Science and Profession The field of immunology deals with the ability of the immune system to react against an enormous repertoire of stimulation by antigens. In most instances, these antigens are foreign infectious agents such as viruses or bacteria. Inherent in this process is the ability to react against nearly any known determinant, whether natural or artificially produced. The most reactive antigenic determinants are proteins, though to a lesser degree, other substances such as carbohydrates (sugars), lipids (fats), and nucleic acids may also stimulate a response.
In general, the body exhibits tolerance during the constant exposure to its own tissue. The precise reasons behind tolerance are vague, but the basis for the lack of response lies in two major mechanisms: the elimination during development of immunological cells capable of responding to the body’s own tissue and the active prevention of existing reactive cells from responding to self-antigens. When this regulation fails, autoimmune disease may result.
There are two major types of immunological defense: humoral immunity and cell-mediated immunity. Humoral immunity refers to the soluble substances in blood serum, primarily antibody and complement, while cellular immunity refers to the portion of the immune response that is directly mediated by cells. Though these processes are sometimes categorized separately, they do in fact interact with and regulate each other.
Antibodies are produced by cells called B lymphocytes in response to foreign antigens. These proteins bind to the antigen in a specific manner, resulting in a complex that can be removed readily by phagocytic white blood cells. More important in the context of autoimmunity, antibody-antigen complexes also activate the complement pathway, a series of some twenty enzymes and serum proteins. The end result of activation is the lysis of the antigenic targets. In general, the targets are bacteria; in autoimmune disease, the target may be any cell in the body.
The cellular response utilizes any of several types of cytotoxic cells. These can include a specialized lymphocyte called the T cell (so named because of its development in the thymus) or another unusual type of large granular lymphocyte called the natural killer (NK) cell. NK and cytotoxic T cells function in a similar manner—by binding to the target and releasing toxic granules in apposition to its cell membrane.
Though autoimmune diseases differ in scope, they do tend to exhibit certain common factors. The pathologies associated with most of these illnesses result in part from the production of autoantibodies, which are antibodies produced against the body’s own cells or tissues. If the antibody binds to tissue in a particular organ, complement is activated in the tissue, causing the destruction of those regions of the organ. For example, Goodpasture’s syndrome is characterized by the deposition of autoantibodies directed against the membrane of the glomerulus in the kidneys. Complement activation can result in severe organ pathology and subsequent kidney failure.
If the autoantibody binds to soluble material in blood serum, the resultant antibody-antigen complexes are carried along in the circulation, and there is the possibility that they will lodge in various areas of the body. For example, systemic lupus erythematosus (SLE) results from the production of autoantibodies against soluble nucleoprotein, which is released from cells as they undergo normal death and lysis. The immune complexes frequently lodge in the kidney, where they can cause renal failure.
This is not to say that all autoimmune diseases result solely from autoantibody production. Though a precise role for either cytotoxic T cells or NK cells in human autoimmune disease has not been fully confirmed, several observations make such an association likely. First, large numbers of T cells are found in certain organ-specific diseases, including thyroiditis and pernicious anemia. Second, animal models of similar diseases show a specific role for such cells in the pathology of these diseases. Thus, it is likely that these cells do participate in the organ destruction.
Autoimmune disorders can be categorized in the form of a disease spectrum. At one end of the spectrum one can place organ-specific diseases. For example, Hashimoto’s disease is an autoimmune thyroid disorder characterized by the production of autoantibodies against thyroid antigens. The extensive infiltration and proliferation of lymphocytes is observed (although, as described above, their roles are unproved), along with the subsequent destruction of follicular tissue.
Likewise, diabetes mellitus, type 1 (formerly called juvenile-onset diabetes) may be an organ-specific autoimmune disease. In this case, however, autoantibodies are directed against the beta cells of the pancreas, which produce insulin. In pernicious (or megaloblastic) anemia, antibodies are produced against intrinsic factor, a molecule necessary for uptake of vitamin B12. Subsequent pathology results from lack of absorption of the vitamin. Addison’s disease, from which US president John F. Kennedy suffered, is a potentially life-threatening condition resulting from antibody production against the adrenal cortex. Myasthenia gravis is characterized by severe heart or skeletal muscle weakness caused by antibodies directed against neurotransmitter receptors on the muscle. In fact, cells from any organ may be potential targets for production of an autoantibody.
Certain organ-specific autoimmune diseases in the spectrum are characterized not by antibodies directed against any specific organ, but by cellular infiltration triggered in some manner by less specific autoantibodies. For example, biliary cirrhosis, an inflammatory condition of the liver, is characterized by the obstruction of bile flow through the liver ductules. Though extensive cellular infiltration is observed, serum antibodies are directed against mitochondrial antigens, which are found within all cells. Certain types of chronic hepatitis also exhibit an analogous situation.
In some cases, antibodies may be directed against circulatory cells. Antibodies directed against red blood cells may cause subsequent lysis of the cells, leading to hemolytic anemia. Often, these are temporary conditions that have resulted from the binding of a pharmacologic chemical such as an antibiotic to the surface of the cell, which triggers an immune response. A more serious condition is hemolytic disease of the newborn (HDN), one example being erythroblastosis fetalis, or Rh disease. In this case, a mother lacking the Rh protein on her blood cells may produce an immune response against that protein, which is present in the blood of the fetus she is carrying during pregnancy. Prior to 1967, when an effective preventive measure became available, HDN was a serious problem for many pregnancies. Antibodies directed against blood platelets can cause a reduction in the number of those cells, resulting in thrombocytopenia purpura. An analogous situation can be seen with other cell types.
At the other end of the autoimmune spectrum are those diseases that are not cell- or organ-specific but result in widespread lesions in various parts of the body. Lupus received its name from the butterfly rash often seen on the faces of patients, which resembles a wolf bite (lupus is Latin for “wolf”). Pathologic changes can be found at various sites in the body, however, including the kidneys, joints, and blood vessels. Likewise, rheumatoid arthritis is characterized by the production of rheumatoid factor, an antibody molecule directed against other antibodies in blood serum. The resultant immune complexes lodge in joints, causing the joint pain and destruction associated with severe arthritis.
In most cases, the specific reason for the production of autoantibodies is unknown. Genetic factors are certainly involved, since some autoimmune diseases run in families. Some may be triggered by bacterial or viral infections. Viral antigens may be expressed on the surfaces of certain cells, or the virus itself may be attached to the cell. Heart muscle appears to express antigenic determinants in common with certain streptococcal bacteria. A mild “strep throat” may be followed several weeks later by severe rheumatic fever.
The binding of drugs to cell surfaces may trigger an immune response. For example, penicillin may bind to the surfaces of red blood cells, triggering a hemolytic anemia. Likewise, sedormid may bind to the membrane of platelets.
Most cases of autoimmune disease, however, are triggered by no apparent cause. They may “simply” involve a breakdown of the normal regulatory mechanisms associated with the immune response.
Diagnostic and Treatment Techniques The regulation of self-reactive lymphocytes is necessary for the maintenance of tolerance by the immune system. When regulation breaks down or is otherwise defective, either humoral or cellular immunity is generated against the cells or tissues. The resultant pathology may be simply a painful nuisance or may have potentially fatal consequences. The difference relates to the extent of damage to particular organs, in the case of organ-specific autoimmune reactions, or to the level of tissue damage in systemic disease.
Despite differences in pathology, the mechanisms of tissue damage are similar in most autoimmune diseases. Most involve the formation of immune complexes. Either antibodies bind to cell surfaces or immune complexes form in the circulation. In either case, the result is complement activation. Components of the complement pathway, in turn, can either directly damage cell membranes or trigger the infiltration of a variety of cytotoxic cells.
Because the damage associated with most autoimmune diseases results from parallel processes, methods of treatment vary little in theory from one illness to another. Most involve the treatment of resultant symptoms; for example, the use of aspirin to reduce minor inflammation and, when necessary, the use of steroids to reduce the level of the immune response. Recently, the focus has shifted from treating symptoms only to attacking the underlying disease mechanism with disease-modifying drugs. Some of these drugs include methotrexate, azathioprine, cyclosporine, and hydroxychloroquine. Newer immune modulators (such as infliximab and etanarcept) and monoclonal antibodies (such as rituximab) are used in some autoimmune conditions that are refractory to other measures.
The treatment of autoimmune diseases does not eliminate the problem. The disease remains, but under ideal conditions, it is held under control. At the same time, there exists the danger of side effects of treatment. For example, most methods that reduce the level of the immune response are nonspecific; reducing the severity of the autoimmune disease may cause the patient to become more susceptible to infections by bacteria or viruses.
Certain approaches have been successful in the palliative treatment of some forms of autoimmune disease. For example, patients with myasthenia gravis (MG) exhibit significant muscle weakness. A myasthenia gravis patient may have difficulty breathing and may experience extreme fatigue, in severe cases being unable to open his or her mouth or eyelids. Associated with the disease are autoantibodies produced against the receptor for the neurotransmitter
acetylcholine (ACh), the chemical utilized by nerves in regulating movement by the muscle. By blocking the ACh receptor, these antibodies inhibit the ability of nerves to control muscle movement. In effect, the patient loses control of the muscles.
Patients with myasthenia gravis often exhibit abnormalities of the thymus, the gland associated with T-cell production. In addition, there is evidence that the thymus contains ACh receptors that are particularly antigenic (perhaps exacerbating the illness). Removal of the thymus, even in adults, often aids in reducing the symptoms of the disease. The thymus, though not superfluous in adults, carries out its main functions during the early years of life, through adolescence. Thus, its removal generally has few major implications.
Often, MG will respond to more conventional forms of treatment. Steroid treatment will often reduce symptoms. Metabolic controls may also aid in reducing symptoms. For example, during normal nerve transmission of ACh, the enzyme cholinesterase is present to break down ACh, thereby regulating muscle movement. The use of anticholinesterase drugs to prolong the presence of ACh at the site of the receptor on the muscle has also been of benefit to some patients.
Systemic lupus erythematosus is among the most common of systemic autoimmune diseases. The disease usually strikes women in the prime of life, between the ages of twenty and forty. It is characterized by a butterfly rash over the facial region and by weakness, fatigue, and often a fever. In many respects, the symptoms are those of severe arthritis. As the disease progresses, tissue or organ degradation may occur in the kidney or heart.
The specific cause of the symptomology is the formation of immune complexes, which consist of antibodies against cell components such as DNA or nucleoprotein. Complexes in the kidney have been large enough to observe with the electron microscope, particularly when the complexes contain cell nuclei. Similar complexes have been observed in regions of the skin characterized by inflammation and a rash. The immune complexes are sometimes ingested (phagocytized) by scavenger neutrophils, which make up the largest proportion (65 percent) of white blood cells. The presence of these so-called LE cells, white cells with ingested antibody-bound nuclei, was at one time used for the diagnosis of lupus.
As is true for many autoimmune diseases, the control of lupus involves the use of steroids and other immunosuppressive drugs. These have included drugs such as cyclosporin, which blocks T-cell function, and antimitotic drugs such as azathioprine or methotrexate, which block the proliferation of immune cells, as well as immune modulators such as rituximab. Generalized immunosuppression as a side effect is a concern. Often, using combinations of steroids and immunosuppressives makes it possible to use lower concentrations of each, increasing the drugs’ effectiveness and reducing the danger of toxicity.
Other palliative treatments of symptomology can increase patient comfort. For example, aspirin may be used to reduce inflammation or joint pain. Topical steroids can reduce the rash. Since lupus may significantly increase the photosensitivity of the skin, staying out of direct sunlight, or at least covering the surface of the skin, may reduce skin lesions. It should be emphasized again that these treatments deal only with symptoms; none will cure the disease.
Since some systemic diseases result from immune complex disorders, a reduction of the levels of such complexes has been found to be beneficial to some patients. Treatment involves a process called plasmapheresis. Plasma, the liquid portion of the blood, is removed from the patient (a small proportion at a time), after which the immune complexes are separated from the plasma. Though a temporary measure, since additional complexes continue to form, the process does prove useful.
Rheumatoid arthritis is another common autoimmune disorder. As is true of most autoimmune diseases, rheumatoid arthritis is primarily a disease of women. Symptomatology results from the lodging of immune complexes in joints, resulting in the inflammation of those joints. Many cases result from the formation of antibodies directed against other antibody molecules—a case of the immune system turning against itself. Pathology results both from complement activation and from the infiltration of a variety of cells into the joint; the result is damage to both cartilage and bone.
Medical treatment usually begins with aspirin or other nonsteroidal anti-inflammatory agents. Other common treatments are those that increase patient comfort: rest, proper exercise, and weight loss, if necessary. In severe cases, steroids, immune modulators, or monoclonal therapy may be necessary.
In general, autoimmune diseases are characterized by alternating periods of symptomatology and remission. Treatments are generally similar in their approach of reducing inflammation as the first line of intervention, with the use of immunosuppression being the last resort. Since the precise origin of most of these disorders is unknown, prevention remains difficult.
Perspective and Prospects During the 1950s, Macfarlane Burnet published his theory of clonal selection. Burnet believed that antibody specificity was predetermined in the B cell as it underwent development and maturation. Selection of the cell by the appropriate antigen resulted in proliferation of that specific cell, a process of clonal selection.
Burnet also had to account for tolerance, however— the inability of immune cells to respond against their own antigens. Burnet theorized that during prenatal development, exposure to self-antigens, or determinants, resulted in the abortion of any self-reactive cells. Only those self-reactive immune cells that were directed against sequestered antigens survived.
Though Burnet’s theories have reached the level of dogma in the field of immunology, they fail to account for certain autoimmune disorders. In the “correct” circumstances, the body does react against itself. Though they were not recognized at the time as such, autoimmune disorders were recognized as early as 1866. In that year, W. W. Gull demonstrated the link between chilling and a syndrome called paroxysmal hemoglobinuria. When external tissue such as skin is exposed to cold, large amounts of hemoglobin are discharged into the urine. In 1904, Karl Landsteiner and Julius Donath established the autoimmune basis for the disease by demonstrating the role of complement in the lysis of red blood cells, causing the release of hemoglobin and the symptomatology of the disorder. Furthermore, they demonstrated that one could cause the lysis of normal cells by mixing them with sera derived from hemoglobinurics. Together the published the first immunohematolgic test, known as the Donath-Landsteiner test.
Hashimoto’s disease was among the first organ-specific autoimmune diseases to be described. The disease was first described in 1912 by Hakaru Hashimoto, a Japanese surgeon, and the immune basis for the disease was established independently by Ernest Witebsky and Noel Rose in the United States, and by Deborah Doniach and Ivan Roitt in Great Britain, in 1957.
Since the 1950s, dozens of autoimmune disorders have been described. Treatment of these disorders remains, for the most part, nonspecific. Research in the area, in addition to attempts to define the precise trigger for autoimmune disease, has attempted to develop ways to suppress specifically those immune reactions responsible for the symptomatology. Successes have been associated with vaccines directed against components involved with the reactions under investigation. For example, since the production of autoantibodies is the basis for some forms of disease, the generation of additional antibody molecules directed against determinants on the autoantibodies at fault could serve to neutralize the effects of those components. This procedure could be likened to a police department that arrests its own dishonest officers. There is a precedent for such an operation. Newborn children of mothers suffering from myasthenia gravis synthesize just such antibodies against the inappropriate MG antibodies that have crossed the placenta. Synthesis does seem to ameliorate the symptoms of the disease.
There is no question that autoimmune disorders represent an aberrant form of immune response. Nevertheless, an understanding of the underlying mechanism will shed light on exactly how the immune system is regulated. For example, it remains \\unclear how antibody production is controlled following a normal immune response. In the presence of an antigen, antibody levels increase for a period of days to weeks, reach a plateau, and then slowly decrease as additional production comes to a halt. The means by which the shutdown takes place remains nebulous.
Tolerance does not result solely from an absence of T or B cells that respond to antigens—it involves an active suppression of the process. A more detailed understanding of the process will lead to a more thorough understanding of the immune system in general.
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