In certain genetically susceptible strains of experimental animals, autoimmune disease can be induced by the injection of ‘self’ tissues that were taken from a genetically identical animal and mixed with strong adjuvants (see Appendix I, Section A-1). This shows directly that autoimmunity can be provoked by inducing a specific adaptive immune response to self antigens. Such experimental systems highlight the importance of the activation of other components of the immune system, primarily dendritic cells, by bacteria contained in the adjuvant. There are drawbacks to the use of such animal models for the study of autoimmunity, however. In humans and genetically autoimmune-prone animals, autoimmunity usually arises spontaneously: that is, we do not know what events initiate the immune response to self that leads to autoimmune disease. By studying the patterns of autoantibodies and particular tissues affected, it has been possible to identify some of the self antigens that are targets of autoimmune disease, although it has yet to be proven that the immune reaction was initiated in response to these same antigens.
Some autoimmune disorders may be triggered by infectious agents that express an epitope resembling a self antigen found in a tissue and that lead to sensitization of the patient against that tissue. There is, however, also evidence from animal models of autoimmunity that some autoimmune disorders are caused by internal dysregulation of the immune system without the apparent participation of infectious agents.
15-9 Autoimmunity can be classified into either organ-specific or systemic disease.
The classification of disease is an uncertain science, especially in the absence of a precise understanding of causative mechanisms. This is well illustrated by the difficulty in classifying autoimmune diseases. From a clinical perspective it is often useful to distinguish between the following two major patterns of autoimmunity: diseases restricted to specific organs of the body, known as ‘organ-specific’ autoimmune diseases; and those in which many tissues of the body are affected, the ‘systemic’ autoimmune diseases. In both types, disease has a tendency to become chronic because, with a few notable exceptions (for example, Hashimoto’s thyroiditis), autoantigens are rarely cleared from the body. Some autoimmune diseases seem to be dominated by the pathogenic effects of a particular immune effector pathway, either autoantibodies or effector T cells. However, both of these pathways often contribute to the overall pathogenesis.
In organ-specific diseases, autoantigens from one or a few organs are targeted, and disease is limited to those organs. Examples include Hashimoto’s thyroiditis and Graves’ disease, which both predominantly affect the thyroid gland; and type 1 diabetes, which is caused by immune attack on insulin-producing pancreatic β cells. Examples of systemic autoimmune disease are SLE and primary Sjögren’s syndrome, in which tissues as diverse as the skin, kidneys, and brain may all be affected (Fig. 15.10).
The autoantigens recognized in these two categories of disease are themselves organ-specific and systemic, respectively. Thus, Graves’ disease is characterized by the production of antibodies against the thyroid-stimulating hormone (TSH) receptor, Hashimoto’s thyroiditis by antibodies against thyroid peroxidase, and type 1 diabetes by anti-insulin antibodies. By contrast, SLE is characterized by the presence of antibodies against antigens that are ubiquitous and abundant in every cell of the body, such as chromatin and the proteins of the pre-mRNA splicing machinery—the spliceosome complex.
A strict separation of diseases into organ-specific and systemic categories does, however, break down to some extent, because not all autoimmune diseases can be usefully classified in this manner. For example, autoimmune hemolytic anemia, in which red blood cells are destroyed, sometimes occurs