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What is Autoimmunity?



Definition of autoimmunity. The healthy human body is equipped with a powerful set of tools for resisting the onslaught of invading microorganisms (such as viruses, bacteria, and parasites). Unfortunately, this set of tools, known as the immune system, sometimes goes awry and attacks the body itself. These misdirected immune responses are referred to as autoimmunity, which can be demonstrated by the presence of autoantibodies or T lymphocytes reactive with host antigens.

Definition of autoimmune disease. Autoimmunity is present in everyone to some extent. It is usually harmless and probably a universal phenomenon of vertebrate life. However, autoimmunity can be the cause of a broad spectrum of human illnesses, known as autoimmune diseases. This concept of autoimmunity as the cause of human illness is relatively new, and it was not accepted into the mainstream of medical thinking until the 1950s and 1960s. Autoimmune diseases are, thus, defined when the progression from benign autoimmunity to pathogenic autoimmunity occurs. This progression is determined by both genetic influences and environmental triggers. The concept of autoimmunity as the actual cause of human illness (rather than a consequence or harmless accompaniment) can be used to establish criteria that define a disease as an autoimmune disease. By this approach, Rose and Bona (Immunology Today, 14: 426-430, 1993) have distinguished the evidence for an autoimmune etiology at three different levels: direct, indirect, and circumstantial.

Direct evidence requires transmissibility of the characteristic lesions of the disease from human to human, or human to animal. In the real world, such evidence is attainable at this time only for diseases mediated by autoantibody, since we do not yet have the means for reliably studying T lymphocyte-mediated autoimmune diseases by transfer to animals. Examples of autoimmune diseases that fulfill the criteria of direct evidence are idiopathic thrombocytopenic purpura (in which deliberate human experimentation in the early 1950s showed that the platelet destruction is directly caused by an autoantibody), Graves' disease and myasthenia gravis (in which there are temporary signs of disease in the infant due to transplacental transfer), pemphigus vulgaris and bullous pemphigoid (where the disease can be transmitted from humans to animals by autoantibody). Another, more feasible, way to demonstrate pathologic effect of autoantibody is to reproduce the functional defects characteristic of the disease in vitro. For example, inhibition of the fixation of vitamin B12 by intrinsic factor can be produced by autoantibodies from certain patients with pernicious anemia, and overproduction of thyroid hormones can be produced by autoantibodies from patients with Graves' disease.

Indirect evidence requires re-creation of the human disease in an animal model. The majority of autoimmune diseases fit in this category. For example, the autoimmune basis of systemic lupus erythematosus is well accepted because of the availability of several genetically determined mouse models which, while not simulating lupus as seen in the clinic, do very closely replicate the serological features and some pathological features. Hashimoto's thyroiditis and multiple sclerosis can be reproduced by immunizing the animal with an antigen analogous to the putative autoantigen of the human disease. The development of animal models is increasing rapidly as methods of genetic and immunologic manipulation become commonplace. For example, knock-out mice have provided the best models of inflammatory bowel disease; neonatal thymectomy of mice can produce excellent analogs of human oophoritis and autoimmune gastritis. It is worth noting that animal models must be viewed with caution as being an analog rather than the exact copy of the human counterpart, because they invariably differ to some degree from the human disease.

When direct and indirect evidence to define an autoimmune disease are not available, investigators are left with  circumstantial evidence, that is, with listing "markers" descriptive of autoimmune disease. Examples of these markers are:

  • positive family history for the same disease, or for other diseases known to be autoimmune
  • presence in the same patient of other known autoimmune diseases
  • presence of infiltrating mononuclear cells in the affected organ or tissue
  • preferential usage of certain MHC class II allele
  • high serum levels of IgG autoantibodies
  • deposition of antigen-antibody complexes in the affected organ or tissue
  • improvement of symptom with the use of immunosuppressive drugs (such as corticosteroids)

The dimensions of the problem. Autoimmune diseases are a major threat to the health of all Americans. At least ten millions Americans suffer from the more than eighty illnesses caused by autoimmunity. They are a special threat to women; about 75% of the patients are women. Autoimmune diseases are among the ten leading causes of death among women in all age groups up to 65. The bar graph shows the prevalence of the top 10 autoimmune diseases in the United States in 1996 (from Jacobson DL et al. Clin Immunol Immunopathol, 84: 223-243, 1997).

The broad spectrum of autoimmune diseases. Autoimmune diseases can strike any part of the body, and thus symptoms vary widely and diagnosis and treatment are often difficult. The broad spectrum of autoimmune diseases includes multiple sclerosis and the severe type 1 diabetes mellitus. Some autoimmune diseases such as lupus and pemphigus can be life threatening unless properly diagnosed and treated. Chromic autoimmune disorders like rheumatoid arthritis cripple the patient and also create heavy burdens on patients’ families. Some types of uveitis may cause blindness. Diseases such as scleroderma require skillful, lifelong treatment. Still other autoimmune diseases, including Graves’ disease and chronic thyroiditis, can be successfully treated if correctly diagnosed, but they are frequently missed because of their subtle onset.

Toward a collective approach to autoimmune diseases. Another problem is that diseases of autoimmune origin are allocated to different medical specialties based on the organ system immediately affected. Autoimmune diseases of the blood, for example, are treated by hematologists, those of the nervous system by neurologists, those of the endocrine system by endocrinologists and those of the joints and muscles by rheumatologists. This compartmentalization has hampered communication among physicians and scientists interested in autoimmune diseases. Yet the basic principles governing one autoimmune disease are applicable to others. Common threads uniting the autoimmune diseases are the presence of an autoimmune response based on cumulative genetic risk factors, combined with an environmental contribution (infectious, chemical, physical, or other). Equally important, innovative treatments applied to one autoimmune disease may be useful in others. To seize the new opportunities for moving research and treatment forward, leading investigators are calling for a collective approach to the autoimmune diseases. The answer has been the creation of the Johns Hopkins Autoimmune Disease Research Center.



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