led to improvements in classification and diagnosis and, most importantly, research advances in new therapies.
Introduction The diverse immune system developed to fulfil the primary function of protecting hosts from infectious agents. Figure 1 Open in figure viewer PowerPoint.
Positive and negative selection in the thymus. Medullary thymic epithelial cells mTEC as well as dendritic cells DCs or macrophages play important roles in this process. Figure 2 Open in figure viewer PowerPoint. Summary of the development of autoimmune disease. However, they will remain harmless unless there is a genetic predisposition to break tolerance and an environment trigger or triggers.
The epidemiology of autoimmunity Autoimmune diseases are generally thought of as being relatively uncommon, but their effects on mortality and morbidity are significant. The genetic basis of autoimmunity Many of the concepts of autoimmunity can be exemplified by discussing the rare monogenic autoimmune diseases, which pinpoint the concept of genetic background Figure 3 Open in figure viewer PowerPoint. Genetic basis of autoimmunity. Multiple genes with specific gene mutations i. The genes highlighted in bold text were found in more than three different autoimmune diseases, respectively.
The environmental influence of autoimmunity The identification of specific environmental factors has critical importance for understanding individual susceptibility, but there are very few agents that clearly have a role and identification of generic risk factors remains elusive. Figure 4 Open in figure viewer PowerPoint. Environmental factors in autoimmunity. Multiple environmental factors have been implicated in the development of autoimmunity.
In addition, by modulating innate and adaptive immunity, the microbiota and nutrition e. Mechanisms of tissue destruction Tissue destruction can be divided into a variety of effector pathways depending on the autoimmune disease. Figure 5 Open in figure viewer PowerPoint.
Through different mechanisms, autoantibodies may mediate tissue damage. By secretion of cytotoxic granules, activation of Fas—Fas ligand or release of cytokines, autoreactive cytotoxic T lymphocytes CTLs cause tissue injury. Figure 6 Open in figure viewer PowerPoint.
Figure 7 Open in figure viewer PowerPoint. Conflict of interest statement No conflicts of interest to declare. Diagnostic criteria for systemic lupus erythematosus: a critical review. J Autoimmun ; 48—49 : 10 — 3. Crossref PubMed Google Scholar. PubMed Google Scholar. Google Scholar. Citing Literature.
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