By Noel R. Rose, M.D., Ph.D., Professor of Pathology and Professor of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, Maryland

     Autoimmunity is a major cause of human disease. A recent survey of epidemiological studies suggests that autoimmune diseases affect at least 10 million Americans [while other studies show at least 50 million Americans with at least one autoimmune disease]. Many of these diseases are chronic and debilitating. Although they may strike persons of any age and either sex, they tend to be more prevalent in women. Most autoimmune diseases can be treated symptomatically; but so far, few have been cured.

      Much has been learned about autoimmune disease in humans by studies of models induced in experimental animals such as rats and mice. Well studied examples of autoimmune responses are encephalomyelitis, thyroiditis, myasthenia gravis, and uveitis. Each model has taught us many lessons about the relative roles of T cells and B cells in inducing autoimmune pathology and about the genetics of disease susceptibility.

      An unexpected recent finding is that diseases resembling inflammatory bowel disease spontaneously develop in many genetically manipulated "knockout" mice incapable of producing such cytokines as interleukin-2 or IL-10. These studies have taught us that autoimmune disease results from a fundamental dysregulation of the immune system.

      The first piece of evidence that a human disease is autoimmune in origin is finding the presence of autoantibodies. It must be recognized, however, that autoantibodies are frequently the result, not the cause, of a pathologic process; they may contribute secondarily to the disease or have no pathologic importance at all.

      Autoimmune diseases tend to cluster so that a given patient may have more than one disease, e.g., Hashimoto thyroiditis and type I diabetes mellitus; Sj?gren syndrome and rheumatoid arthritis; or the same or related autoimmune diseases may be found in other members of the same family. This observation has led to the concept of an autoimmune diathesis--that is, a genetic predisposition to autoimmune disease.

      In principle, autoimmune diseases arise when a T cell recognizes a self-antigen and escapes normal regulation. Such effects are known to occur in multiple sclerosis, chronic thyroiditis, and other human diseases. Once the immune response is initiated, they tend to spread to additional antigenic determinants of the disease-inducing molecule or even to other molecules of the same target organ. Moreover, most of the T cells found in autoimmune lesions are recruited nonspecifically. In some cases, the evidence shows that autoimmunity results from a previous infection.

      For most human autoimmune disease, there is one common critical pathway: the mobilization of self-reactive helper (CD-4) cells.

      Sometimes a self-antigen is mimicked by an extrinsic molecule that differs enough from self that the immune response recognizes it as foreign. Mimicking antigens can be provided by invading pathogens or even by alteration of endogenous antigens due to infection, environmental chemicals, or drugs. The beta hemolytic strep, for example, has a myosin-like antigen that can induce myocarditis. Finally, there may be genetic defects in the selective mechanism for eliminating T cells in the thymus so that the host is left with a residuum of high affinity, self-reactive T cells.

      An important group of autoimmune diseases is mediated by antibody-to-cell surface receptors. These autoantibodies may impede the action of the receptor, as occurs with the acetyl choline receptor in myasthenia gravis. Alternatively, the autoantibody may mimic the natural hormone and stimulate the receptor, as occurs when an antibody to the thyrotropin (TSH) receptor mimics TSH, producing the hyperthyroidism of Graves disease.

Treatments and prevention

      When the goal is to develop specific methods for arresting an autoimmune response, it is likely that the T cell will be a primary target.

      Early experiments in animals suggested that inactive clones of self-reactive T cells could be utilized as a preventive "vaccine" by administering them to the animal before an autoimmune response had been generated.

      Another possible treatment is to shift the balance to TH1 and TH2 cells. Administration of particular cytokines or of cytosine inhibitors will have this effect. The cytosine network has wide-ranging ramification, however; and a change in one cytosine often has unexpected effects. Research in this area is still in its infancy.

      Antigens administered orally may induce a state of unresponsiveness. Oral tolerance is under clinical investigation for the treatments of several diseases, including multiple sclerosis, rheumatoid arthritis, diabetes mellitus, and uveitis.

      Autoimmunity is inherited as a polygenic trait. The summation of a number of unrelated genes leads to the autoimmune diathesis. If the susceptibility genes can be identified before the autoimmune process is fully underway, early preventive interventions may be feasible. In the absence of some environmental trigger, autoimmune disease may not occur at all, even in genetically susceptible individuals. One can envision low tech methods of simply avoiding environmental factors in predisposed subjects. The cost would be minimal.