Causes and Symptoms
Autoimmunity refers to a group of widely varying diseases or disorders that include familiar examples (type 1 diabetes mellitus, myasthenia gravis, multiple sclerosis, rheumatoid arthritis) and many that are not as familiar (idiopathic thrombocytopenic purpura, Graves disease, Felty syndrome, Hashimoto’s thyroiditis). The list is long and growing as researchers continue to ferret out the root causes of many disorders that have been known for one hundred years or more. In many cases, environmental triggers or environmentally controlled flare-ups are common. All autoimmune disorders have one thing in common: the failure of the human immune system
to distinguish between self (own) and nonself antigens, thus leading the body to attack itself and destroy tissues or organs.
Autoimmunity is not a rare event; it occurs in all people, and it does not necessarily give rise to disease. For instance, aged or damaged cells of the body are normally destroyed by autoantibodies (antibodies directed against the self). However, other autoantibodies, which arise by chance combinations of genes, are normally suppressed during development in the thymus gland. This is referred to as selection. If the thymus fails to do its job, then these autoantibodies may be released into the lymph nodes and into the bloodstream, seeking out tissue or antigens to attack and destroy.
Autoimmune disorders can be classified in several ways. Some diseases affect only one organ system, and some affect multiple systems. Examples of organ-specific disorders are Addison’s disease and Graves disease; non-organ-specific disorders include systemic
lupus erythematosus and scleroderma. Alternatively, one can classify autoimmune disorders by the type of immune system cells involved in their onset. Some diseases are caused by the antibody-secreting B cells; they include myasthenia gravis, multiple sclerosis, rheumatic fever, systemic lupus erythematosis, and Graves disease. Other disorders are the result of the action of the systemic T cells; they include Addison’s disease and Hashimoto’s thyroiditis.
The onset of an autoimmune disorder hinges on many factors, some of which are still being identified. It is well established, however, that autoimmunity is multifactorial and multigenic. In other words, many environmental factors and many genes are involved in determining susceptibility to autoimmune disorders. In addition, many environmental factors are thought to be involved in controlling remission and flare-ups of autoimmune disorders. Most autoimmune disorders are probably the result of the release of T or B cells that, because they did not properly distinguish between self and nonself, should have been suppressed by the body’s immune system but were not. Some autoimmune responses are a result of damage to, or tumors of, the immune system tissues (lymphatic system).
A variety of studies have established genetic links in autoimmune diseases, but because most are multigenic, there is no simple Mendelian inheritance pattern seen. Nonetheless, there seems to be a clear correlation between certain human leukocyte
antigen (HLA) genes and certain autoimmune disorders. For instance, those who have HLA allele B27 have a ninetyfold greater risk than the normal population of developing ankylosing spondylitis. Those with allele DR3 have a twelvefold greater risk of celiac disease and a tenfold greater risk of Sjögren syndrome. In the case of insulin-dependent diabetes, the relative risk factor is fivefold if one has the DR3 allele or the DR4 allele, but if both are present, then the risk jumps to twentyfold. If the DR3 and DQw8 alleles are present, then the risk factor is one hundredfold. Yet, these alleles themselves do not automatically cause autoimmune disease, as evidenced by several studies on identical twins in which the rate of disease in the twin of an affected person ranged from 25 to 50 percent. Clearly environmental factors can change susceptibility to autoimmune disease into actual manifestation.
Autoimmune disorders are much more common in women than in men. In addition, they are usually more severe in women. This is likely due to the effects of estrogen, which has a role in enhancing the expression of HLA genes and activating macrophages, thus leading to higher tissue destruction. Some autoimmune responses are noted to flare and subside throughout the menstrual cycle, in conjunction with the rise and fall of estrogen levels. Stress has also been shown to be a contributing factor that can cause an autoimmune disorder to flare. This response is likely mediated through the hypothalamus and pituitary glands, which release hormones that directly stimulate the immune system.
It has been known for many years that expression of some autoimmune diseases is preceded by infection by a virulent organism. Infections may contribute to autoimmunity in several ways. Some microbes produce antigens that are very close in structure to human antigens. When antibodies are produced against the invading organism, the antibodies also attack self-antigens because of the chemical similarity. Examples of this response are poststreptococcal glomerulonephritis and rheumatic fever. Other invaders may damage human cells and release proteins that are not normally seen by the immune system (sequestered proteins). These proteins are seen as foreign, and an immune response is set up against these self-antigens (a similar response may be seen when normally sequestered proteins are released through trauma or injury). An example is sympathetic ophthalmia, in which eye lens proteins that are normally not seen in the circulation are released, triggering antibodies that may then attack the opposite (uninjured) eye as well.
The symptoms of autoimmune disorders are as varied as the disorders themselves. No one set of symptoms fits all disorders. Symptoms may be systemic or localized, progressive or stable. Symptoms may also be life threatening or simply annoying.
Multiple sclerosis (MS) is an autoimmune disorder involving the central nervous system. Nerve axons of the white matter of the brain are normally surrounded by myelin protein sheaths that protect the nerves and speed the process of transmission. In individuals with MS, these myelin sheath proteins are gradually attacked and destroyed, slowing transmission so that patients develop a loss of control of motor function and vision. This disease often progresses irregularly and unpredictably and is irreversible. It appears to be the result of both B cells (producing antibodies against oligodendroglia, the cells that make myelin protein) and T cells (acting against a peptide product from the myelin protein). Although what triggers the initial response is unclear, it has been suggested that onset may follow infection with either Epstein-Barr
or hepatitis B virus. More than 2.1 million people worldwide are affected by MS, mostly women diagnosed between age twenty and fifty.
Systemic lupus erythematosus
(SLE), known simply as lupus, is a generalized disorder that occurs predominantly in women. It is clearly linked to B cells and the production of antibodies against parts of the DNA molecule. These DNA antibodies cause tissue damage by combining with free DNA (from cells that have been damaged through disease or the normal aging process), and they may form immune complexes that are deposited in the kidneys and arterioles, leading to tissue destruction and fibrosis, and in the joints, leading to arthritis. Autoantibodies against red blood cells or platelets may also be found in SLE. Antibodies against muscles may be present and contribute to muscle inflammation, while the presence of antibodies to heart muscle may lead to myocarditis and endocarditis. Antibodies against skin components lead to a characteristic “butterfly rash” on the bridge of the nose and the area around the eyes seen in many patients with SLE; this rash worsens in the presence of sunlight.
Rheumatoid arthritis
is a common, crippling disease. It is controlled by B cells in the joints that are activated to produce several antibodies, including rheumatoid factor. The result is the formation and deposition of immune complexes in the joint cartilage. Antibodies directed against cartilage may also be seen. The resulting destruction activates chemicals that stimulate T cells to come to the area, and they in turn release destructive enzymes, just as they would if bacteria were invading the joints. All these responses lead to joint damage, inflammation, and pain. As the disease progresses, the synovia swell and extend into the joints, causing further pain and discomfort along with disfigurement of the joints. The cause of antibody activation is unknown and may be quite variable.
Both Hashimoto’s thyroiditis and Graves disease are forms of autoimmune thyroiditis. In Hashimoto’s disease, antibodies are formed against a protein within the thyroid cells, leading to attack of the cells and destruction of much of the thyroid tissue. In Graves disease, antibodies are formed that bind to the receptors for thyroid-stimulating hormone (TSH), the pituitary hormone that stimulates the thyroid gland to produce thyroid hormone. The receptors in turn are stimulated. Thus, the thyroid gland is hyperstimulated, and excess thyroid hormone is turned out, a condition known as thyrotoxicosis.
An individual with myasthenia gravis experiences muscle fatigue and extreme weakness with only mild exercise, such as walking short distances. It is caused by autoantibodies that are directed against the acetylcholine (ACh) receptor molecule. In normal neural cells that control large muscles, ACh is stimulated to be released from the neuron and bind to receptors on the muscle fiber end plate. If that receptor is blocked or destroyed by an antibody, the ACh cannot bind, and therefore the muscle is not stimulated to respond (contract). If a few receptors are blocked, then the muscle may still respond weakly. If enough antibody is present to block a large number of receptors, however, then the threshold limit for muscle response will not be achieved, and the muscle will not respond even in the presence of repeated stimulation from the neuron.
Scleroderma, also known as progressive systemic sclerosis, predominantly affects middle-aged women and is caused by collagen deposition in a variety of tissues of the body. Antibodies may be found against the centromere portion of the DNA. Symptoms include calcium deposition in the skin, sensitivity to cold, and decreased esophageal motility. The lungs often experience fibrosis, as do the kidneys.
Treatment and Therapy
Most autoimmune disorders cannot be cured; they develop into chronic conditions that require a lifetime of care and monitoring. Treatment is quite varied and depends on the underlying cause and etiology of the disease. Overall, the goals of treatment are to reduce the symptoms and to control the disease or disorder while at the same time allowing the immune system to continue fighting the viruses and bacteria affecting the body on a daily basis. The most generalized treatment is the administration of immunosuppressive drugs. The most commonly used drugs are azathioprine and cyclophosphamide; corticosteroids are also used to reduce the inflammatory responses seen in many autoimmune disorders. Drugs such as methotrexate have gained wide acceptance in the treatment of rheumatoid arthritis and other autoimmune disorders, but they have systemic side effects that in some cases may be worse than the autoimmune disorder itself, such as suppression of the basic immune responses involved in fighting off everyday viruses and bacteria. While the doses
used to fight autoimmunity are much lower than those used to suppress organ graft rejection, these general effects may still be seen, especially in older individuals whose immune systems are declining as a result of age. Thus, a significant amount of effort has been put into finding drugs that will be able to suppress only the self-reactive antibodies and not the entire immune system.
Hormones, proteins, or other substances normally produced or secreted by the cells or organs damaged in autoimmune disease (such as thyroid hormone or insulin) can usually be supplemented to the point that they are within the proper physiologic range. Sometimes this works well. For instance, Graves disease can be effectively controlled by removing the overactive thyroid gland and then supplementing thyroid hormone in the patient. Treating type 1 diabetes in children by supplementing insulin, however, is a much trickier proposition, as the finely controlled release of insulin from the beta cells of the pancreas cannot be duplicated by a single injection.
Many investigators have worked on vaccinations for autoimmune disorders, using animal models of varying types. Some results have been promising, even if the mechanism of action is still mostly unexplained. Vaccinations against autoimmune thyroiditis, encephalitis, and arthritis have been successful in some animal models.
Another approach that has been tried experimentally is the use of oral tolerance therapy. Large quantities of the offending autoantigen are given to the patient in the hope that tolerance to the particular protein will develop. This approach is similar to the way in which desensitization is used with allergy sufferers. Oral doses of myelin, for instance, have shown some success as a treatment for patients with multiple sclerosis.
Perspective and Prospects
The history of human understanding of autoimmune disorders is quite short. Paul Ehrlich, early in the twentieth century, described a condition of “horror autotoxicus,” the attack of the human immune system against the body's own tissues. His studies set the stage for fairly rapid advancement in understanding of the human immune system. Understanding of the genetic and molecular basis for autoimmunity, however, along with the realization that autoimmunity is a normal part of immune system development, began in the 1980s mainly as a result of the development of genetic and biochemical tools that allowed new insights into the cause of symptoms that were established long ago. Even where the cause was well established (such as with insulin-dependent diabetes, established in the 1920s), no significant changes in treatment were made until new genetic tools became available. Indeed, the entire field of immunology, which until the 1970s was in its infancy as a medical field, has grown exponentially as new molecular tools have enabled researchers to elucidate the pathways by which autoimmunity exacts its toll.
There is still plenty to do, both in terms of determining pathways and in developing new therapies aimed at specific targeting of these pathways. With completion of the Human Genome Project, an incredible amount of new knowledge is available that will help researchers produce treatments that are much more targeted and specific than those used in the past. As more is learned about the immune system and pathways of inflammation, new therapies may be designed that may prevent the development of most autoimmune diseases.
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