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 defined as diseases in which 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

1. idiopathic thrombocytopenic purpura (in which deliberate human experimentation in the early 1950s showed that the platelet destruction is directly caused by an autoantibody)


2. Graves' disease and myasthenia gravis (in which there are temporary signs of disease in the infant due to transplacental transfer)


3. 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 (in the laboratory). 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 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 symptoms with the use of immunosuppressive drugs (such as corticosteroids)