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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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